Category Archives: Cell Therapy

The manufacturing of cell therapies is highly complex, often depending on skilled manual labor. The Israeli startup Adva Biotechnology aims to use automation, optical sensing and artificial intelligence to remove the manual component from the process.

Cancer cell therapies such as CAR-T immunotherapies have demonstrated enormous potential for treating forms of blood cancer. Currently available therapies involve extracting a cancer patients immune T cells, genetically engineering them in the lab, and returning them to the patient to kill cancer cells.

One of the drawbacks of these therapies is that growing cells in a manufacturing setting is highly complex. This means that the therapies are expensive and largely limited to the wealthiest nations.

According to Noam Bercovich, vice president of development at the Israeli firm Adva Biotechnology, CAR-T cell therapies have been something that most cancer patients are unable to receive.

All the companies manufacturing this therapy use semi-automated solutions, which demand lots of human input in terms of quantity and expertise, Bercovich added.

To bring more automation into the cell therapy manufacturing process, Adva Biotechnology was founded in 2016 by its CEO Ohad Karnieli in Bar-Lev High-Tech Park in Israel. Adva Biotechnology is working on an automated cell culture kit powered by artificial intelligence and optical sensors.

Prior to founding Adva Biotechnology, Karnieli had served as vice president of technology and manufacturing at the cell therapy firm Pluristem Therapeutics, which is now known as Pluri. He also founded the CDMO Atvio Biotechnology, which was acquired by Orgenesis in 2018.

Bercovich was a process engineering manager at Pluristem and had known Karnieli for almost 12 years before ADVA Biotechnology was founded.

We worked together and [Karnieli] left the place, called me and told me about his idea. And I said Id join right away, recalled Bercovich.

In an online presentation, Advas founder and CEO Ohad Karnieli explained that current manufacturers are only able to measure a few parameters in cell cultures on a few occasions.

We dont really know whats happening inside the system or inside our cultures, he stated. We put the cells in the incubator and we have no idea whats happening. We need much more in-process controls.

The equipment, named ADVA X, uses sensors and artificial intelligence to handle the fine adjustments that are often required when growing cells, such as monitoring and tweaking levels of nutrients in the cell culture medium. It consists of a single-use kit that slots into an electronic system. According to Adva Biotechnology, the kit can culture from 10 million to 20 billion cells in the same chamber. In addition, the kit has the ability to grow CAR-T cells, natural killer (NK) cells, exosomes, viruses and more.

At present, ADVA X is available only to early adopters. After a patent dispute with the CDMO giant Lonza, Adva entered a licensing agreement with Lonza in May 2022 to enable the startup to launch its equipment in the U.S. The device will face its first field test manufacturing an advanced therapy for a clinical trial in 2023.

Once its tested in a clinical trial that is when we can look at the device and say, We made it. Its the real thing, said Bercovich.

Adva is part of a wave of startups geared towards bringing automation to the world of advanced therapy manufacturing, such as Ori Biotech and Cytera Cellworks. Bercovich said that Advas fast adoption of optical sensing technology is what helps the company stand out from the crowd.

Automated cell therapy manufacturing technology such as the ADVA X could also enable the advent of decentralized manufacturing. In this scenario, for example, a CAR-T therapy could be produced at the hospital where a cancer patient is staying, rather than being shipped off to a large, expensive central location.

If I can take my manufacturing and bring it to the patient, a lot of the logistics and the huge footprint are basically eliminated, stated Karnieli. We need decentralized manufacturing with centralized control, meaning remote access, alerts and all these different automation properties.

Adva Biotechnology bankrolled its research with a crowdfunding campaign in 2020, and with a seed round in 2021. The company is now in the middle of raising another funding round.

According to Bercovich, while a lot of attention has been paid to the business potential of automation in cell therapy manufacture, Advas also mindful that these advances can lead to more treatments that save lives.

Behind all this, its a potential cancer treatment, said Bercovich. This is something that we speak about every now and then to not forget.

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Adva Biotechnology is using artificial intelligence to manufacture cell therapies - Labiotech.eu

CAR T-cell therapy products will soon be available in Saudi Arabia, Singapore and Brazil, following the launch of Gilead and Kite Oncologys latest operations.

Commenting on the expansion into KSA, Eslam Khedr, Regional Business Unit Director for Cell Therapy and Oncology, Gilead and Kite Middle East said: Saudi Arabias Vision 2030 is a key reason Kite selected Saudi Arabia as the location of its first Middle East operation. We are establishing a fully functional oncology/cell therapy business unit in line with international best-in-class protocols with the aim of giving those with cancer the chance to be treated and to offer healthcare of an international standard.

Dedicated Gilead and Kite teams will work to qualify leading hospitals to administer CAR T-cell therapy in each of the new countries after local regulatory approvals. Plans are also in place to increase its workforce in these countries this year.

To date, Kite is the only company dedicated exclusively to the research, development, and manufacturing of cell therapy on a global scale. All its functions dedicated to this focus area are vertically integrated under one leadership team for efficient delivery of the highly specialised and complex end-to-end processes needed to support CAR T-cell therapy.

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CAR T-Cell Therapy operations launched in Saudi Arabia - Omnia Health Insights

BEIJING & GUANGZHOU, China--(BUSINESS WIRE)--Biocytogen Pharmaceuticals (Beijing) Co., Ltd. ("Biocytogen", HKEX: 02315) announced a strategic collaboration with Guangzhou FineImmune Biotechnology Co., LTD. (FineImmune) to co-develop cell-based therapeutic drugs targeting intracellular tumor-associated antigens. Biocytogen will use its proprietary TCR-mimic antibody platform to discover fully human antibody sequences that will be further developed using FineImmunes unique cell therapy platform.

Biocytogens TCR-mimic antibody development platform utilizes its proprietary fully human antibody RenMiceTM (RenMabTM and RenLite mice) that have been further engineered to express a human leukocyte antigen (HLA) gene. Antibodies against intracellular tumor-associated antigens are subjected to advanced high-throughput antibody screening technologies to discover antibodies with high specificity and affinity.

Most tumor antigens are intracellular, and our TCR-mimic platform provides a solution for developing antibodies against these valuable targets, said Dr. Yuelei Shen, Founder, Chairman and CEO of Biocytogen. TCR-mimic antibodies generated by our TCR-mimic platform have potentials to be developed into multiple drug modalities such as T cell engagers, bispecific/multispecific antibodies and CAR-T therapies. We are pleased to collaborate with FineImmune to explore the application of our antibodies in the field of cell therapies.

FineImmune is a pioneering T cell therapy company, and has solved multiple critical barriers in the microenvironment of solid tumors by using multiple proprietary technology platforms, such as GSOP for T-cell engineering, HAP for TCR identification, CMP for personalized TCR-T cell production and in vivo T-cell delivery platform (TDP). FineImmunes product pipelines include TCR-T, CAR-T, TAL, TIL, etc. The company developed the first personalized neoantigen-specific TCR-T cell therapy, which is in phase I clinical trial now. In addition, FineImmune possesses technologies for the precision prediction of the efficacy and side effects of immunotherapy, enabling healthcare professionals to provide effective and safe immunotherapy to patients with common malignant tumors.

