Category Archives: Stem Cell Therapy

Hematopoietic stem cell transplantation and gene therapy are the only curative therapies for severe combined immunodeficiency (SCID). In patients lacking a matched donor, TCR/CD19-depleted haploidentical family donor transplant (TCR-HaploSCT) is a promising strategy. Conditioned transplant in SCID correlates to better myeloid chimerism and reduced immunoglobulin dependency. We studied transplant outcome in SCID infants according to donor type, specifically TCR-HaploSCT, and conditioning, through retrospective cohort analysis of 52 consecutive infants with SCID transplanted between 2013 and 2020. Median age at transplant was 5.1months (range, 0.816.6). Donors were TCR-HaploSCT (n=16, 31.4%), matched family donor (MFD,n=15, 29.4%), matched unrelated donor (MUD,n=9, 17.6%), and matched unrelated cord blood (CB,n=11, 21.6%). Forty-one (80%) received fludarabine/treosulfan-based conditioning, 3 (6%) had alemtuzumab only, and 7 (14%) received unconditioned infusions. For conditioned transplants (n=41), 3-year overall survival was 91% (95% confidence interval, 5299%) for TCR-HaploSCT, 80% (4198%) for MFD, 87% (3698%) for MUD, and 89% (4398%) for CB (p=0.89). Cumulative incidence of grade IIIV acute graft-versus-host disease was 11% (279%) after TCR-HaploSCT, 0 after MFD, 29% (7100%) after MUD, and 11% (279%) after CB (p=0.10). 9/10 patients who received alemtuzumab-only or unconditioned transplants survived. Myeloid chimerism was higher following conditioning (median 47%, range 0100%) versus unconditioned transplant (median 3%, 09%) (p<0.001), as was the proportion of immunoglobulin-free long-term survivors (n=29/36, 81% vsn=4/9, 54%) (p<0.001). TCR-HaploSCT has comparable outcome to MUD and is a promising alternative donor strategy for infants with SCID lacking MFD. This study confirms that conditioned transplant offers better myeloid chimerism and immunoglobulin freedom in long-term survivors.

Excerpt from:
TCR-Depleted Haploidentical Grafts Are a Safe Alternative to HLA-Matched Unrelated Donor Stem Cell Transplants for Infants with Severe Combined...

Significance

Osteoarthritis (OA) is a chronic disease affecting millions of people worldwide with no curative solution. In the present study, we developed a minimally invasive injectable system using amnion membrane (AM) from the human placenta as a carrier for fat tissue-derived stem cells (adipose-derived stem cells [ADSCs]) to treat OA. Both AM and ADSCs are rich sources of bioactive molecules that can target the sites of inflammation and reduce the inflammation-driven articular cartilage damage. Our study demonstrated the disease-modifying and regenerative potential of AM hydrogel, a comparable regenerative and disease-modifying effect of AM hydrogel and ADSCs, and the synergistic effect of AM with ADSCs in regenerating cartilage and attenuating OA.

Current treatment strategies for osteoarthritis (OA) predominantly address symptoms with limited disease-modifying potential. There is a growing interest in the use of adipose-derived stem cells (ADSCs) for OA treatment and developing biomimetic injectable hydrogels as cell delivery systems. Biomimetic injectable hydrogels can simulate the native tissue microenvironment by providing appropriate biological and chemical cues for tissue regeneration. A biomimetic injectable hydrogel using amnion membrane (AM) was developed which can self-assemble in situ and retain the stem cells at the target site. In the present study, we evaluated the efficacy of intraarticular injections of AM hydrogels with and without ADSCs in reducing inflammation and cartilage degeneration in a collagenase-induced OA rat model. A week after the induction of OA, rats were treated with control (phosphate-buffered saline), ADSCs, AM gel, and AM-ADSCs. Inflammation and cartilage regeneration was evaluated by joint swelling, analysis of serum by cytokine profiling and Raman spectroscopy, gross appearance, and histology. Both AM and ADSC possess antiinflammatory and chondroprotective properties to target the sites of inflammation in an osteoarthritic joint, thereby reducing the inflammation-mediated damage to the articular cartilage. The present study demonstrated the potential of AM hydrogel to foster cartilage tissue regeneration, a comparable regenerative effect of AM hydrogel and ADSCs, and the synergistic antiinflammatory and chondroprotective effects of AM and ADSC to regenerate cartilage tissue in a rat OA model.

Osteoarthritis (OA) affects the entire synovial joint, including the articular cartilage, synovium, and subchondral bone (1). In the United States alone, 27 million people are affected by this disease, and the associated healthcare cost has been estimated at more than $185 billion annually (2). Recent studies have shown that inflammation and its induced catabolism play an important role in promoting OA symptoms and accelerating the disease (3). The best-known and critical inflammatory mediators are tumor necrosis factor alpha (TNF-alpha) and interleukin-1 beta (IL-1) expressed during the early stages of OA (4, 5). The catabolic effects of proinflammatory cytokines lead to reduced cartilage cellularity, changes in chondrocyte functions, and further breakdown of cartilage extracellular matrix (ECM) (6, 7). Both nonsurgical and surgical therapies are currently being used in OA treatment which provide temporary relief but have failed to treat OA pathogenesis.

Since inflammation is the key factor in OA progression, developing novel therapies that can suppress inflammation and promote regenerative pathways may prevent/delay OA progression and thus hold promise for OA treatment. Along this line, a variety of studies investigated the potential role of adipose-derived stem cells (ADSCs) in treating OA (3). The therapeutic properties of ADSCs are multifaceted (7, 8) as they contain several antiinflammatory and chondroprotective agents which inhibit inflammation, suppress immune recognition, and reduce apoptosis and dedifferentiation of chondrocytes (911). Recently, the beneficial effects of ADSCs on OA treatment via intraarticular injections have been studied in different animal models (1214) as well as clinical trials (15, 16). Although stem cell therapy has achieved promising results in OA treatment, the long-term therapeutic application of stem cells remains limited. Previous studies have shown that stem cells provide a temporary/early-stage effect rather than prolonged effectiveness in treating OA, indicating the need for higher cell numbers and multiple cell injections. The short-term effects of stem cells are mainly due to limited long-term cell survival/retention, extensive cell death and poor cellular function, and inadequate cellular distribution following injection in the target site (17). To overcome these challenges, large doses of cells and multiple injections have been tried; however, these approaches are not economically viable and are associated with the risk of cell overexpansion (17).

To overcome these limitations, delivery systems capable of sustaining the survival and maintaining functions of implanted cells are needed to stimulate endogenous regeneration through interactions of transplanted cells and the host tissue. In our previous study (18), we developed an injectable amnion membrane (AM)based hydrogel as a stem cell delivery system. These AM hydrogels supported cellular functionalities such as cell viability, proliferation, and stemness. Also, our studies showed the ability of both AM hydrogels and AM hydrogelADSC combinations to provide an immunomodulatory and chondroprotective environment in an invitro osteoarthritic model (18). AM is the innermost layer of placental tissue which is easily accessible and includes collagens (types I, III, IV, V, and VI), fibronectin, laminin, proteoglycans, and hyaluronan. AM has been shown to suppress the expression of potent proinflammatory cytokines, such as IL-1 and IL-1 and decrease matrix metalloproteinase (MMP) levels through the expression of natural MMP inhibitors present in the membrane. AM also contains IL-1Ra, a receptor antagonist for IL-1, a proinflammatory cytokine that has been shown to up-regulate in OA (19). Placenta also plays an important role in reducing host immune response in case of allogeneic transplantation as it possesses the unique function of preventing the fetal allograft from being rejected (19). The feasibility of using AM as a carrier system for chondrocytes which promoted cell proliferation, cellular phenotype invitro, and cartilage regeneration invivo has been demonstrated in various studies (20, 21). However, the major limitation of these studies is the use of AM in the form of sheets, which would require invasive surgical procedures. To overcome the surgery-associated complications, minimally invasive therapies using micronized AM in saline were developed which also have demonstrated efficacy in attenuating OA invivo (22, 23). However, intraarticular injections experience rapid clearance of therapeutics, which may limit efficacy and produce nonsignificant effects (24). Thus, localization and prolonged retention are critical for a sustained release of therapeutics to act efficiently with minimal injections.

The overall goal of this study was to improve the efficacy of stem cell therapy to treat OA using our previously designed cell-protective and cell-supporting injectable AM hydrogel as a stem cell delivery system. We investigated the potential of AM hydrogel as a delivery system for ADSCs and evaluated the effect of AM hydrogels with and without ADSCs to prevent inflammation and cartilage degeneration and promote cartilage tissue regeneration in a collagenase-induced knee OA rat model.

In total, 376 proteins were identified in the AM gel by liquid chromatographymass spectrometry (LC-MS) (Dataset S1). The important proteins which might impart the beneficial effects of amnion for tissue regeneration include collagen, laminin, fibronectin, small leucine-rich proteoglycans (SLRPs), proteoglycans, and tissue inhibitors of metalloproteinases (TIMPs) (19). The proteins identified in AM gel were categorized according to their predominant location and functions using the Human Proteome Reference Database and UniProt database (Fig. 1). The identified proteins were found to be largely located in the extracellular environment of AM tissue (Fig. 1A). The predominant functions of these proteins were to facilitate ECM and cytoskeleton organization (EC + SC + SM: >85%; Fig. 1B). To further identify the biological implications of these proteins observed in AM gel, the proteins were associated with their Gene Ontology (GO) terms. (Dataset S2). The top five GO terms for the biological process of protein observed in AM gel were extracellular matrix organization (GO:0030198), cell adhesion (GO:0007155), collagen fibril organization (GO:0030199), neutrophil degranulation (GO:0043312), and cornification (GO:0070268)/keratinization (GO:0031424) (Fig. 1C). Table 1 summarizes the list of proteins identified in AM gel related to cartilage tissue regeneration.