T cells play an important role in treating cancers. Biocytogens advanced TCR-mimic platform makes it possible for us to develop T cell therapies against crucial but low-expressed intracellular tumor antigens, said Dr. Penghui Zhou, Founder and Chief Technology Officer of FineImmune. We focus on providing efficient and safe immunotherapy using advanced technologies. This collaboration will promote the development of new cell therapeutic drugs and the expansion of the potential of immunotherapy to benefit patients.

About the TCR-Mimic Platform Biocytogens T Cell Receptor (TCR)-Mimic platform utilizes HLA-expressing fully human antibody mice (HLA/RenMice) to generate antibodies to intracellular tumor-associated antigens when immunized with MHC-antigen-peptide complexes. Subsequently, Biocytogens high-throughput antibody screening platform aims to swiftly identify TCR-mimic antibodies with higher specificity and affinity than endogenous TCRs derived from patients. Currently, antibody sequences against multiple intracellular targets have been obtained, and their efficacies have been verified in vitro and in vivo. Fully human antibody sequences obtained from the TCR-mimic platform can empower the development of T cell engagers, bispecific/multispecific antibodies, and CAR-T therapies.

About BiocytogenBiocytogen Pharmaceuticals (Beijing) Co., Ltd. is a global biotechnology company that drives the research and development of novel antibody-based drugs with innovative technologies. Using its proprietary RenMabTM /RenLite mice platforms for fully human monoclonal and bispecific antibody development, Biocytogen has integrated its in vivo drug efficacy screening platforms and strong clinical development expertise to streamline the entire drug development process. Biocytogen is undertaking a large-scale project to develop antibody drugs for more than 1000 targets, known as Project Integrum, and has entered ongoing collaborations with dozens of partners worldwide to produce a variety of first-in-class and/or best-in-class antibody drugs. The company's pipeline includes 12 core products, among which two products are in phase II multi-regional clinical trials and two products are in phase I. Headquartered in Beijing, Biocytogen has branches in Haimen Jiangsu, Shanghai, Boston, USA and Heidelberg, Germany. On September 1, 2022, Biocytogen was listed on the Main Board of the Stock Exchange of Hong Kong Limited with the stock code: 02315.HK. For more information, please visit http://en.biocytogen.com.cn.

About FineImmuneGuangzhou FineImmune Biotechnology Co., Ltd. is an innovation driven company based in China. The company is mainly engaged in the development of solid tumor immunotherapy drugs and related businesses. It has solved key technical bottlenecks in solid tumor immunotherapy and possesses core technologies. A number of T-cell therapy products for solid tumors are in clinical trials, as well as diagnostic reagents for accurate identification of effective populations. It has a 2000 square meter immunotherapy R&D laboratory and a GMP production workshop for cell therapy products in Guangzhou Science City. The company's individualized TCR-T cell therapy product (new drug) has been carried out clinical research in the Affiliated Tumor Hospital of Sun Yat sen University. At present, more than 20 immune cell therapy products and technologies are under research and development. For more information, please visit http://www.fineimmu.com/.

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Biocytogen Announces Collaboration with FineImmune to Develop TCR-Mimic Antibody-Based Cell Therapy - Business Wire

DUBLIN--(BUSINESS WIRE)--The "Cell Therapy Technologies Market by Product (Media, Sera & Reagents, Cell Culture Vessels, Single Use Equipment, Systems & Software), Process (Cell Processing), Cell Type (T-cells, Stem Cells), End User (Biopharma, CMOs), Region - Global Forecast to 2027" report has been added to ResearchAndMarkets.com's offering.

The cell therapy technologies market is projected to reach USD 8.0 Billion by 2027 from USD 4.0 Billion in 2022, at a CAGR of 14.6%

The growth can be attributed to the increasing public-private partnerships. Several government and private organizations have made significant investments to strengthen R&D in cell therapy leading to a surge in cell therapy technologies demand, hence propelling market growth.

Cell therapy instruments and consumables are used in the development of novel cell therapies for the treatment of different diseases and the mass production of cells from given samples or tissues.

Cell therapy technologies find major applications in regenerative medicine, stem cell research, cancer research, and cell biology research. These technologies are also extensively used in research centers and research institutes for life science and biopharmaceutical R&D.

The rising government investments in cell-based research, increasing incidence of chronic and infectious diseases, a large number of oncology-related cell therapy clinical trials, and increasing GMP certifications for cell therapy production facilities are the key factors driving the growth of this market.

The cell preservation and distribution and handling process segment accounted for the second largest share of the market in 2021.

Cell preservation and distribution is an essential and vital step in the cell scaling-up process. In addition, with the growth in the demand for cell-based medical products and therapies, the demand for reliable storage equipment to preserve finite cell lines and cells manufactured in excess is expected to increase. This factor is expected to drive the growth of this market segment.

The CROs and CMOs accounted for the second largest share of the cell therapy technologies market in 2021.

To cater the large demand, pharmaceutical companies need to speed up clinical timelines, maintain business continuity, and free up resources for projects. This has increased outsourcing analytical tests to CROs and CMOs, thereby boosting the segment market growth.

Asia Pacific: The fastest-growing region in the cell therapy technologies market.

The Asia Pacific market is expected to register the highest CAGR during the forecast period. Some of the major factors contributing to the growth of the Asia Pacific market are low-cost manufacturing advantage, increasing per capita income, and the growing need to curb cancer. In addition, the growth of the geriatric population is also fueling the cell therapy technologies market in the region.

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For more information about this report visit https://www.researchandmarkets.com/r/2wd9fd

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Cell Therapy Technologies Markets, 2027 - Emergence of IPSCs as Alternatives to ESCs & Increased Focus on Personalized Medicine -...

Advancements in immune checkpoint inhibitors (ICIs) have revolutionized oncology therapy.1 Several ICIs targeting PD-1 or PD-L1 are available for the treatment of advanced nonsmall cell lung cancer (NSCLC).1,2 However, there remains a need for alternative treatments due to ICI resistance, failure to respond to therapy, or disease relapse.2-5 Even when ICIs are used in combination with chemotherapy, patients may experience cancer progression within 12 months.6 Oncology providers should identify opportunities for clinical trials and investigational strategies that provide options for patients with advanced NSCLC beyond ICIs and biomarker-directed therapies.