Relative abundance of proteins identified in the AM. Pie chart representing the distribution of all identified proteins in the AM according to their subcellular location (A) and function (B). Assignments were made according to their primary location and function as reported in the Human Protein Reference (http://www.hprd.org/) and UniProt (https://www.uniprot.org/) databases. Primary subcellular location: CP, cytoplasm and cytosol; CS, cytoskeleton; EC, extracellular environment; ER, endoplasmic reticulum; G, Golgi apparatus; M, mitochondrion; MB, integral to membrane and plasma membrane; N, nucleus or nucleolus; R, ribosome; V, vesicles including cytoplasmic vesicle, endosome, and lysosome. Function: EC, ECM structural constituent; I, immune response; M, metabolism and energy pathways; RN, regulation of nucleotide; SC, structural constituent of cytoskeleton; SM, structural molecule activity; ST, signal transduction; T, transporter activity; O, other functions including apoptosis, cell cycle, cell growth, motor activity, organization, extracellular ligands, and unknown. The value was rounded off to one decimal place. (C) Top five GO annotations for biological processes of the detected proteins in AM gel.

The identification of proteins related to cartilage tissue regeneration in AM

Pathogenesis of OA in the rat knee joints occurred after 1 wk of collagenase II injection. The hematoxylin and eosin (H&E) images indicated that the sham knee did not show signs of synovial inflammation (Fig. 2A). The collagenase-injected group showed a high degree of synovial inflammation (Fig. 2B, black arrows) with an increase in the number of synovial lining cell layers and infiltration of inflammatory cells. The Safranin O image reflected smooth joint surfaces of the sham (Fig. 2C), while the collagenase-injected group showed erosion of the articular cartilage showing signs of OA development (Fig. 2D, black arrow). The knee diameter data showed that the OA group had significantly higher joint swelling on day 7 compared to the sham group (Fig. 2E).

H&E staining images of rat knee joint: (A) Sham group with saline injection, (B) OA group treated with collagenase enzyme. Safranin-O staining images of rat knee joint: (C) Sham group with saline injection, (D) OA group treated with collagenase enzyme. (E) Joint swelling evaluation of sham and OA groups. n = 6 showing mean and SD (****P<0.0001). (Scale bars: A and B, 200 m; C and D, 2 mm.)

After 1 wk of collagenase injection, the rats were divided into four groups: control (phosphate-buffered saline [PBS]), ADSC, AM gel, and AM-ADSC.

Joint swelling analysis at day 7 after collagenase injection showed a significant increase in joint diameter compared to day-0 groups (before collagenase injection), indicating synovitis of the knee joint. No significant difference was observed in the groups at days 3 and 7 posttreatment. At days 14 and 21 posttreatments, knee swelling of the AM-ADSC group was lower compared to control, AM, and ADSC groups. At 28 d posttreatment, ADSC (0.8 0.3, P<0.05), AM gel (0.5 0.1, P <0.0001), and AM-ADSC (0.4 0.1, P <0.0001) treatment groups showed a significant decrease in joint diameter compared to the control group (1.4 0.8). Importantly, the knee diameter in the AM-ADSC group was found to be significantly lower than ADSC (P <0.001) and AM groups (P <0.05), indicating decreased synovial inflammation in the combination group AM-ADSC (Fig. 3).

Joint inflammation for different treatment groups (n = 6) showing mean and SD (****P<0.0001, ***P<0.001, **P<0.01, *P < 0.05). All treatments groups showed significant decrease in joint swelling 28 d posttreatment compared to control group. The combination group (AM-ADSC) showed significant decrease in joint swelling compared to ADSCs alone and AM gel alone.

The cytokine profiling analysis of serum showed an increase in intercellular adhesion molecule 1 (ICAM-1), leptin, selectin, and monocyte chemoattractant protein-1 (MCP-1) and a decrease in TIMP-1 7 d after collagenase treatment (Fig. 4 AE). The level of TIMP-1 was found to significantly increase on day 28 in AM-ADSC (39,536 pg/mL 2,277) compared to control (28,485 pg/mL 4,087, P <0.0001) and ADSC (26,520 pg/mL 3,416, P <0.0001) groups (Fig. 4A). No significant difference was found in ICAM-1 and MCP-1 levels from day 3 to 14 posttreatment. On day 21 the AM-ADSC group (5,778 pg/mL 549) showed a significant decrease (P < 0.05) in ICAM-1 compared to the control group (8,641 pg/mL 1,439). A significant decrease in MCP-1 levels was also noted in AM-ADSC group (5,089 pg/mL 810) compared to control groups (7,748 pg/mL 304, P < 0.0001) after day 21. Both AM and ADSC groups showed a comparable decrease in the levels of MCP-1, ICAM-1, leptin, and selectin and an increase in TIMP-1, though not significant compared to control on day 28. The AM-ADSC group further showed a significant reduction of ICAM- 1, leptin, and MCP-1 levels compared to all other groups on day 28 (Fig. 4 B, C, and E), indicating a synergistic antiinflammatory effect (SI Appendix, Table S1). Selectin level was found to decrease for all groups compared to the control group from day 21; however, the effect was not significant (Fig. 4D). An increase in up-regulation of other proinflammatory cytokines was not detected as they were below the detection limit by the enzyme-linked immunosorbent assay (ELISA) multiplex array.

Cytokine profiling of serum isolated from whole blood from different groups: (A) TIMP-1, (B) ICAM-1, (C) leptin, (D) selectin, and (E) MCP-1; n = 6 showing mean and SD (****P<0.0001, ***P<0.001, **P<0.01, *P<0.05).

Raman spectroscopic changes of serum were measured by quantifying the integrated peak area in the spectral region 1 (SR1, 1,372 cm1 to 1,599 cm1) and region 2 (SR2, 1,601 cm1 to 1,776 cm1). Upon normalization of the area of these two spectral regions SR1 and SR2 with the integrated peak area of phenylalanine band at 1,004 cm1, it was observed that the normalized integrated areas for both the regions increased upon collagenase treatment (day 7 after collagenase injection) compared to day-0 serum samples. As presented in Fig. 5, the normalized integrated area in SR1 decreased in all the treatment groups with a significant decrease in the AM-ADSC group (2.4 0.6) compared to the control group (7.5 0.5, P < 0.0001) and AM gel group (5.5 1.8, P < 0.05). The normalized integrated area in SR2 also showed a similar trend with a significant reduction in all treatment groups compared to the control group. It is also important to note that the AM-ADSC group for 28-d treatment showed a significant decrease in the peak area (4.4 0.7) compared to both the ADSC group (9.9 1.4, P < 0.05) and AM gel group (10.3 1.7, P < 0.05), indicating a synergistic antiinflammatory effect.

Normalized peak area of (A) region 1 (B) region 2; mean and SD with n = 6 (****P<0.0001, ***P<0.001, *P<0.05).

Fig. 6 shows the gross appearance of the cartilage plateau in all groups. The sham group (Fig. 6A) showed a smooth, glossy cartilage surface. The control group (Fig. 6B) showed cartilage lesions, erosion, and fissures, indicating severe damage. ADSC groups (Fig. 6C) showed improvement compared to the control group; however, the lesions were still prominent. The AM group (Fig. 6D) also showed signs of erosion which was less prominent compared to the ADSC group and control group. The AM-ADSC (Fig. 6E) groups showed slightly damaged cartilage surface which was closer to the sham group, indicating a synergistic chondroprotective effect.

Gross appearance of cartilage surface after 4 wk posttreatment showing smooth surface in (A) sham group, erosion in (B) control group and (C) ADSC group, less erosion in (D) AM group, and fewer signs of lesion in (E) AM-ADSC group with closer appearance to sham group. Yellow arrows indicate the cartilage damage.

Control animals at 4 wk showed pronounced synovial inflammation with an increase in the number of synovial lining cell layers (Fig. 7A, black arrows), and lesions and areas of erosion were prominent along with diminished Safranin O staining for both femoral and tibial surface, suggesting the loss of proteoglycan content (Fig. 7E). ADSC treatment reduced the synovial inflammation (Fig. 7B) and preserved the loss of proteoglycan content of cartilage ECM, but the synovial inflammation, lesion, and areas of erosion were still evident (Fig. 7 B and F). In contrast, histological analysis of AM gel (Fig. 7 C and G) and AM-ADSC (Fig. 7 D and H) treated joints showed a significant reduction in synovial inflammation. Both AM gel and AM-ADSC groups showed smooth cartilage surfaces with no lesions and strong Safranin O staining. However, the AM-ADSC group showed more prominent Safranin O staining with a consistently more uniform cartilage tissue compared to the AM gel group. Safranin O staining of sagittal sections was used to assess the degenerated cartilage matrix area caused by the OA phenotype (Fig. 7I). The calculated total degeneration area was found to be 35.1 13.3% in the control group. AM gel groups showed a significant decrease in the total degenerated area (24.4 7.6%) compared to the control group (P < 0.05), indicating the chondroprotective potential of AM gel. ADSC-injected groups showed a significant decrease in total degeneration area which was found to be 21 6.6% compared to the control group (P < 0.05), indicating a comparable chondroprotective effect. Furthermore, treatment with the AM-ADSC (6.9 3.6%) observed a significant reduction in cartilage degeneration compared to control (P < 0.0001), ADSC group (P < 0.05), and AM group (P < 0.05) and the degenerated area was comparable to the sham (6.6 2.2%), demonstrating the synergistic chondroprotective effect.

H&E staining images of rat knee joints treated with (A) control, (B) ADSC, (C) AM hydrogel, and (D) AM-ADSC after 4 wk. Safranin O staining of rat knee joint treated with (E) control, (F) ADSC, (G) AM gel, and (H) AM-ADSC. (I) Percentage joint degenerated area calculation. n = 6 showing mean and SD (***P<0.001, **P<0.01, *P<0.05). (Scale bars: AD, 200 m; EH, 2 mm.)

Stem cell therapy has emerged as a potential therapy to provide a more reliable and curative solution to treat OA. However, the effectiveness of stem cell therapy is limited by difficulties in achieving the right therapeutic doses within the target site. In view of this, we developed an injectable AM hydrogel as a stem cell delivery system with an aim to localize stem cells at the target site, maintain cellular functionalities and synergistically reduce inflammation, and activate regenerative pathways, thereby attenuating OA progression. The AM hydrogel has been characterized in our previous studies to understand the swelling, degradation, and rheological behavior. Our previous study showed that the stiffness of AM hydrogels ranged between 120 and 1,600 Pa, indicating that the matrix stiffness can be tuned by varying the protein concentration (18). The physical properties of hydrogels play an important role in regulating stem cell fate (25). The AM hydrogels were shown to support ADSC functionalities as softer hydrogels with lower matrix stiffness <1 kPa are known to maintain stem cell viability, proliferation, and stemness (26). Softer hydrogels have also been shown to prevent transplanted cell death after cell delivery, improving the therapeutic efficacy of stem cell delivery at the target site after injection (27). Also, the AM hydrogels exhibited a shear-thinning property which is an important criterion for translating an injectable hydrogel as highly viscous or shear thickening material that may block the syringe while injecting (18). Also, the potential of AM with or without stem cells to present antiinflammatory and chondroprotective effects was demonstrated in an invitro OA model (18). In the present study, a comprehensive proteomic analysis of AM gel was done to understand its composition which may regulate tissue regeneration. LC-MS characterization of AM revealed the presence of proteins such as collagen, laminin, fibronectin, SLRPs, and proteoglycans. Collagen is the most abundant ECM family in the articular cartilage, including mainly collagen II along with IX, X, XI, VI, XII, and XIV collagen (28), which regulates the structurefunction relationship of the cartilage tissue. The presence of collagen VI may play an important role in promoting chondrocyte proliferation (29). Other proteins found in AM such as collagen XII are known to interact with collagen VI, resulting in up-regulation of tissue regeneration (30). The presence of keratin could also be beneficial as studies have shown its role in increasing cellular adhesion and inducing polarization of inflammatory M1 macrophages to antiinflammatory M2 phenotype (31). PLEC is a large cytoskeletal protein that regulates signaling from the extracellular environment to the cell nucleus (32). In cartilage, the OA-associated single-nucleotide polymorphism correlates with differential expression of PLEC and with differential methylation of PLEC CpG dinucleotides (33). Intact vimentin intermediate filament network contributes to the maintenance of the chondrocyte phenotype (34). Heparan sulfate proteoglycans bind to many proteins that regulate cartilage homeostasis. Agrin expression is decreased in OA, and exogenous agrin enhanced cartilage differentiation (35). SLRPs have important effects on cell behavior by interacting with collagens to modulate fibril formation and binding various cell-surface receptors and growth factors. Alterations in the distribution and production of SLRPs could lead to the development of OA (36). TIMPs are the primary endogenous inhibitors of MMPs. TIMP-3 has the broadest inhibition spectrum as it inhibits several members of a disintegrin and metalloprotease (ADAM) and ADAM with thrombospondin motifs (ADAMTS) (37). The proteomic profiling indicates that the AM gel used in our study still retains a rich source of important proteins, which makes it a highly effective biomaterial for OA treatment and cell delivery applications.

A collagenase-induced OA rat model was used to evaluate the effectiveness of AM hydrogel with or without ADSCs to attenuate OA. This is an established model and has been predominantly used to investigate the mechanisms underlying joint damage (38). Collagenase treatment directly digests the collagen from cartilage ECM, resulting in pain, changes in the synovial membrane and subchondral bone, and degeneration of articular cartilage (39). Similar features were observed in our study, which showed inflammation in the synovial membrane and degeneration of cartilage in a collagenase-injected group, thereby reproducing some of the main features associated with onset and development of OA in humans (40). The dosage of collagenase (500 U) was chosen based on a previous study that compared two different dosages (250 U and 500 U) of collagenase to induce OA in the rat model and found 500 U was more effective in inducing inflammation and cartilage degeneration (38).

An early time point of week 1 was chosen to study the effect of the treatments in inhibiting inflammation and cartilage degeneration (38). Intraarticular injection of amnion suspension in a monosodium iodoacetate (MIA) OA model has been previously shown to reduce joint swelling on day 14 (0.7 mm). However, an increase in the joint swelling was noticed on day 21 (1.1 mm) (41). In the present study, all three treatment groups, ADSC (0.8 0.3, P<0.001), AM gel (0.5 0.1, P <0.0001), and AM-ADSC (0.4 0.1, P <0.0001), significantly reduced joint swelling compared to the control group (1.4 0.8) at day 28. The joint swelling was found to comparable in the AM gel group and ADSC group. Moreover, the AM-ADSC group significantly reduced joint swelling compared to other groups. This demonstrated the antiinflammatory properties of AM gel alone and synergistic advantages of combining AM with ADSC in inhibiting inflammation, an early indication of OA onset and progression. This was corroborated by the cytokine profiling wherein AM hydrogel and ADSC showed a comparable decrease in inflammation. AM-ADSC significantly reduced inflammation markers such as MCP-1, leptin, and ICAM-1 and increased TIMP-1 compared to the control group and other treatment groups. MCP-1 is a chemokine produced by synovial cells which attract monocytes to facilitate the OA immune response, leading to clinical symptoms such as redness, swelling, and pain (42). ICAM-1 is a critical mediator of inflammation that mediates activation, migration of leukocytes, and adhesion of antigen-presenting cells to T lymphocytes and has been found to be higher in OA patients (43). Willett etal. (23) previously showed that intraarticular injection of micronized AM reduced MCP-1 levels (132 113 pg/mL) after 21 d in a medial meniscal transection (MMT)induced OA model in rats. However, another study using amnion suspension for OA treatment in an MIA model did not find any significant reduction in MCP-1 or increase in TIMP-1 levels compared to the saline group (38). The present study showed a decrease in the inflammatory markers in AM gel group in a collagenase-induced OA model.

The biomolecular changes in the serological composition were then evaluated by Raman spectroscopy (RS). RS can be used to follow arthritic changes in serum and synovial fluids by determining the changes in the protein secondary structure (44, 45). Studies have also shown the effectiveness of RS in detecting protein changes in inflammatory conditions (45). The spectra regions 1 and 2 used in the present study to detect the changes in serological composition have been previously used to study serum samples from arthritic patients (45). The study showed an increase in the peak area of regions 1 (70 a.u., arbitary unit P < 0.05) and 2 (55 a.u., P < 0.05) in serum samples from arthritis patients compared to the healthy individuals (region 1, 65 a.u.; region 2, 50 a.u.). SR1 reflects signatures from the amide II band and SR2 reflects the changes in the amide I peaks. An increase in SR1 and SR2 peak area indicates more disordered protein secondary structure with altered electrostatic interactions as evident from RS analysis of serum and synovial fluid samples from arthritic patients (44, 45). In the present study, the RS spectra profile showed a significant decrease in the peak area of SR2 in all the three treatment groups compared to control at day 28 posttreatment, which can be attributed to less-disordered protein secondary structure. Overall, the RS observation corroborates the cytokine profile data indicating a comparable effect of AM hydrogel and ADSCs in reducing inflammation and a synergistic antiinflammatory property of AM-ADSC and the unique advantages of combining AM with ADSC to reduce inflammation in an OA environment.

Macroscopic and microscopic evaluations of the treatment groups showed degenerated cartilage tissue in the control group. Compared to the control group, AM hydrogel showed a disease-modifying and regenerative effect by significantly decreasing cartilage degeneration. The disease-modifying and regenerative effect was also found to be comparable in AM and ADSC groups. The disease-modifying and regenerative capability of AM hydrogel was further enhanced upon the addition of ADSCs, indicating a synergistic effect of AM and ADSC. Previous studies have shown that injection of MSC suspension fails to engraft with the cartilage tissue, indicating a short-lived effect of stem cells (46, 47). Sato etal. reported that only a small number of stem cells was detected within the OA cartilage 1 wk posttreatment, which were found to disappear after 5 wk (48). Studies have shown that 90% of cells usually die postinjection at the target site due to physical stress, hypoxia, and inflammation (49). This shows that a single injection of stem cells may not be enough to improve the OA condition, indicating the need for periodic injections (50). While stem cells injected as a suspension do not engraft into the cartilage, MSCs encapsulated in a matrix such as hyaluronic acid (HA) appear to engraft and contribute significantly to cartilage repair. Studies have shown that combining HA and stem cells improves the quality of cartilage compared to cells and HA alone (48, 51, 52). However, recent studies have demonstrated a modest benefit of HA in OA treatment (53). Thus, to develop an alternative solution, AM has been used in the present study as a cell delivery system for OA treatment. It is evident from the present study that ADSCs showed some positive response in reducing inflammation and cartilage degeneration using the collagenase-induced OA model. However, the effect is not as significant as in the combination group, indicating an advantage of combing AM with ADSCs. The use of AM in attenuating OA has also been shown in different studies. The efficacy of intraarticular injection of micronized AM suspension was investigated in a rat MMT model 24 h after MMT surgery and found smaller lesions and fewer defect volume compared to a saline-treated group 21 d postinjection (23). Saline-treated joints showed an average incidence of 2.8 0.2 erosion, 2.4 0.4 lesion, and an average lesion volume of 0.00725 0.005 mm3, whereas the AM suspension showed significant reduction in erosion sites (1.2 0.374) and no lesions (23). Another study using amnion suspension (total joint score, 13.7 0.2) 7 d after OA induction showed no significant improvement in the joint scores compared to the control group (total joint score, 13.5 0.4) (41) in an MIA-induced OA model. Another study demonstrated a dose-dependent benefit of particulate AM along with umbilical cord tissue in attenuating OA. It was noticed that at 4 wk postinjection 100 g/L of particulate AM/UC (umbilical cord) significantly reduced both lesion area and percent lesion area compared to control and 50 g/L of AM/UC group (54). In the present study AM gel (24.4 7.6%) even at a lower concentration of 6 g/L significantly reduce cartilage degeneration compared to control groups (35.1 13.3%) in a collagenase-OA model. The addition of ADSCs further improved the potential of AM gel (6.9 3.6%) to attenuate OA progression. This indicated the advantages of using an AM gel at a lower concentration over particulate AM at a higher concentration in suspension.

The findings of the present study thus indicate that the AM hydrogel can foster cartilage tissue regeneration. The study also demonstrated a comparable effect of AM hydrogel and ADSCs in regenerating the cartilage tissue and synergistic antiinflammatory and chondroprotective properties of AM-ADSC. This indicates the unique advantages of combining AM with ADSC to reduce inflammation and slow down cartilage degeneration and regenerate cartilage tissue in an OA environment. The invivo study also validated our previous study which demonstrated a synergistic antiinflammatory and chondroprotective effect of AM-ADSC in an invitro OA model (18). In addition, since inflammation is a key regulator of OA progression, and as of now there is no solution to modulate the inflammatory processes and prevent OA, the use of AM gel alone or in with ADSC may provide disease-modifying effects to control the disease (3). However, further studies will be needed to evaluate the degradation of AM hydrogel invivo, release kinetics and retention profile of stem cells, and the paracrine effect of cells within the target site.