Adoptive cell therapy (ACT) is a type of immunotherapy where an individuals immune cells are harvested and expanded to help elicit a tumor-specific, cell-mediated response against cancer cells; it includes chimeric antigen receptor (CAR) T-cell therapy (CAR-T), engineered T cell receptor (TCR)-based T cell (TCR-T) immunotherapy and tumor-infiltrating lymphocytes (TILs).7 The first promising results evaluating the use of autologous (self) TILs in patients with metastatic melanoma were published in 1988, and they sparked further research.7,8

Endogenous TILs

Endogenous TILs are composed of T cells isolated from tumor tissue that can recognize tumor-specific antigens to target and attack cancer cells.9,10 In most cancers, immune infiltrate includes various macrophage subtypes and several different types of T lymphocytes.11 Helper T lymphocytes and cytotoxic T lymphocytes (CTLs) play an important role in identifying cancer cells and arresting their growth.

During tumorigenesis, genetic instability can lead to somatic mutations producing new proteins, or neoantigens, in cancer cells. Neoantigens expressed only in tumor cells are referred to as tumor-specific antigens (TSAs). All T cells, including CTLs, express a unique T-cell receptor (TCR) specific to a single TSA. Major histocompatibility complex molecules present TSAs on the tumor cell surface, which are recognized upon TCR binding. Once tumor cells are recognized as non-self, T-cell activation occurs.12,13 CTLs release cytotoxic granules, which fuse with the target cell membrane. Granulysin and perforin create pores in the cell membrane, allowing granzymes to be released into the cytoplasm. Granzymes then initiate a caspase cascade leading to apoptosis.1,14,15 However, tumor cells can initiate adaptive mechanisms to evade CTL activity, including the production of immunosuppressive cytokines that can impede the antitumor immune response.9,16 Therefore, methods to overcome immune evasion and improve upon TIL-mediated tumor cell destruction have been explored.

Development and Potential Utility of TILs for Treatment of Solid Tumors

As noted above, endogenous TILs possess TCRs with the ability to recognize and destroy tumor cells. Removing TILs from the immunosuppressive tumor environment through tumor excision allows for ex vivo assessment of antitumor activity. Once highly active TILs are identified, they are rapidly expanded to produce billions of activated, tumor-specific T cells, which are then infused back to the host to target and destroy tumor cells (Figure).13 This approach has potential utility for treating a variety of solid tumors, including NSCLC.7,17-19

Addressing Limitations of Current Treatment Strategies

TIL Therapy in Immunologically Cold Tumors

NSCLC tumors are often categorized as immunologically cold, meaning that they have features thought to impede a strong immune response, including the lack of TILs within the tumor microenvironment. This may be due to a lack of tumor antigens, defective recruitment of antigen-presenting cells, lack of T-cell costimulation and activation, and modified production of chemokines and cytokines involved in cell trafficking and activation.6,20 TIL therapy may improve immunological response within the tumor by providing more T cells to mount an attack. Moreover, TIL therapy given in combination with an ICI may help to prevent T-cell inactivation via tumor-mediated mechanisms once they have infiltrated the tumor.4,21

Limitations With Other Adoptive Cell Therapies

ACT methodologies are centered around the manipulation of an individuals own immune cells to generate a tumor-specific, cell-mediated response against cancer.7 However, CAR-T and TCR-T therapies have faced challenges in the treatment of solid tumors, including the lack of stable tumor antigen expression and the need for human leukocyte antigen restriction. Severe and unpredictable toxicities can also occur with CAR-T and TCR-T due to cross-reactivity or trace expression of tumor-associated antigens in healthy cells.22-24 Further, acquired resistance can occur following a clinical response, which may be attributed to deletion or mutation of the target antigen, antigenic heterogeneity, or impaired trafficking.6,24,25

Unlike other ACTs, TILs are composed of polyclonal cells capable of simultaneously recognizing multiple tumor antigens.19 TILs are derived from genetically unmodified host cells, which may reduce the risk for complications from immune-mediated responses. TILs are also capable of targeting truncal neoantigens clonally expressed by a cancer cell, which may reduce the risk of resistance due to deficient target antigen expression.7

Durable Remissions With TIL Therapy

TIL therapy has the potential for durable, complete remissions.26 This partially is due to the transdifferentiation potential and lifespan of memory T cells.6 Such responses have been observed in heavily pretreated patients with metastatic melanoma after disease progression following treatment with chemotherapy, IL-2, antiCTLA-4 monoclonal antibodies, or a combination of these.26 Additionally, durable remissions following TIL therapy have been reported in a variety of other solid tumor types, including cholangiocarcinoma and cervical, colorectal, and breast cancers.27-30

Future Directions

Clinical trials in metastatic melanoma have demonstrated complete and durable responses from TIL therapy, even in patients who progressed on multiple prior therapies, including antiPD-1 agents.31,32 These findings suggest that TIL therapy may be a viable option for patients with PD-1 resistance or in cancers with lower immunogenicity. Observed similarities between NSCLC and melanoma suggest a role for TIL therapy in the treatment of NSCLC and warrant further investigation.

For information regarding advancements in TIL therapy, resources and further information are available from TILs Working Group at https://www.tilsinbreastcancer.org/.

References

1. Raskov H, Orhan A, Christensen JP, Gogenur I. Cytotoxic CD8+ T cells in cancer and cancer immunotherapy. Br J Cancer. 2020;124:359-367. doi:10.1038/s41416-020-01048-4

2. Horvath L, Thienpont B, Zhao L, Wolf D, Pircher A. Overcoming immunotherapy resistance in non-small cell lung cancer (NSCLC) - novel approaches and future outlook.Mol Cancer. 2020;19(1):141. doi:10.1186/s12943-020-01260-z

3. Nowicki TS, Hu-Lieskovan S, Ribas A. Mechanisms of resistance to PD-1 and PD-L1 blockade.Cancer J. 2018;24(1):47-53. doi:10.1097/PPO.0000000000000303

4. Adoptive cell therapy plus checkpoint inhibitors show promise in non-small cell lung cancer. New release. Moffitt Cancer Center. August 12, 2021. Accessed July 29, 2022. https://moffitt.org/newsroom/press-release-archive/adoptive-cell-therapy-plus-checkpoint-inhibitors-show-promise-in-non-small-cell-lung-cancer/

5. Pathak R, Pharaon RR, Mohanty A, Villaflor VM, Salgia R, Massarelli E. Acquired resistance to PD-1/PD-L1 blockade in lung cancer: mechanisms and patterns of failure.Cancers (Basel). 2020;12(12):3851. doi:10.3390/cancers12123851

6. Creelan BC, Wang C, Teer JK, et al. Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung cancer: a phase 1 trial.Nat Med. 2021;27(8):1410-1418. doi:10.1038/s41591-021-01462-y

7. Hulen TM, Chamberlain CA, Svane IM, Met O. ACT up TIL now: the evolution of tumor-infiltrating lymphocytes in adoptive cell therapy for the treatment of solid tumors. Immuno. 2022;1(3):194-211. doi:10.3390/immuno1030012

8. Rosenberg SA, Packard BS, Aebersold PM, et al. Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report.N Engl J Med. 1988;319(25):1676-1680. doi:10.1056/NEJM198812223192527

9. Zur RT, Adler G, Shamalov K, et al. Adoptive T-cell immunotherapy: perfecting self-defenses. In: Klink M, Szulc-Kielbik I, eds. Interaction of Immune and Cancer Cells. Springer International Publishing AG; 2022:253-294.