Cell therapy is widely used to address the current unmet needs of complex degenerative diseases such as OA. However, the lack of an ideal delivery system resulted in inconsistent outcomes, indicating the need for a more reliable strategy. This study demonstrated the feasibility of using a biomimetic injectable hydrogel using AM as a delivery system for ADSCs to attenuate OA and regenerate cartilage tissue in a rat OA model. Our study showed the potential of AM hydrogels for disease modification and regenerating the cartilage tissue. Both AM and ADSC groups showed comparable disease-modifying and cartilage tissue regeneration effects. In addition, the study also confirmed the synergistic effect of the combination group (AM-ADSC) for disease modification and cartilage tissue regeneration. Future studies need to investigate the mechanism of the synergistic effect of AM and ADSCs and the translation potential of AM hydrogels with and without ADSCs using larger animal models.

Discarded, deidentified placental tissues were obtained after getting approval from the institutional ethical committee (University of Connecticut Health). The isolation methods were performed in accordance with the experimental guidelines and regulations approved by the Institutional Review Board, University of Connecticut Health (study number IE-08-310-1). The amnion hydrogel was developed according to a previously published protocol (18). Briefly, AM was decellularized, solubilized in a pepsin solution, and neutralized to form a hydrogel. The neutralized AM was diluted to the desired final AM concentration (6 mg/mL) with PBS on ice. AM was then characterized by LC-MS to evaluate the complex protein composition of AM.

AM was suspended in 5% sodium dodecyl sulfate in 0.1 M TrisHCl (pH 8.5), subjected to sonication, and prepared for downstream proteomics analysis using the S-trap midi column technology (Protifi, LLC). Proteins were subjected to Cys reduction, alkylation using iodoacetamide, and trypsin digestion using Protifis instructions. Eluted tryptic peptides were desalted using Pierce C18 peptide desalting spin columns (P/N 89851) using the manufacturers instructions, dried to completion using a Labconco speedvac concentrator, and resuspended in 0.1% formic acid in water prior to mass spectrometry analysis.

The peptides generated from AM were independently analyzed using ultrahigh-performance LC coupled to tandem MS (UPLC-MS/MS) on a Dionex Ultimate 3000 RSLCnano UPLC system coupled to a Q Exactive HF mass spectrometer (Thermo Scientific). About 1.25 g of each desalted peptide were directly loaded onto a 75-m 25-cm nanoEase m/z Peptide BEH C18 analytical column (Waters Corporation) and separated using a 3-h reversed-phase UPLC gradient at a flow rate of 300 nL/min. Eluted peptides were directly ionized into the Q Exactive HF using positive polarity electrospray ionization. MS/MS data were acquired using a data-dependent Top15 acquisition method. All raw data were searched against the full UniProt Homo sapiens reference proteome (UP000005640, last updated 29 June 2020) using the Andromeda search engine embedded in the MaxQuant software platform (v1.6.43.10) (55, 56). The following modifications were used: fixed carbamidomethyl Cys and variable oxidation of Met, acetylation of protein N termini, deamidation of Asn and Gln, and peptide N-terminal Gln-to-pyro-Glu conversion. Enzyme specificity was set to trypsin, minimum peptide length was set to 5, and all peptide- and protein-level identifications were filtered to a 1% false discovery rate following a target-decoy database search. Label-free quantitation was achieved using the MaxLFQ feature in MaxQuant. All other parameters were kept at default settings. Search results were uploaded into Scaffold v5 (Proteome Software) for visualization and further analysis. All detected proteins were searched and categorized according to their primary location and function using the Human Protein Reference (http://www.hprd.org/) and UniProt (https://www.uniprot.org/) databases. Pie charts were created based on the quantified amounts of detected proteins. GO terms for the biological processes were searched by UniProt database.

ADSCs were isolated from 6- to 8-wk-old Sprague-Dawley rats in accordance with the experimental guidelines and regulations approved by the University of Connecticut Health Center Institutional Animal Care and Use Committee (IACUC)approved protocol. The isolation and characterization by flow cytometry were done according to our previously optimized protocol (18).

Animal experiments were approved by the IACUC at the University of Connecticut Health. Male Sprague-Dawley rats (8 wk old) were used for the study and divided into two groups (sham and collagenase-injected group). Briefly, rats were anesthetized by isoflurane (4% isoflurane for anesthesia induction, 2% for maintenance) and an intraarticular injection was performed with the use a 29-gauge needle inserted through the patella ligament into the joint space of the right knee. They received two injections (day 0 and 3) according to the group. The collagenase-injected group (n = 6) received about 500 U of collagenase type II (Sigma-Aldrich) in 100 L of normal saline after filtering through a 0.22-m membrane (38). The sham group (n = 6) received 100 L of normal saline.

A week after the first collagenase injection, the OA-induced rats were divided into four groups according to the treatments they would receive: control (PBS), ADSCs, AM gel (6mg/mL), and AM-ADSCs combination (n = 6 each group). Using a 29-gauge needle inserted through the patella ligament into the joint space of the right knee, all the OA knees received 100-L injections according to the specific treatment of the group. About 1 106 ADSCs were reconstituted in PBS and AM gel for the ADSC and AM-ADSC groups, respectively.

The knee diameters were measured to determine the extent of joint swelling with a manual caliper. Results were presented as the difference in knee diameter (ipsilateralcontralateral) (35).

Whole blood was collected from the saphenous vein at regular time points. Blood was then allowed to clot for 30 min and the serum was separated by centrifugation at 1,500 g for 10 min. The levels of cytokines in the serum were measured using the Quantibody Rat Cytokine Array 2 multiplex ELISA kit that quantitatively measured 10 rat inflammatory factors: ICAM-1, interferon , IL-1, IL-6, IL-10, leptin, L-selectin, MCP-1, TIMP-1, and TNF-alpha (RayBiotech). All ELISA procedures were performed according to the manufacturers protocols.

Raman measurements were carried out from the serum samples at an excitation wavelength of 785 nm using a free-space custom-built inverted Raman microspectroscopy system as described previously (57). Briefly, the Raman spectrometer consisted of a 193-mm focal length spectrograph (Shamrock 193i; Andor) equipped with a thermoelectric cooled charge-coupled device camera (iDus DU420A-BEX2-DD; Andor). Both excitation and collection were performed using the same 60 objective with the numerical aperture of 1.1 (LUMFLN60XW; Olympus). Serum was isolated and placed onto a quartz coverslip (Ted Pella, Inc.). The average power at the sample was held constant at 25 mW; the integration time for a single Raman measurement was 30 s, and two accumulations were averaged. The raw Raman spectra were preprocessed by removing cosmic rays, subtracting Raman signals from quartz coverslip and smoothing. The area of peaks in region 1 (1,372 cm1 to 1,599 cm1), region 2 (1,601 cm1 to 1,776 cm1) were calculated and normalized with respect to the area of phenylalanine peak at 1,004 cm1 (48) using Origin Pro software.

Animals were killed 4 wk after treatment. The cartilage surface was exposed by carefully removing the surrounding soft tissue including the joint capsule and meniscus. The effect of different treatment groups on osteoarthritic joints was examined macroscopically and photographed using a digital camera.

The dissected knee joints were fixed with 10% neutral-buffered formalin and subsequently decalcified, embedded in paraffin, and cut into 5-m sections. Specimen slides were then deparaffinized and hydrated by soaking them sequentially for the time indicated in xylene, ethanol, and deionized water. For H&E, sections were stained with hematoxylin Harris (Sigma-Aldrich) and counterstained with eosin (Sigma-Aldrich). For Safranin O, sections were stained with Weigerts iron hematoxylin (Sigma-Aldrich) working solution and fast green solution (Sigma-Aldrich) then counterstained with Safranin O solution (Sigma-Aldrich). Slides were viewed with the aid of the light microscope after being cleared with alcohol and xylene (Sigma-Aldrich). Articular surface areas of sagittal joint sections (areas stained red with Safranin O on the articular surface of the tibia and the femur) were quantified using ImageJ image analysis software. Areas of degeneration where there was no red staining by Safranin O were measured using ImageJ and the percent degeneration at the joint was measured using the following formula:%Degeneration=DegeneratedAreasTheoreticalHealthyArticularSurfaceArea*100.

All statistical analysis was done using GraphPad Prism 6. A two-sided ANOVA with 95% confidence interval with Tukeys means comparison was run in GraphPad Prism 6 to evaluate intergroup differences of percent total degenerated areas. For joint swelling, cytokine analysis, and Raman spectroscopic analysis a oneway ANOVA was run with a Tukeys post hoc test to assess statistical significance between groups.

All study data are included in the article and/or supporting information.

We gratefully acknowledge the quantitative proteomics analysis conducted by Dr. Jeremy L. Balsbaugh and Dr. Jennifer C. Liddle of the UConn Proteomics & Metabolomics Facility, a component of the Center for Open Research Resources and Equipment at the University of Connecticut. We are also thankful to Dr. Zhifang Hao, Research Histology core, UConn Health for helping out with the histology studies. We also gratefully acknowledge funding from NIH DP1AR068147 and NIH T32 AR079114.

Author contributions: M.B., L.S.N., and C.T.L. designed research; M.B., J.L.E.I., H.-M.K., R.B., M.B., N.N., R.P., L.S.N., and C.T.L. performed research; M.B., S.S., T.O., R.P., L.S.N., and C.T.L. analyzed data; and M.B., S.S., R.P., L.S.N., and C.T.L. wrote the paper.

Competing interest statement: A patent titled Injectable Amnion Hydrogel as a Cell Delivery System has been filed and published on behalf of the inventors, C.T.L., L.S.N., and M.B. L.S.N. has competing financial interest with Soft Tissue Regeneration/Biorez. C.T.L. has the following competing financial interests: Mimedx (a company that makes amnion-based biologics), Alkermes Company, Biobind, Soft Tissue Regeneration/Biorez, and Healing Orthopaedic Technologies-Bone.

Reviewers: J.G., Johns Hopkins University; and R.L., University of Chicago Division of the Biological Sciences.

This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2120968119/-/DCSupplemental.

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Injectable amnion hydrogel-mediated delivery of adipose-derived stem cells for osteoarthritis treatment - pnas.org

Systemic sclerosis (SSc) is an intractable autoimmune disease with unmet medical needs. Conventional immunosuppressive therapies have modest efficacy and obvious side effects. Targeted therapies with small molecules and antibodies remain under investigation in small pilot studies. The major breakthrough was the development of autologous haematopoietic stem cell transplantation (AHSCT) to treat refractory SSc with rapidly progressive internal organ involvement. However, AHSCT is contraindicated in patients with advanced visceral involvement. Mesenchymal stem cells (MSCs) which are characterized by immunosuppressive, antifibrotic and proangiogenic capabilities may be a promising alternative option for the treatment of SSc. Multiple preclinical and clinical studies on the use of MSCs to treat SSc are underway. However, there are several unresolved limitations and safety concerns of MSC transplantation, such as immune rejections and risks of tumour formation, respectively. Since the major therapeutic potential of MSCs has been ascribed to their paracrine signalling, the use of MSC-derived extracellular vesicles (EVs)/secretomes/exosomes as a cell-free therapy might be an alternative option to circumvent the limitations of MSC-based therapies. In the present review, we overview the current knowledge regarding the therapeutic efficacy of MSCs in SSc, focusing on progresses reported in preclinical and clinical studies using MSCs, as well as challenges and future directions of MSC transplantation as a treatment option for patients with SSc.

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Mesenchymal Stem CellBased Therapy as a New Approach for the Treatment of Systemic Sclerosis - Newswise

Stem Cell and Gene Therapy Biological Testing Market research report are based upon SWOT analysis on which businesses can rely confidently. With the precise and high-tech information about healthcare industry, businesses can know about the types of consumers, consumers demands and preferences, their perspectives about the product, their buying intentions, their response to particular product, and their varying tastes about the specific product already existing in the market through this report. This information and market insights covered in the superior Stem Cell and Gene Therapy Biological Testing market document assists with maximizing or minimizing the production of goods depending on the conditions of demand.

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Key Market Players mentioned in this report:MEDIPOSTSmith & NephewANTEROGEN.CO.,LTDPHARMICELL Co., LtdJCR Pharmaceuticals Co., LtdNuVasive, IncGilead Sciences, IncDendreon Pharmaceuticals LLCOrganogenesis IncOsirisSTEMCELL Technologies

Stem Cell and Gene Therapy Biological Testing Market Segmentation:-

By Types:Cell Therapy and Gene Therapy

By Application:Hospitals, Wound Care Centres, Cancer Care Centres, Ambulatory Surgical Centres and Others

Market Analysis and Insights: Global Stem Cell and Gene Therapy Biological Testing Market

Data Bridge Market Research analyses that the stem cell and gene therapy biological testing market will exhibit a CAGR of around 14.87% for the forecast period of 2022-2029. Rising approvals of GMP-certified facilities to manufacture stem cells, rising stem cell research activities and increasing public and private expenditure for the development of healthcare infrastructure especially in emerging economies are the major factors attributable to the growth of stem cell and gene therapy biological testing market. This signifies that the stem cell and gene therapy biological testing market value, which was USD 1,497.03 million in 2021, will rocket up to USD 4,538.22 million by the year 2029.

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Global Stem Cell and Gene Therapy Biological Testing Market Scope and Market Size

The stem cell and gene therapy biological testing market is segmented on the basis of product type and end users. The growth amongst these segments will help you analyse meagre growth segments in the industries, and provide the users with valuable market overview and market insights to help them in making strategic decisions for identification of core market applications.

By product type, the global stem cell and gene therapy biological testing market is segmented into cell therapy and gene therapy.

Stem Cell and Gene Therapy Biological Testing Market, By Region:

The stem cell and gene therapy biological testing market is analysed and market size insights and trends are provided by product type and end users as referenced above.

The countries covered in the stem cell and gene therapy biological testing market report are U.S., Canada and Mexico in North America, Germany, France, U.K., Netherlands, Switzerland, Belgium, Russia, Italy, Spain, Turkey, Rest of Europe in Europe, China, Japan, India, South Korea, Singapore, Malaysia, Australia, Thailand, Indonesia, Philippines, Rest of Asia-Pacific (APAC) in the Asia-Pacific (APAC), Saudi Arabia, U.A.E, South Africa, Egypt, Israel, Rest of Middle East and Africa (MEA) as a part of Middle East and Africa (MEA), Brazil, Argentina and Rest of South America as part of South America.

Table of Contents: Global Stem Cell and Gene Therapy Biological Testing Market

1 Introduction2 Market Segmentation3 Executive Summary4 Premium Insight5 Market Overview6 Covid-19 Impact on Stem Cell and Gene Therapy Biological Testing in Healthcare Industry7 Global Stem Cell and Gene Therapy Biological Testing Market, by Product Type8 Global Stem Cell and Gene Therapy Biological Testing Market, by Modality9 Global Stem Cell and Gene Therapy Biological Testing Market, by Type10 Global Stem Cell and Gene Therapy Biological Testing Market, by Mode11 Global Stem Cell and Gene Therapy Biological Testing Market, by End User12 Global Stem Cell and Gene Therapy Biological Testing Market, by Geography13 Global Stem Cell and Gene Therapy Biological Testing Market, Company Landscape14 Swot Analysis15 Company Profiles16 Questionnaire17 Related Reports

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Stem Cell and Gene Therapy Biological Testing Market Future Developments, Business Insights, End Users, Application and Forecast to 2029 - Digital...

To Skip or Delay a Stem Cell Transplant

A stem cell transplant may be the best treatment option for many patients with multiple myeloma. But is it always the answer? And can you put off the procedure?

First off, its important to note that not all multiple myeloma patients are eligible for a stem cell transplant. Factors that can impact a persons eligibility include age, fitness and co-morbidities (other current medical problems) such as heart, lung, kidney or liver problems. But even if youre unable to have a stem cell transplant, that doesnt mean your treatment wont be as effective as others who are eligible.

In a conversation with SurvivorNet, Dr. Jing Ye, a hematologist and oncologist at the University of Michigan Medicine, discusses the possibility of patients achieving lasting remission without undergoing a stem cell transplant. Multiple myeloma patients who are not eligible for a stem cell transplant typically have a prolonged period of induction treatment followed by maintenance therapy.

According to Dr. Ye, clinical trial data has shown that these patients can enjoy the same progression-free survival.

This has also opened up the conversation surrounding timing of the stem cell transplant for those who are eligible. In fact, some myeloma specialists think that a stem cell transplant should be performed right after induction treatment, but others think its OK to collect the stem cells and save them for actual implementation later on when the disease has relapsed.

Its interesting that the transplant actually is a treatment option developed quite some time ago, several decades ago, Dr. Ye says. Nowadays we have more and more chemo-free types of multiple myeloma treatment available. So there is also a debate in our myeloma field among experts (about when to offer the stem cell transplant).

And many multiple myeloma patients actually do try to save the treatment for relapse, according to Dr. Ye.

Patients now have an option if they would like to consider transplant at a later stage of their disease, she says.

Like the other variable aspects of multiple myeloma treatment, these different approaches will suit different people with different goals and circumstances. All of these options should be weighed with the close guidance of a multiple myeloma specialist.

Learn more about SurvivorNet's rigorous medical review process.

Joe Kerwin is a writer and researcher at SurvivorNet, based in New York City. Read More

First off, its important to note that not all multiple myeloma patients are eligible for a stem cell transplant. Factors that can impact a persons eligibility include age, fitness and co-morbidities (other current medical problems) such as heart, lung, kidney or liver problems. But even if youre unable to have a stem cell transplant, that doesnt mean your treatment wont be as effective as others who are eligible.

According to Dr. Ye, clinical trial data has shown that these patients can enjoy the same progression-free survival.

This has also opened up the conversation surrounding timing of the stem cell transplant for those who are eligible. In fact, some myeloma specialists think that a stem cell transplant should be performed right after induction treatment, but others think its OK to collect the stem cells and save them for actual implementation later on when the disease has relapsed.

Its interesting that the transplant actually is a treatment option developed quite some time ago, several decades ago, Dr. Ye says. Nowadays we have more and more chemo-free types of multiple myeloma treatment available. So there is also a debate in our myeloma field among experts (about when to offer the stem cell transplant).

And many multiple myeloma patients actually do try to save the treatment for relapse, according to Dr. Ye.

Patients now have an option if they would like to consider transplant at a later stage of their disease, she says.

Like the other variable aspects of multiple myeloma treatment, these different approaches will suit different people with different goals and circumstances. All of these options should be weighed with the close guidance of a multiple myeloma specialist.

Learn more about SurvivorNet's rigorous medical review process.

Joe Kerwin is a writer and researcher at SurvivorNet, based in New York City. Read More

Original post:
Can Multiple Myeloma Patients Achieve a Durable Remission After Induction Therapy & Skip or Delay a Stem Cell Transplant? - SurvivorNet

During a Targeted Oncology live event, Grzegorz S. Nowakowski, MD, discussed the case of a patient treated with tafasitamab plus lenalidomide in the second line for diffuse B-cell lymphoma.

Targeted OncologyTM: What are the options for second-line therapy in this patient with DLBCL?

NOWAKOWSKI: The current NCCN [National Comprehensive Cancer Network] guidelines [for patients who are not candidates for transplant] have gemcitabine [Gemzar] plus oxaliplatin [Eloxatin] plus or minus rituximab as a preferred regimen.1

Polatuzumab vedotin [Polivy] plus bendamustine [Treanda] plus rituximab is also included in the NCCN guidelines. Tafasitamab [Monjuvi] plus lenalidomide [Revlimid], which is another option, is FDA approved for second-line therapy and beyond. A lot of us in the field, in patients who are not willing to go for more intensive regimens [such as] transplant or CAR [chimeric antigen receptor] T-cell therapy, are looking more into these chemotherapy combinations, particularly if the patient progresses after chemotherapy. The idea is its going to be a different mode of action. CAR T-cell therapy is [used in the third-line setting] as of now. Again, this may change in the future.

What is the rationale behind the patient receiving this combination?