10. Investigational TIL Therapy. Iovance Biotherapeutics. 2022. Accessed September 8, 2022. https://www.iovance.com/about-til/

11. Linette GP, Carreno BM. Tumor-infiltrating lymphocytes in the checkpoint inhibitor era.Curr Hematol Malig Rep. 2019;14(4):286-291. doi:10.1007/s11899-019-00523-x

12. Zhang Z, Lu M, Qin Y, et al. Neoantigen: a new breakthrough in tumor immunotherapy.Front Immunol. 2021;12:672356. doi:10.3389/fimmu.2021.672356

13. Qin SS, Melucci AD, Chacon AC, Prieto PA. Adoptive T cell therapy for solid tumors: pathway to personalized standard of care.Cells. 2021;10(4):808. doi:10.3390/cells10040808

14. Cullen SP, Brunet M, Martin SJ. Granzymes in cancer and immunity.Cell Death Differ. 2010;17(4):616-623. doi:10.1038/cdd.2009.206

15. Nirmala JG, Lopus M. Cell death mechanisms in eukaryotes.Cell Biol Toxicol. 2020;36(2):145-164. doi:10.1007/s10565-019-09496-2

16. Vinay DS, Ryan EP, Pawelec G, et al. Immune evasion in cancer: mechanistic basis and therapeutic strategies.Semin Cancer Biol. 2015;35(suppl):S185-S198. doi:10.1016/j.semcancer.2015.03.004

17. Sarnaik AA, Hamid O, Khushalani NI, et al. Lifileucel, a tumor-infiltrating lymphocyte therapy, in metastatic melanoma. J Clin Oncol. 2021;39(24):2656-2666. doi:10.1200/JCO.21.00612

18. Restifo NP, Dudley ME, Rosenberg SA. Adoptive immunotherapy for cancer: harnessing the T cell response.Nat Rev Immunol. 2012;12(4):269-281. doi:10.1038/nri3191

19. Wang S, Sun J, Chen K, Ma P, et al. Perspectives of tumor-infiltrating lymphocyte treatment in solid tumors.BMC Med. 2021;19(1):140. doi:10.1186/s12916-021-02006-4

20. Bonaventura P, Shekarian T, Alcazer V, et al. Cold tumors: a therapeutic challenge for immunotherapy.Front Immunol. 2019;10:168. doi:10.3389/fimmu.2019.00168

21. Lanitis E, Dangaj D, Irving M, Coukos G. Mechanisms regulating T-cell infiltration and activity in solid tumors.Ann Oncol. 2017;28(suppl 12):xii18-xii32. doi:10.1093/annonc/mdx238

22. Blumenschein GR, Devarakonda S, Johnson M, et al. Phase I clinical trial evaluating the safety and efficacy of ADP-A2M10 SPEAR T cells in patients with MAGE-A10+advanced non-small cell lung cancer.J Immunother Cancer. 2022;10(1):e003581. doi:10.1136/jitc-2021-003581

23. Duinkerken CW, Rohaan MW, de Weger VA, et al. Sensorineural hearing loss after adoptive cell immunotherapy for melanoma using MART-1 specific T cells: a case report and its pathophysiology.Otol Neurotol. 2019;40(7):e674-e678. doi:10.1097/MAO.0000000000002332

24. Sterner RC, Sterner RM. CAR-T cell therapy: current limitations and potential strategies.Blood Cancer J. 2021;11(4):69. doi:10.1038/s41408-021-00459-7

25. Haas AR, Tanyi JL, O'Hara MH, et al. Phase I study of lentiviral-transduced chimeric antigen receptor-modified T cells recognizing mesothelin in advanced solid cancers.Mol Ther. 2019;27(11):1919-1929. doi:10.1016/j.ymthe.2019.07.015

26. Rosenberg SA, Yang JC, Sherry RM, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy.Clin Cancer Res. 2011;17(13):4550-4557. doi:10.1158/1078-0432.CCR-11-0116

27. Zacharakis N, Chinnasamy H, Black M, et al. Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer.Nat Med. 2018;24(6):724-730. doi:10.1038/s41591-018-0040-8

28. Stevanovi S, Draper LM, Langhan MM, et al. Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumor-infiltrating T cells.J Clin Oncol. 2015;33(14):1543-1550. doi:10.1200/JCO.2014.58.9093

29. Tran E, Robbins PF, Lu YC, et al. T-cell transfer therapy targeting mutant KRAS in cancer.N Engl J Med. 2016;375(23):2255-2262. doi:10.1056/NEJMoa1609279

30. Tran E, Turcotte S, Gros A, et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer.Science. 2014;344(6184):641-645. doi:10.1126/science.1251102

31. Robertson J, Salm M, Dangl M. Adoptive cell therapy with tumour-infiltrating lymphocytes: the emerging importance of clonal neoantigen targets for next-generation products in non-small cell lung cancer.Immunooncol Technol. 2019;3:1-7. doi:10.1016/j.iotech.2019.09.003

32. Dafni U, Michielin O, Lluesma SM, et al. Efficacy of adoptive therapy with tumor-infiltrating lymphocytes and recombinant interleukin-2 in advanced cutaneous melanoma: a systematic review and meta-analysis.Ann Oncol. 2019;30(12):1902-1913. doi:10.1093/annonc/mdz398

Figure. Development Process of TIL Therapy for Solid Tumors13

TIL, tumor-infiltrating lymphocyte.

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TIL Therapy as a Personalized Treatment Strategy for NSCLC - Targeted Oncology

Tessa developing allogeneic off-the-shelf CD30-CAR EBVST cell therapy TT11X targeting relapsed or refractory CD30-positive lymphomas

SINGAPORE, Sept. 14, 2022 (GLOBE NEWSWIRE) -- Tessa Therapeutics Ltd. (Tessa), a clinical-stage cell therapy company developing next-generation cancer treatments for hematological malignancies and solid tumors, today announced that TT11X, the companys allogeneic off-the-shelf CD30.CAR EBVST cell therapy, has been recognized in the Most Promising Off-the-Shelf Therapies category at the Asia-Pacific Cell & Gene Therapy Excellence Awards (ACGTEA) 2022. The ACGTEA 2022 Awards were held in conjunction with the 6th Cell & Gene Therapy World Asia 2022.

TT11X is based on Tessas proprietary CD30.CAR-modified Epstein-Barr virus-specific T-cell (EBVST) platform. This technology was developed following decades-long research by the companys Scientific Co-Founder, Malcolm Brenner, M.D., Ph.D., and researchers at Baylor College of Medicine, into the unique properties of virus specific T-cells (VSTs). These highly specialized T cells have the ability to recognize and kill infected cells while activating other parts of the immune system for a coordinated response. Allogeneic VSTs without any form of genetic modification have demonstrated a strong safety profile and efficacy in early trials with minimal risk of graft rejection and Graft vs Host Disease (GVHD).