The FDA granted accelerated approval for the combination of tafasitamab and lenalidomide for relapsed or refractory DLBCL based on [results from] the L-MIND study [NCT02399085].2

Tafasitamab has a cool concept where the antibody cells target CD19, just as in CAR T-cell therapy and loncastuximab tesirine [Zynlonta], which is another recently approved antibody. There were initial developments before studying [CD19] where we felt it could be a good target, but some antibodies didnt work so well. Now there is this renaissance of interest in CD19-targeting agents such as CAR T-cell therapy, tafasitamab, and loncastuximab.

The [tafasitamab] antibody is engineered to have this enhanced Fc function that increases ADCC [antibody-dependent cellular cytotoxicity], ADCP [antibody-dependent cellular phagocytosis], and cell death. It causes direct cell death because CD19 is important in B-cell receptor signaling and not only in the immune system, but it gives some antisignaling properties as well.3

Lenalidomide has the properties of immune activation and microenvironment function and there are dozens of papers postulating many mechanisms of action for lenalidomide. Its very pleiotropic, but it does immune activation, and we know from R2 [lenalidomide plus rituximab] and other antibody combinations that it tends to synergize with the antibodies very well. This preclinical idea led to the development of the combination of this naked antibody and lenalidomide in patients with relapsed or refractory DLBCL.

Which trial data supported the approval of tafasitamab/lenalidomide?

L-MIND was a single-arm, phase 2 study [that enrolled patients who had] 1 to 3 prior regimens and who were either relapsing after transplant or were not eligible for transplant. The primary refractory patients were to be excluded, but because of changing definitions, they accrued, to some degree, to the study, and had pretty good results anyway.4

Tafasitamab is an infusion, just like other antibodies. Its given on days 1, 8, 15, and 22, for 1 to 3 cycles. In cycles 4 to 12, it is given every 2 weeks. Lenalidomide is given at 25 mg daily on days 1 to 25, [just as] in multiple myeloma. This is a different dose [from the R2 regimen], which is 20 mg, but the 25 mg was well tolerated, and this was based on the initial [pilot study]. After 12 cycles of therapy, patients received tafasitamab until disease progression.3,4

Frequently [we are asked] why we would plan on continuing forever. I was involved in the design of the study, and the salvage options for patients were quite limited for those who were not transplant eligible and some of the investigators asked why we would want to stop if it is working. We gave investigators discretion to [decide] whether the patient was benefiting from the treatment and to continue until disease progression. The primary end point of the study was overall response rate [ORR], which has frequently been the most reliable end point for the activity of the combination in this setting because it tends to have less bias in patient selection. The secondary end points were PFS [progression-free survival], duration of response [DOR], overall survival [OS], and so forth.4,5

There were some lenalidomide dose reduction studies where patients were given doses of 25 mg down to 5 mg using step reductions.5

This was a study of the [safety] population, and 81 patients were accrued overall. The median age was 72. The IPI risk score, Ann Arbor stage, and LDH results were typical for refractory DLBCL. Patients with primary refractory disease were supposed to be excluded, but 19 of 81 patients had it and 44 of 81 patients were refractory to prior therapies. Relatively few patients had a prior stem cell transplant and the majority were not eligible for it due to comorbidities, unwillingness to do so, or not responding to salvage therapy. [Not responding] to previous therapies was a major reason [for not getting a transplant].5

How did patients do on the L-MIND trial?

The ORR for this combination was quite high at greater than 60%, which is comparable with what we see in CAR T-cell therapy or intensive chemotherapy. So this was quite significant and impressive at the time the [results were] published. The CR [complete response] rate was even more impressive at 43%. Again, this was in patients who were relapsed or refractory, not transplant eligible, or those relapsing after transplant, so a 43% CR rate is high.5,6

As clinicians, we care about the DOR, too. So if you are a regulator, say at the FDA, you only worry about response rates because its less about patient selection, but clinicians like responses to be durable. The median PFS was 12.1 months.5 The median PFS doesnt fully reflect the activity of this regimen because it plateaus just after the median. CAR T-cell therapy data look very similar, too. For a relatively well-tolerated combination, these were very impressive results at the time of presentation. The median OS was not reached and, as with the PFS results, the OS also plateaued. So these were very impressive results in terms of DOR.

The patients in CR were primarily driving this benefit, but even the patients in PR [partial response] had [an approximately] 30% sustained response.6 The treatment was active in the patients treated both with 1 prior or 2 or more prior lines of therapy. Responses, particularly the CR rates, were somewhat higher in the patients who were on second-line treatment. This would be the patients who were not eligible for transplant.

Do you feel comfortable using this regimen in patients with GCB [germinal center B-celllike] subtypes because they were underrepresented in the study?

There was a whole debate about it. We believe that the combination of the antibodies and lenalidomide works well in GCB subtypes as well. It is a little bit different with single agents because the data showed response rates and activity were better in ABC [activated B-cell] or nonGCB subtypes of DLBCL, but in combination, there appeared to be less of a differential by cell of origin.

But in the [forest plot] analysis, both subtypes benefited. There was a trend toward a little bit of a high response rate in patients with the ABC subtype, but overall, the response rate was high in patients with GCB patients as well. I believe it was approximately 45% to 50% in both subtypes.

What about the R2 regimen? Do you prefer not to use it in GCB subtypes?

Yes, I prefer not to use it in GCB subtypes. [Results of] the ECOG-ACRIN E1412 study [NCT01856192] were recently published in the Journal of Clinical Oncology and I was a PI [principal investigator] in it.7 This study was looking at all-comers, so it was the only randomized frontline phase 2 study, where lenalidomide was added to R-CHOP. This one was cell-of-origin agnostic, so they could have the GCB or ABC subtype. There was [approximately] a 12% difference in PFS in this study and a favorable hazard ratio.

Another study, the ROBUST study [NCT02285062], was focused on patients with the ABC subtype.8 It didnt show a difference using different lenalidomide scheduled doses, though there were other patient selection issues in the study. As a single agent, lenalidomide is more active in the ABC subtype and I use it myself in clinical practice more in ABC or nonGCB subtypes. In combination with the antibodies, or even chemotherapy, this may not be necessarily true. Because most of these patients are already exposed to rituximab, I think based on the R2 study [results], they didnt see much of a differential based on cell of origin, which is a little bit disappointing, because we were hoping we could [use it to] select the high responders, but that didnt pan out. REMARC [NCT01122472] was a study done by a French group that used lenalidomide maintenance after R-CHOP but didnt track the cell of origin.

In fact, the GCB subtype tended to benefit more, and an idea was that maybe some microenvironment influences played a role. In my clinical practice, in nonGCB subtypes, I use a single agent, but for combination of the antibodies, the activity seems to be agnostic to cell of origin.

How does an anti-CD19 antibody downregulate the CD19 receptor?

There is limited information, but they did a study looking at the CD19 expression after tafasitamab exposure in chronic lymphocytic leukemia and [there was no impact] and in DLBCL as well. The CD19 expression is just a part of the story because you worry that a part of the CD19 molecule could be mutated and then the CAR T-cell agents would not bind or that part of the molecule could be missed because of alternative splicing or losing one of the exons because of the evolutionary pressure of the treatment. We did whole exome and RNA sequencing and saw no abnormalities within the CD19 cells. It appears to be expressed after tafasitamab exposure, and there are no point mutations, exon deletions, or other changes that would affect the integrity of CD19, to the best of our knowledge.

Of course, the best data would come from clinical evidence if we note that CAR T-cell therapy is working. In this study, only 1 patient proceeded with CAR T-cell therapy and had good clinical benefit and was in remission last time I saw the data. So it appears that in anecdotal experiences CAR T-cell therapy will still work in those patients.

The opposite is true, too. There is a huge interest now in this combination and [whether] it will be active in post CAR T-cell relapses. Lenalidomide as a single agent is frequently used in this setting. How active will this combination be in postCAR T-cell relapse? We know that lenalidomide is active. A lot of patients with CAR T-cell relapses will still have CD19, so we believe that is also an option, but more data will be needed.

Do patients tolerate the 25-mg lenalidomide dose in combination with tafasitamab, or is the dose modified often?

[Approximately] 30% of patients will have to drop to 20 mg, particularly with subsequent cycles. The nice thing for lenalidomide is that you can use the growth factor support because it is primarily neutropenia that causes some of the dose reductions. Studies are different from real life, so in the real world we always have some patients who are already cytopenic from the previous therapy. I usually support them with a growth factor, and sometimes I start my patients at 20 mg. The dosing intensity of lenalidomide seems to be important, though.

I wouldnt very liberally decrease it because there appears to be some dose relation to the response, at least as a single agent in a refractory setting in DLBCL in contrast to follicular [lymphoma], but somewhere from 15 mg to 20 mg is the golden spot for response.

The 25 mg was used in those studies as a single agent, so, about one-third of patients did require dose reductions. If you use this combination, you follow the lenalidomide package inserts, and if you need to reduce because of creatinine clearance, you reduce the lenalidomide or if you see significant neutropenia despite the growth factor used, then you can reduce on a subsequent cycle to 20 mg, or interrupt and reduce to 20 mg.

Does patient preference weigh into the decision to choose finite therapy vs therapy until progression of disease in the second-line setting?

Yes, it comes down to the patients preference. I dont practice in the community, so I dont have more experience with this. We have this policy at Mayo Clinic that [any clinician] from around the world can call us at any time for advice about their patients. So, routinely, we are getting quite a few phone calls from those who are responsible for patients with lymphoma, or for any other disease type from outside, and practitioners call asking what to do.

I am always surprised by how many patients do not want to proceed with CAR T-cell therapy or stem cells or even clinical trials, which we often have here, because of the preference of being near the local center. Travel is not always possible and some patients want to stay where they are, which is a very reasonable option.

Are there trials comparing this with transplant or something lenalidomide alone?

We did 2 things to differentiate this from lenalidomide alone. A study called RE-MIND [NCT04150328] with close matching of the patients with real-world data showed that the combination was definitely much more active than lenalidomide alone. [We knew this] but wanted to double-check in a very close-matched cohort. A confirmatory study for this is [the frontMIND study (NCT04824092), which is a frontline study that compares] R-CHOP as standard therapy vs R2-CHOP plus tafasitamab.

I am the principal investigator globally for this study, and one of the reasons why we designed it this way was there was some activity already from randomized phase 2 studies using lenalidomide. It was safe and effective and also the doublet was already approved, so it was logical to move it forward.

However, the biggest [issue we had when] presenting this concept to some regulatory authorities was that we were a little bit naive in the past, thinking that adding 1 drug at a time is going to move the bar a whole lot. R-CHOP already has 5 different compounds, so I think the sixth one probably is not going to move the bar a whole lot. There are some studies that failed, I think, 1 drug at a time. So the ambitious plan here is to add a doublet. But the study is designed to capture very high-risk patients, [meaning] IPI 3 and above. Its looking at the highest-risk population and is adding doublet on top of R-CHOP. There are some study centers in the United States that are in the process of either opening or even have it open currently.

Could tafasitamab/lenalidomide be moved to the first-line setting with more targeted agents as chemotherapies are eliminated?

Yes. There is a pilot study led by my colleague Dr [Jason] Westin at [The University of Texas MD Anderson Cancer Center]. He is basically pioneering the so-called smart-start, or smart-stop now, where he is adding exactly this combination to R-CHOP. The question is: Can he strip some of the chemotherapy agents [such as anthracyclines]?

[The patient] tried to shorten and then to remove different cytotoxic drugs with the idea that maybe over time he can develop a chemotherapy-free regimen. [Results of] the initial pilot study have shown this combination plus ibrutinib [Imbruvica] is producing high response rates. He still added chemotherapy later because he was worried that he may miss the possibility of curing the patient, but after initial feasibility, he is slowly stripping chemotherapy. We may get there one day.

What are the similarities and differences of loncastuximab tesirine and tafasitamab?

I think cross-study comparisons are usually difficult. I am very cautious always when comparing different study results because the patient population is not always the same. I happen to be involved with the FDA in different reviews and I do believe that the response rate is what tends to reflect the most activity and is less dependent on patient selection, though not completely.

The ORR of loncastuximab is [approximately] 50% or very close to that. The DOR appears to be a little bit shorter, but this could be due to patient selection, so it looks very encouraging. It has a little bit of a different adverse event [AE] profile. At this point it doesnt have as strong a follow-up as this study, so we dont know if the same very encouraging plateaus in responding patients will be seen with it.

Maybe its going to happen, but it is more of a traditional cytotoxic therapy that is directed like polatuzumab. It works more on the immune microenvironment in immune activation. There is this renaissance of CD19 targeting and for CAR T-cell therapies, all the approved products target CD19, and now loncastuximab and tafasitamab.

I usually tell the industry to not develop any more agents targeting CD19. We have enough. There are some other good targets, too. Some of the CAR T-cell therapies are targeting different molecules on the surface.

How many of these patients on the L-MIND trial stopped therapy early? What is the safety profile of combination lenalidomide and tafasitamab?

The primary reason for stopping therapy early was disease progression because some patients just didnt respond. The toxicities were primarily hematologic, which is consistent with what you would see with lenalidomide. Nonhematologic AEs [included] fatigue and diarrhea, but nothing striking or unusual. Discontinuation of combination [therapy due to] AEs was seen in 12% of the patients [n = 10/81].5

A comparison of the AEs of combination therapy vs monotherapy showed the hematologic and other toxicities were driven by lenalidomide. Tafasitamab alone had [an approximate] 27% ORR and when combined with lenalidomide the response rate doubles, so theres a true synergy between those drugs.

The monotherapies are quite well tolerated. Some patients can develop neutropenia, as was seen in the monotherapy trials, but overall the toxicity is minimal for the antibody alone.

What is the rapidity of the response for this regimen? Who wouldnt be eligible for it?

The first evaluation was done after 2 cycles of therapy, so within 8 weeks the response was right there. The response is quite brisk. If I had any concern about putting [a patient] on lenalidomide, it would be for reasons such as it can cause some rashes as seen previously with lenalidomide combinations, so with previous hypersensitivity, I probably would not [use it].

If patients have very rapidly progressive symptoms, I may stabilize them with radiation or some other treatment first, maybe hydroxysteroids, rituximab, or something such as that just to remove the disease burden before I start this combination. I expected that the responses would be dipping over time, but the responses were brisk and happened after 2 cycles of therapy.

REFERENCES

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Nowakowski Considers CD19 Therapy in Transplant-Ineligible DLBCL - Targeted Oncology

This article was originally published here

Biomed J. 2022 Jan 15:S2319-4170(22)00005-1. doi: 10.1016/j.bj.2022.01.005. Online ahead of print.

ABSTRACT

Allograft rejection is one of the obstacles in achieving a successful vascularized composite allotransplantation. Treatments of graft rejection with lifelong immunosuppression subject the recipients to a lifelong risk of cancer development and opportunistic infections. Cell therapy has recently emerged as a promising strategy to modulate the immune system, minimize immunosuppressant drug dosages, and induce allograft tolerance. In this review, the recent works regarding the use of cell therapy to improve allograft outcomes are discussed. The current data supports the safety of cell therapy. The suitable type of cell therapy in allotransplantation is clinically dependent. Bone marrow cell therapy is more suitable for the induction phase, while other cell therapies are more feasible in either the induction or maintenance phase, or for salvage of allograft rejection. Immune cell therapy focuses on modulating the immune response, whereas stem cells may have an additional role in promoting structural regenerations, such as nerve regeneration. Source, frequency, dosage, and route of cell therapy delivery are also dependent on the specific need in the clinical setting.

PMID:35042019 | DOI:10.1016/j.bj.2022.01.005

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Cell Therapy in Vascularized Composite Allotransplantation - DocWire News

REGULATED INFORMATION

Recruitment for ALLOB tibial facture Phase IIb study ongoing and on schedule to release topline data in Q1 2023, despite COVID slowdown

New scientific advisory board appointments to bolster the further development of the next generation iMSCg platform

Discussions for ALLOB global partnership still ongoing. Completion of potential global partnership delayed and now anticipated in Q1 2022

Financial position strengthened following equity fundraising in Q4 2021 with runway expected into Q3 2022

Gosselies, Belgium, 19 January 2022, 7am CET BONE THERAPEUTICS (Euronext Brussels and Paris: BOTHE), the cell therapy company addressing unmet medical needs in orthopedics and other diseases, announces today a business update for the fourth quarter, ending 31 December 2021 as well as a business outlook for 2022.

Bone Therapeutics activity in Q4 2021 has resulted in a broadened pipeline and stronger therapeutic potential for the company. The pandemic continues to be a concern across the cell and gene therapy, biopharma and healthcare industries. Bone Therapeutics has, however, put measures in place to reduce the impact of the pandemic on its clinical development., said Miguel Forte, Chief Executive Officer, Bone Therapeutics. In addition, the deal for the global rights for the allogeneic osteoblastic cell therapy product ALLOB, when and if completed, will allow Bone Therapeutics, together with its partners, to ensure the development of ALLOB towards commercialization, while at the same time continue to explore options to expand the iMSCg platform. This includes the development of a next generation of genetically engineered mesenchymal stromal cells and the use of highly scalable and versatile cell sources such as induced pluripotent stem cells. Bone Therapeutics has expanded its Scientific Advisory Board purely for this purpose.

Operational highlights

Corporate highlights

Financial highlights (1)

Outlook for 2022

Financial Calendar 2022

The financial calendar is communicated on an indicative basis and may be subject to change.

(1) Unaudited number

About Bone Therapeutics

Bone Therapeutics is a leading biotech company focused on the development of innovative products to address high unmet needs in orthopedics and other diseases. The Company has a diversified portfolio of cell therapies at different stages ranging from pre-clinical programs in immunomodulation to mid stage clinical development for orthopedic conditions, targeting markets with large unmet medical needs and limited innovation.

Bone Therapeutics core technology is based on its cutting-edge allogeneic cell and gene therapy platform with differentiated bone marrow sourced Mesenchymal Stromal Cells (MSCs) which can be stored at the point of use in the hospital. Currently in pre-clinical development, BT-20, the most recent product candidate from this technology, targets inflammatory conditions, while the leading investigational medicinal product, ALLOB, represents a unique, proprietary approach to bone regeneration, which turns undifferentiated stromal cells from healthy donors into bone-forming cells. These cells are produced via the Bone Therapeutics scalable manufacturing process. Following the CTA approval by regulatory authorities in Europe, the Company has initiated patient recruitment for the Phase IIb clinical trial with ALLOB in patients with difficult tibial fractures, using its optimized production process. ALLOB continues to be evaluated for other orthopedic indications including spinal fusion, osteotomy, maxillofacial and dental.

Bone Therapeutics cell therapy products are manufactured to the highest GMP (Good Manufacturing Practices) standards and are protected by a broad IP (Intellectual Property) portfolio covering ten patent families as well as knowhow. The Company is based in the BioPark in Gosselies, Belgium. Further information is available at http://www.bonetherapeutics.com.

For further information, please contact:

Bone Therapeutics SAMiguel Forte, MD, PhD, Chief Executive OfficerLieve Creten, Chief Financial Officer ad interimTel: +32 (0)71 12 10 00investorrelations@bonetherapeutics.com

For Belgian Media and Investor Enquiries:BepublicBert BouserieTel: +32 (0)488 40 44 77bert.bouserie@bepublicgroup.be

International Media Enquiries:Image Box CommunicationsNeil Hunter / Michelle BoxallTel: +44 (0)20 8943 4685neil.hunter@ibcomms.agency / michelle@ibcomms.agency

For French Media and Investor Enquiries:NewCap Investor Relations & Financial CommunicationsPierre Laurent, Louis-Victor Delouvrier and Arthur RouillTel: +33 (0)1 44 71 94 94bone@newcap.eu

Certain statements, beliefs and opinions in this press release are forward-looking, which reflect the Company or, as appropriate, the Company directors current expectations and projections about future events. By their nature, forward-looking statements involve a number of risks, uncertainties and assumptions that could cause actual results or events to differ materially from those expressed or implied by the forward-looking statements. These risks, uncertainties and assumptions could adversely affect the outcome and financial effects of the plans and events described herein. A multitude of factors including, but not limited to, changes in demand, competition and technology, can cause actual events, performance or results to differ significantly from any anticipated development. Forward looking statements contained in this press release regarding past trends or activities should not be taken as a representation that such trends or activities will continue in the future. As a result, the Company expressly disclaims any obligation or undertaking to release any update or revisions to any forward-looking statements in this press release as a result of any change in expectations or any change in events, conditions, assumptions or circumstances on which these forward-looking statements are based. Neither the Company nor its advisers or representatives nor any of its subsidiary undertakings or any such persons officers or employees guarantees that the assumptions underlying such forward-looking statements are free from errors nor does either accept any responsibility for the future accuracy of the forward-looking statements contained in this press release or the actual occurrence of the forecasted developments. You should not place undue reliance on forward-looking statements, which speak only as of the date of this press release.