Clinical data from an ongoing Phase 1 study (NCT04288726) of TT11X in CD30-positive lymphomas demonstrated a favorable safety profile and encouraging signs of efficacy with clinical responses observed in seven of nine patients, including a complete disappearance of tumors reported in four patients.

We are very excited to be recognized among the innovators in developing off-the-shelf cell therapy technologies and greatly appreciate the ACGTEA 2022 award, Dr. Ivan Horak, Chief Medical Officer and Chief Scientific Officer of Tessa Therapeutics, said. Allogeneic cell therapy technology has the potential to transform the accessibility and affordability of CAR-T, but toxicity concerns remain a key obstacle. Data from our ongoing Phase 1 trial of TT11X suggest that our CD30.CAR EBVST platform has the potential to overcome these toxicity challenges, including GVHD, while also eliciting promising signals of efficacy.

About Tessa Therapeutics Tessa Therapeutics is a clinical-stage biotechnology company developing next-generation cell therapies for the treatment of hematological cancers and solid tumors. Tessas lead clinical asset, TT11, is an autologous CD30-CAR-T therapy currently being investigated as a potential treatment for relapsed or refractory classical Hodgkin lymphoma as both a monotherapy (Phase 2) and combination therapy (Phase 1b). TT11 has been granted RMAT designation by the FDA and access to the PRIME scheme by European Medicine Agency. Tessa is also advancing an allogeneic off-the- shelf cell therapy platform targeting a broad range of cancers in which Epstein Barr Virus Specific T Cells (EBVSTs) are augmented with CD30-CAR. A therapy using this platform is currently the subject of a Phase 1 clinical trial in CD30-positive lymphomas. Tessa has its global headquarters in Singapore, where the company has built a state of the art, commercial cell therapy manufacturing facility. For more information on Tessa, visit http://www.tessacell.com.

Cautionary Note on Forward Looking StatementsThis press release contains forward-looking statements (within the meaning of the Private Securities Litigation Reform Act of 1995, to the fullest extent applicable) including, without limitation, with respect to various regulatory filings or clinical study developments of the Company. You can identify these statements by the fact that they use words such as anticipate, estimate, expect, project, intend, plan, believe, target, may, assume or similar expressions. Any forward-looking statements in this press release are based on managements current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation, those related to the Companys financial results, the ability to raise capital, dependence on strategic partnerships and licensees, the applicability of patents and proprietary technology, the timing for completion of the clinical trials of its product candidates, whether and when, if at all, the Companys product candidates will receive marketing approval, and competition from other biopharmaceutical companies. The Company cautions you not to place undue reliance on any forward-looking statements, which speak only as of the date they are made, and disclaims any obligation to publicly update or revise any such statements to reflect any change in expectations or in events, conditions or circumstances on which any such statements may be based, or that may affect the likelihood that actual results will differ from those set forth in the forward-looking statements. Any forward-looking statements contained in this press release represent the Companys views only as of the date hereof and should not be relied upon as representing its views as of any subsequent date. The Companys products are expressly for investigational use pursuant to a relevant investigational device exemption granted by the U.S. Food & Drug Administration, or equivalent competent body.

Tessa Therapeutics Investor Contact

Wilson W. CheungChief Financial Officerwcheung@tessacell.com

Tessa Therapeutics Media Contact

Tiberend Strategic Advisors, Inc.Bill Borden+1-732-910-1620bborden@tiberend.com

Dave Schemelia+1-609-468-9325dschemelia@tiberend.com

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Tessa Therapeutics Recognized in Most Promising Off-the-Shelf Therapies Category at Asia-Pacific Cell & Gene Therapy Excellence Awards 2022 -...

Clinical trial outcomes

Previously we reported the safety and efficacy of interim results of the trial (61 patients)24. Here after completion of the trial, 99 patients with relapsed/refractory multiple myeloma (r/r MM) were included (Fig.1a). The primary outcome was to evaluate the safety of BCMA CAR-T cells in the treatment of r/r MM. All patients were evaluated for safety analysis. Cytokine release syndrome (CRS) was observed in 97% (96/99) patients, including 50 (52.1%) patients with grades 12 CRS, 42 (43.8%) and 4 (4.1%) with grades 3 and 4 CRS. None grade 5 CRS occurred. The neurotoxicities were reported for 11 patients (11.1%), of whom 10 (10.1%) and 1 (1.0%) had grade 1 and grade 2 events, no grade 3 or higher neurotoxic effect was observed. After treatment, all episodes of CRS and neurotoxicity were resolved. The secondary outcome was to evaluate the efficacy and characterization of BCMA CAR-T cells in the treatment of r/r MM. Within 1 month after BCMA CAR-T cell infusion, 1 patient died of cerebral hemorrhage and 3 died of severe infections. Of the 95 remained patients, 91 (95.8%) had an overall response. In all, 55.8% (53/95), 15.8% (15/95), and 24.2% (23/95) of patients achieved a complete remission (CR), very good partial response (VGPR), or partial response (PR), respectively. With a median follow-up time of 21.2 months (95% CI, 18.432.1), the median progression free survival (PFS) was 12.2 (95% CI, 9.115.7) months. The 1-year OS and PFS rates were 0.71 (95% CI, 0.620.81) and 0.51 (95% CI, 0.420.62), respectively. BCMA CAR-T cells expanded dramatically in vivo. The BCMA CAR-T/CD3+ T-cell percentages in peripheral blood (PB) peaked on day 11 (range: 531) after CAR-T cell infusion. The median BCMA CAR-T/CD3+ T-cell percentages was 81.95% (range: 6.0797.30%).

a Patient enrollment. b AntiBCMA single-chain variable fragment (scFv), a hinge and transmembrane regions, and 4-1BB costimulatory moiety, and CD3 T-cell activation domain. c Blood and fecal sample collection. d Clinical response; CRS grade distribution in 43 r/r MM patients. e Numbers of BCMA CAR-T cell percentages in PB assessed by FACS in different therapy stages after CAR-T cell infusion and serum concentrations of IL-10 and IFN- in different therapy stages among the CR (n=24 biologically independent patients), VGPR (n=6 biologically independent patients), and PR (n=11 biologically independent patients) groups. Blue, green, and red colors indicate CR, VGPR, and PR group, respectively. Data are presented as mean valuesSEM. Significance determined by two-sided Kruskal-Wallis test and adjustments were made for multiple comparison. P values for CAR-T percent in PB, serum IL-10 and IFN- between CR and PR groups in CRSb stage were 0.004, 0.048, 0.085, respectively. *p<0.05, **p<0.01. f Body temperature and serum concentrations of IL-6 and IFN- in different therapy stages among CRS grade groups. (Grade 1 CRS group: n=8 biologically independent patients, Grade 2 CRS group: n=16 biologically independent patients, and Grade 3 CRS group: n=19 biologically independent patients). Data are presented as mean valuesSEM. Significance determined by two-sided Kruskal-Wallis test and adjustments were made for multiple comparison. P values for serum IL-6 and IFN- between Grade 1 CRS and Grade 3 CRS were 0.002 and 0.006, respectively. *p<0.05, **p<0.01. g Representative MM patients with impressive antimyeloma response. Positron emission tomography-computed tomography scans before and 5 months after CAR-T cell treatment showing complete elimination of large number of MM bone metastases. Before receiving CAR-T cell infusion, 43.5% of bone marrow cells of the patient were plasma cells, but after 1.5 months of infusion, dramatic eradication of MM from the bone marrow was observed; and MM cells became undetectable by flow cytometry. The bar indicates a length of 5m.

Microbiome samples were not available from 12 patients and 16S sequencing depth was not sufficient for analysis on 6 patients. Finally, a total of 81 patients with r/r MM was included for gut microbiome analysis, which included 43 patients for experiment group and 38 patients for validation group (Fig.1a). Number of samples collected, and sequencing depth were summarized in Supplementary Data12. Clinical and sequencing information of patients used in the study are presented in Supplementary Table3 and Supplementary Data3.

The median age of the MM patients was 59 (range 3975) years, and 55.8% were male (Table1). The median number of prior lines of therapy was 4 (range 28), with all receiving proteasome inhibitor therapy and 95.3% immunomodulatory agents. At enrollment, 39.5% had received autologous stem cell transplantation, and 55.8% had extramedullary disease(s).

Three months after infusion of a median dose of 4.4106/kg (range 1.26.9106/kg) of BCMA CAR-T cells, 55.8%, 14%, and 25.5% of patients had a CR, VGPR, or PR, respectively. All 43 MM patients showed CRS, grade 1 in 8 patients (18.6%), grade 2 in 16 (37.2%), and grade 3 in 19 (44.2%). No higher grade was observed (Fig.1d). The CRS was fully controlled and managed for all patients. Of these patients, 24 received only supportive care, 6 received supportive care plus tocilizumab treatment (IL-6 receptor-blocking monoclonal antibody), 10 received supportive care and corticosteroid treatment, and 3 received supportive care accompanied with tocilizumab and corticosteroids treatment. The antibiotics used before or during treatment were -lactam (41 patients), Carbapenems (26 patients), Quinolone (26 patients), Aminoglycosides (1 patient), Macrolide (1 patient), Tetracyclines (4 patients), Cephalosporins (3 patients), and Glycopeptides (6 patients). Although we included age, gender, number of prior lines of therapy, CAR-T cell dose, autologous stem cell transplantation, antibiotic use before or during treatment as covariates into our analyses, no significant differences were observed among different efficacy groups or CRS grade groups (Supplementary Tables12). Two patients died: one from sepsis caused by Pseudomonas aeruginosa and the other from intracranial hemorrhage (Fig.1d). Both the BCMA CAR-T/CD3+ T-cell percentages in peripheral blood (PB) and serum concentrations of interleukin (IL)10 increased during CRS and differed significantly in the CR and PR groups (Fig.1e). Patients temperature and C-reactive protein (CRP), ferritin, and lactic dehydrogenase (LDH) concentrations were elevated, and IL-6 and IFN- concentrations were significantly different in grade 3 vs grade 1 CRS (Fig.1f and Supplementary Fig.1ac). The serum immunoglobulins (IgG, IgA) and immunoglobulin and light chain concentrations decreased dramatically after CAR-T (Supplementary Fig.1df). Figure1g shows the differences of positron emission tomographycomputed tomography (PET-CT) scans and plasma cells detected by Wrights stain of a bone marrow smear (43.5% vs. 0), as well as flow cytometry (68.9% vs. 0) of bone marrow cells before and after CAR-T infusion for a representative subject.

To detect changes in the gut microbiota during CAR-Ttherapy, we collected fecal samples from each patient at five times (FCa, FCb, CRSa, CRSb, and CRSc; Fig.1c), where FCa denotes the baseline before chemotherapy; FCb after chemotherapy; CRSa after CAR T-cell infusion but before the onset of CRS; and CRSb and CRScdenote the peak and during the recovery phase of CRS, respectively. The median date of FCa was 4 days(range 27) before CAR-T cell infusion in MM patients, the median date of FCb was 0 days(range 07) before CAR-T cell infusion, and the median dates of CRSa, CRSb, CRSc after CAR-T cell infusion were 2days (range 15.3), 6days (range 2.517.4), and 14days (range 837.5), respectively.

We first evaluated the diversity of the gut microbiota in all subjects during CAR-T cell therapy in MM patients. Compared with early stage, there was a significant decrease in diversity (measured by the Shannon index) after the CAR-T therapy (Fig.2a). This decrease was observed in the microbiome of patients receiving CAR-T therapy for r/r ALL (Supplementary Fig.4a) or r/r NHL (Supplementary Fig.4b). Refer to Supplementary Table3 for details on the characteristics of r/r B-ALL and B-NHL patients. In addition, we analyzed diversity change in an independent MM sample with 38 patients included and found a decreased Shannon index along different therapy stages (Supplementary Fig.4c). To further assess the similarity of composition between different therapy stages, we performed pairwise Spearman correlation analysis of operational taxonomic unit (OTU) level bacterial abundance (Fig.2b) and found that stronger correlations emerged during the early stages with a value of 0.71, 0.73, and 0.68, respectively, at FCa, FCb, and CRSa. Correlations between late stages (CRSb and CRSc) and early stages were weaker, suggesting that changes in microbiome composition might be related to CRS.

a Shannon diversity indices of gut microbiome across CAR-T stages in all myeloma patients. Differential tests by Friedmans tests and two-tailed Wilcoxon rank-sum tests for 10 pairwise comparisons of the five timepoints (n=14). Bonferroni correction was applied for multiple testing; *FDR<0.05, **FDR<0.01. For FCa versus CRSc, adjusted p=0.023; FCb versus CRSc, adjusted p=0.009; CRSa versus CRSc, adjusted p=0.017. Boxplots indicate the median (thick bar), first and third quartiles (lower and upper bounds of the box, respectively), lowest and highest data value within 1.5 times the interquartile range (lower and upper bounds of the whisker). b Pairwise Spearman correlation of OTU-level bacterial abundance across different timepoints. Rho value for each significant correlation is labeled inside box. c Stacked bar plot of mean phylum-level phylogenetic composition of bacterial taxa in myeloma patients across different therapy stages. d Significant features identified by longitudinal analysis in Qiime2 feature-volatility plugin to identify taxonomic features associated with therapy stages. Scatter plot shows importance and average change of each important features by the longitudinal analysis. Genus-level features are labeled in the figure. Genus identified by both longitudinal analysis in Qiime2 and maSigPro are bolded and underlined. e Bar plot in the left shows significantly changed genera across the therapy identified by Friedmans tests (FDR<0.05, n=14). Effect size was estimated by Kendalls W Test. Heatmap in the right side denotes difference of each genus between two therapy stages. Red represents significant enrichment while blue represents significant depletion of the genus in the posterior stage comprising with the anterior stage. Significant p values were labeled in the boxes. Significances by two-tailed Wilcoxon rank-sum tests with FDR correction.