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Bone Therapeutics provides fourth quarter 2021 business update and 2022 outlook - GlobeNewswire

SEATTLE--(BUSINESS WIRE)--Omeros Corporation (Nasdaq: OMER) today confirmed that earlier this month the company submitted to the U.S. Food and Drug Administration (FDA) its response to the Agencys Complete Response Letter (CRL) for narsoplimab in the treatment of hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA). The response comprises a comprehensive briefing package drafted in close collaboration with external clinical, regulatory and legal experts that addresses in detail the points raised by FDA in its CRL for narsoplimab. Omeros concurrently requested a Type A meeting with FDA to resolve any outstanding items.

Narsoplimab is the first drug candidate submitted to FDA for approval in HSCT-TMA. It has Breakthrough Therapy and Orphan designations in both HSCT-TMA and IgA nephropathy.

About Omeros Corporation

Omeros is an innovative biopharmaceutical company committed to discovering, developing and commercializing small-molecule and protein therapeutics for large-market and orphan indications targeting inflammation, immunologic diseases (e.g., complement-mediated diseases) and cancers. Omeros lead MASP-2 inhibitor narsoplimab targets the lectin pathway of complement and is the subject of a biologics license application pending before FDA for the treatment of hematopoietic stem cell transplant-associated thrombotic microangiopathy. Narsoplimab is also in multiple late-stage clinical development programs focused on other complement-mediated disorders, including IgA nephropathy, atypical hemolytic uremic syndrome and COVID-19. OMS906, Omeros inhibitor of MASP-3, the key activator of the alternative pathway of complement, is in a Phase 1 clinical trial. For more information about Omeros and its programs, visit http://www.omeros.com.

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934, which are subject to the safe harbor created by those sections for such statements. All statements other than statements of historical fact are forward-looking statements, which are often indicated by terms such as anticipate, believe, could, estimate, expect, goal, intend, likely, look forward to, may, objective, plan, potential, predict, project, should, slate, target, will, would and similar expressions and variations thereof. Forward-looking statements, including expectations with regard to interactions and communications with FDA and Omeros pursuit of regulatory approval for narsoplimab in HSCT-TMA, are based on managements beliefs and assumptions and on information available to management only as of the date of this press release. Omeros actual results could differ materially from those anticipated in these forward-looking statements for many reasons, including, without limitation, risks associated with product commercialization and commercial operations, regulatory processes and oversight, and the risks, uncertainties and other factors described under the heading Risk Factors in the companys Annual Report on Form 10-K filed with the Securities and Exchange Commission on March 1, 2021. Given these risks, uncertainties and other factors, you should not place undue reliance on these forward-looking statements, and the company assumes no obligation to update these forward-looking statements, whether as a result of new information, future events or otherwise, except as required by applicable law.

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Omeros Confirms Submission of Response to FDA Regarding the BLA for Narsoplimab in the Treatment of HSCT-TMA - Business Wire

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DUARTE, Calif. & TOA BAJA, Puerto Rico--(BUSINESS WIRE)--City of Hope, a world-renowned cancer research and treatment organization, and CytoImmune Therapeutics, a clinical-stage immunotherapy company that is developing a novel class of natural killer (NK) cell-based cancer therapies, today announced a study published in the high-impact journal Gastroenterology that demonstrates off-the-shelf anti-prostate stem cell antigen (PSCA) chimeric antigen receptor (CAR) NK cells significantly suppressed pancreatic cancer in vitro and in vivo using a method known as freeze-thaw.

This press release features multimedia. View the full release here: https://www.businesswire.com/news/home/20220118005366/en/

The therapy PSCA CAR_s15 NK cells, also known as CYTO NK-203 persisted more than 90 days after infusion and significantly prolonged the survival of mice with pancreatic cancer, showing that the freeze-thaw method works. For the study, PSCA CAR_s15 NK cells were produced and then frozen. The cells were then thawed and used in preclinical studies at City of Hope.

Our patients need additional ways to attack their pancreatic cancer. The work presented by City of Hopes team is distinctive and promising for two reasons: First of all, it is based on a precision medicine approach that is a special target in the patient's pancreatic cancer PSCA. Secondly, it is an immunologic approach, using human natural killer cells, which are specifically engineered to attack the patient's cancer. These findings should be accelerated to a clinical trial as rapidly as possible, said Daniel D. Von Hoff, M.D., a distinguished professor in the Molecular Medicine Division of the Translational Genomics Research Institute (TGen), an affiliate of City of Hope. He also is senior consultant-clinical investigator at City of Hope and is one of the nations leading authorities on the treatment and care of pancreatic cancer patients.

City of Hope is committed to finding more effective and innovative treatments for difficult-to-treat solid cancers, and pancreatic cancer is clearly one of them, said Saul Priceman, Ph.D., assistant professor in the Department of Hematology & Hematopoietic Cell Transplantation at City of Hope and a study author. These new PSCA CAR_s15 NK cell preclinical studies provide tremendous support for the anticipated upcoming clinical trials to evaluate efficacy and safety of this novel CAR-engineered NK cell therapy in patients with pancreatic cancer, which is a promising expansion of our existing clinical programs that target PSCA in solid cancers using CAR-engineered T cell therapy.

Pancreatic cancer is the third leading cause of cancer-related death in the United States with a five-year survival rate of approximately 10%. The cancer is typically detected when it is at a late stage and incurable. Chemotherapy or other therapies provide modest benefit. Therefore, the development of new therapies for pancreatic cancer is crucial. The therapy can also be used for other PSCA+ cancers, such as stomach and prostate.

NK cell technology works by using natural killer cells from a patient or donor. NK cells are then engineered so they express a receptor a CAR that is specific for a protein expressed by cancerous cells, along with the secretion of IL-15, which sustains the survival of the NK cells.

Christina Coughlin, M.D., CEO of CytoImmune Therapeutics, said, "We are excited to share this data on our CAR NK candidate for pancreatic cancer. This foundational data supports robust anti-tumor activity with CYTO NK-203, making us confident our innovative and off-the-shelf NK cell therapy approach has the potential to deliver more accessible, safe and effective cell-based treatment options to cancer patients. We are encouraged by these findings and look forward to continuing our work with City of Hope in order to move this initiative to the clinic.

This immunotherapy is revolutionizing the treatment of some blood cancers; however, its use in the treatment of solid tumors has been limited, in part because most of the proteins currently used to target CAR cells to solid tumors are present in low levels on other normal tissues, leading to toxic side effects.

Based on research by Michael Caligiuri, M.D., president of City of Hope National Medical Center and the Deana and Steve Campbell Physician-in-Chief Distinguished Chair, and Jianhua Yu, Ph.D., professor and director of the Natural Killer Cell Biology Research Program, who have nearly 55 years of collective laboratory investigation of NK cells, CytoImmune is developing an NK cell platform designed to overcome the limitations and challenges of current technologies for engineering NK cells. The platform is designed to generate an abundant supply of CAR NK cells from a single umbilical cord donor, engineered with the CAR for effective recognition of tumor targets, and secreting IL-15 to improve the persistence of CAR NK cells for sustained activity in the body. The process enables scientists to freeze, transport and store engineered CAR NK cells for off-the-shelf use for the treatment of cancer.

The study titled Off-the-shelf PSCA-directed chimeric antigen receptor natural killer cell therapy to treat pancreatic cancer can be found here.

About City of Hope

City of Hope is an independent biomedical research and treatment center for cancer, diabetes and other life-threatening diseases. Founded in 1913, City of Hope is a leader in bone marrow transplantation and immunotherapy such as CAR T cell therapy. City of Hopes translational research and personalized treatment protocols advance care throughout the world. Human synthetic insulin, monoclonal antibodies and numerous breakthrough cancer drugs are based on technology developed at the institution. A National Cancer Institute-designated comprehensive cancer center and a founding member of the National Comprehensive Cancer Network, City of Hope is ranked among the nations Best Hospitals in cancer by U.S. News & World Report. Its main campus is located near Los Angeles, with additional locations throughout Southern California and in Arizona. Translational Genomics Research Institute (TGen) became a part of City of Hope in 2016. AccessHopeTM, a subsidiary launched in 2019, serves employers and their health care partners by providing access to NCI-designated cancer center expertise. For more information about City of Hope, follow us on Facebook, Twitter, YouTube or Instagram.

About CYTO NK 203

CYTO NK-203 is an off-the-shelf allogeneic CAR NK cell therapy derived from umbilical cord blood, expressing a CAR against prostate stem cell antigen and soluble IL-15 and engineered with proprietary features designed to improve the safety and efficacy of NK cells as a potential therapy.

About CytoImmune Therapeutics Inc.

Founded in 2017, CytoImmune Therapeutics is a clinical-stage biotechnology company, focused on developing an innovative and differentiated pipeline of NK cell therapies, using proprietary, robust and well characterized NK cell expansion and engineering technologies pioneered by Michael Caligiuri, M.D., and Jianhua Yu, Ph.D. The pipeline includes cytokine induced NK (CI-NK) for lung cancer, FLT3 CAR-NK for acute myeloid leukemia, PSCA CAR-NK cells for solid tumors and GPRC5D BiKE secreting BCMA CAR-NK cells for multiple myeloma. CytoImmunes lead product, CYTO-102 (CI-NK) cell therapy, aims to enter the clinic in combination with atezolizumab (anti-PD-L1 monoclonal antibody) for nonsmall cell lung cancer in 2022.

View source version on businesswire.com: https://www.businesswire.com/news/home/20220118005366/en/

City of HopeLetisia Marquezlemarquez@coh.org626-476-7593

CytoImmuneWilliam Roselliniwill@cytoimmune.com

Source: City of Hope

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City of Hope and CytoImmune announce study demonstrating novel off-the-shelf chimeric antigen receptor (CAR) natural killer (NK) cell-based therapy...