We next explored community structure and temporal shift of bacterial abundance at multiple taxonomic levels during CAR-T therapy. In these myeloma patients, bacterial communities were dominated by Firmicutes and Bacteroidetes at the phylum level (Fig.2c). Abundance of Firmicutes increased but that of Bacteroidetes decreased at later stages compared with the baseline (Wilcoxon rank-sum test, p<0.05, Supplementary Fig.4d). By applying the longitudinal analysis in the Qiime2 microbiome analysis platform, we detected changes in the gut microbial communities at taxonomic levels from phylum to genus (Fig.2d and Supplementary Data3). We further employed a negative binominal (NB) regression model-based time-course analysis to identify genera with significant temporal changes (Supplementary Data4). Five genera were detected by both Qiime2 and maSigPro procedures, which included increases in Enterococcus, Lactobacillus, and Actinomyces and decreases in Bifidobacterium and Lachnospira (bolded genera in Fig.2d). Most changes were aggravated during the late stages (Supplementary Fig.4e). Additionally, for repeated measure data (Subjects=10), we applied Friedmans test and found nine genera affected significantly by CAR-T therapy among which the genus Enterococcus had the largest difference between stages (Fig.2e).

Moreover, by checking changes in the five genera in ALL and NHL patients, we observed consistent shift trends in NHL (two genera; Supplementary Fig.4f) and ALL (four genera; Supplementary Fig.4g), respectively. These results were further verified in another independent MM sample, showing that CAR-T therapy correlated significantly with decreased Shannon diversity (Supplementary Fig.4c) and increased abundance of genus Enterococcus and Actinomyces (Supplementary Fig.4h).

We next determined whether microbial compositions or changes were associated with the response to CAR-Ttherapy. Because we wanted to identify maximum differences and only six subjects presented in the VGPR group, we performed comparisons only between the CR and PR groups.

In MM patients, notable differences in microbial alpha and within-sample diversity were observed in patients with CR and PR at CRSb stage (Fig.3a, b). Although no differences were detected at baseline, PR patients descended more dramatically in alpha diversity and had significantly lower Shannon indices than CR patients after CAR-T infusion (Fig.3a). As the degree of differences between CR and PR groups changed across therapeutic stages, we characterized the periods with greater differences by summarizing the amount of CR/PR-enriched OTU at each timepoint. The most pronounced differences occurred at CRSb (Fig.3c).

a Shannon diversity indices of gut microbiome differed between CR and PR groups across CAR-T stages. Significances were assessed by two-sided Wilcoxon rank-sum test (n=35). P values were 0.077, 0.040, 0.036 for FCb, CRSa, and CRSb, respectively. Boxplots indicate the median (thick bar), first and third quartiles (lower and upper bounds of the box, respectively), lowest and highest data value within 1.5 times the interquartile range (lower and upper bounds of the whisker). b Principal coordinate analysis of fecal samples in CRSb stage by response (CR versus PR) using Canberra distance. P value was calculated by PERMANOVA (n=35). c Summary of number of PR or CR-enriched OTUs in different therapy stages. Difference between CR and PR groups was assessed by two-sided Wilcoxon rank-sum test. P value significant cutoff was 0.05 (n=35). d Heatmap for abundance of OTUs with significant temporal differences between CR and PR groups identified by maSigPro (FDR<0.05). Rows denote bacterial OTUs grouped into three sets according to regression coefficients and sorted by mean abundance within each set. Individual fecal samples were organized in columns and grouped by therapy stages. Columns in the blue and red dashed box show abundance and longitudinal changes of these OTUs in CR and PR groups across the five timepoints. Color of the heatmap is proportional to OTU abundance (red indicates higher abundance and blue indicates lower abundance). e Profiles of significant gene clusters correspond to d. Solid lines denote median profile of abundance of OTUs within cluster for each experimental group through time. Fitted curve of each group is displayed as dotted line. f Phylogenetic composition of OTUs within each cluster in d at phylum and order levels.

To explore longitudinal differences between CR and PR across all therapeutic stages, we identified OTU features with differential dynamic profiles by applying negative binominal regression-based time-course differential analysis with the maSigPro package. In total, 125 OTUs were found to have differential time-course patterns between CR and PR patients (Fig.3d and Supplementary Data5). The significant OTUs were further grouped into three clusters according to profiles of their abundance. Most of these OTUs were in clusters 1 and 2 (Fig.3e). Cluster 1, characterized by enrichment in the CR group, was comprised mainly of OTUs, which belong to the phyla Firmicutes and Bacteroidetes and the orders Clostridiales and Bacteroidales. Cluster 2 was comprised of OTUs from a broader taxonomy, which included the orders Clostridiales, Bacteroidales, Lactobacillales, and Actinomycetales (Fig.3f).

In genus level, we identified 30 genera with differential time-course patterns in MM patients with CR and PR (Fig.4a left panel, Supplementary Data6). To explore these differences further, we divided the therapeutic period into before and after CAR-T infusion and performed genus-level class comparisons using linear discriminant analysis (LDA) of effect size (LEfSe)25 and generalized linear-mixed model (Fig.4a middle and right panel). Consistent with the results from OTU-level pattern analysis, most of the significant genera such as Faecalibacterium, Roseburia, and Ruminococcus were enriched in CR patients after CAR-T. The genera Bifidobacterium, Prevotella, Sutterella, Oscillospira, Paraprevotella, and Collinsella had a higher abundance in CR versus PR patients both before and after CAR-T (Fig.4a and Supplementary Fig.5a). We also took patients with VGPR into consideration and analyzed the above-mentioned genera before and after CAR-T infusion. The bacterial abundance in VGPR patients fell somewhere between CR and PR patients, but no statistical significance was evident for most of genera (Fig.4b and Supplementary Fig.5b).

a Differentially abundant genera between CR and PR group. Bubble plot in the left represents p values by maSigPro. Bar plots in the middle and right show significances and coefficients by generalized linear-mixed models (GLMMs) before and after CAR-T infusion (n=35). Blue bars indicate significant enrichment in CR group while red bars indicate significant enrichment in PR group (FDR<0.05). Red stars marked genera that was identified to be differentially abundant by linear discriminant analysis (p<0.05 for KruskalWallis H statistic and LDA score >2). P values by linear discriminant analysis for Sutterella, Collinsella, Paraprevotella, Bifidobacterium, Anaerotruncus, Prevotella, and Oscillospira before CAR-T were 0.0017, 0.0014, 0.038, 0.0015, 0.0064, 0.030, and 0.006, respectively; P values by linear discriminant analysis for Sutterella, Collinsella, Paraprevotella, Bifidobacterium, Anaerotruncus, Prevotella, Oscillospira, Faecalibacterium, Gemmiger, Clostridium, Odoribacter, Roseburia, Dialister, Enhydrobacter, Ruminococcus, and Dorea after CAR-T were 0.00012, 0.00076, 0.0060, 0.0.0067, 0.042, 0.0049, 0.011, 0.00017, 0.0035, 0.0058, 0.0073, 0.0013, 0.000038, 0.021, 0.0056, and 0.017, respectively. b Mean bacterial abundance [log2 (percentage+1)] of CR, VGPR, and PR myeloma patents before and after CAR-T cell infusion (n=43). Red stars indicate significant difference between CR and PR group by all three methods in panel a. P values for Sutterella by maSigPro were 1.17e-06, by generalized linear-mixed model were 7.86e-12 and 1.51e-14 before and after CAR-T, by linear discriminant analysis were 0.0017 and 0.00012 before and after CAR-T, respectively; P values for Faecalibacterium by maSigPro were 0.0093, by generalized linear-mixed model and linear discriminant analysis were 1.22e-10 and 0.00017 after CAR-T, respectively; P values for Bifidobacterium by maSigPro were 2.19e-06, by generalized linear-mixed model were 5.67e-08 and 1.51e-08 before and after CAR-T, by linear discriminant analysis were 0.0015 and 0.0067 before and after CAR-T, respectively; P values for Ruminococcus by maSigPro were 1.49e-08, by generalized linear-mixed model and linear discriminant analysis were 0.00031 and 0.0056 after CAR-T, respectively. c Relative abundance [log2 (percentage+1)] of top discriminative signatures at baseline (FCa) timepoint identified by RF feature selection procedure (n=35). Genera with highest scores of mean decreases in Gini were selected. Importance scores in RF classification model and fold-change levels in log2 scale are noted below plot for each genus. Blue and red colors indicate CR and PR group, respectively. d Same as panel c for post-chemotherapy (FCb) timepoint (n=35). Only signatures enriched in CR patents are displayed. Those depleted in CR patents are displayed in Fig. S2C. e Receiver operating characteristic (ROC) curve of RF model using discriminatory genera as predictors for baseline timepoint. f Same as panel e for post-chemotherapy timepoint. g KaplanMeier (KM) plot of PFS curves by log-rank test for patients with high (dark blue), median (green), or low (red) abundance of Sutterella. Abundance of genus Sutterella was in terms of median abundance of all timepoints. Boxplots indicate the median (thick bar), first and third quartiles (lower and upper bounds of the box, respectively), lowest and highest data value within 1.5 times the interquartile range (lower and upper bounds of the whisker).

To explore whether early bacterial abundance was indicative of therapeutic response, we used RF feature selection to identify key discriminatory genera for responses26. By defining the stages before CAR-T infusion as early, we applied feature selection procedures individually at both baseline (FCa) and post-chemotherapy (FCb) and identified gut microbiome signatures comprising 8 and 14 discriminatory genera separately for baseline and post-chemotherapy (Fig.4c, d and Supplementary Fig.5c). The area under the receiver operating characteristic curve (ROC) of the two RF models using these discriminatory features was 0.73 and 0.85, respectively (Fig.4e, f). Prevotella, Collinsella, Bifidobacterium, and Sutterella were enriched in CR versus PR both before and after CAR-T infusion and were identified by RF analysis as significant at baseline and post-chemotherapy. This indicates potential associations between these genera and the response to CAR-T.

We also checked the abundance of these genera in r/r NHL and ALL patients. In NHL, Faecalibacterium, Bifidobacterium, and Ruminococcus were significantly (or almost significantly) enriched in CR versus PR and in patients not having a remission (NR), consistent with our results in myeloma (Supplementary Fig.5e). However, for ALL, we observed enrichment of Bifidobacterium, Roseburia, and Collinsella in NR (Supplementary Fig.5f), which differed from the results for MM and NHL but might be determined by the small NR sample.

In the independent 38 validation MM patients, no significance of Shannon diversity was observed between CR and PR (Supplementary Fig.5g). Given that genus Sutterella, Prevotella, Collinsella, and Bifidobacterium were detected to be significant by both differential analysis and RF analysis at baseline and post-chemotherapy, we then examined abundance of these significantly changed bacteria of interest in an independent 38 MM validation sample. We found that abundance of genera Sutterella and Prevotella were higher in CR group than that in non-CR group at multiple stages. No significance was observed for Collinsella and Bifidobacterium (Supplementary Fig.5d).

To further demonstrate the association between these taxa and outcome, we assessed PFS following CAR-T therapy. By stratifying patients by tertile of bacterial abundance, we observed that for Sutterella, patients in the highest-abundance tertile had significantly prolonged PFS (Fig.4g). Even after stratification by timepoints, this association remained significant (Supplementary Fig.6a). However, for genus Faecalibacterium, which was reported to be significantly associated with PFS and anti-PD-1 therapy19, we did not observe an association (Supplementary Fig.6b, c).

Manifestations of severe CRS, namely high fever and greater amounts of cytokines, typically develop within several days after CAR-T cell infusion and may cause death if untreated27. We scaled CRS from level 1 to 528. To analyze associations between bacterial communities associated with CRS, we compared patients with severe (level 3) versus mild (level 1) CRS and severe and moderate CRS (level 2) in MM patients. We found 146 OTUs with different time patterns in the severe and mild groups (Supplementary Fig.7 and Supplementary Data7), and 99 OTUs with different patterns in the severe and moderate CRS groups (Supplementary Fig.8 and Supplementary Data8). The profiles of the OTU clusters for the comparisons were similar, with OTUs in clusters 1 and 3 having a higher abundance during late therapy in patients with severe versus mild CRS (Supplementary Figs.7b and 8b).

By analyzing associations between CRS grade and taxa at the genus level, we identified signatures discriminating severe from mild CRS, including decreases in amount of Bifidobacterium and Leuconostoc in patients with severe CRS (Fig.5a and Supplementary Data9). Bifidobacterium was increased in patients with worse CRS, not only during the window of CRS, but also at early stages (Fig.5a, b). Leuconostoc was significantly enriched during the window in patients with high CRS grade (Fig.5a, b). In the 38 validation MM patients, no significance was observed for Bifidobacterium or Leuconostoc among different CRS grade groups (Supplementary Fig.9).

a Correlation of differentially abundant genera with CRSgrade. Bubble plot in the left shows significant genera between severe and mild CRS groups by maSigPro (n=27). Bar plots in the middle and right show significances and coefficients by generalized linear-mixed models (GLMMs) before and during CRS. Orange bars indicate positive correlation with CRS. Green bars indicate negative correlation. Red stars marked genera that was identified to be differentially abundant by linear discriminant analysis (p<0.05 for Kruskal-Wallis H statistic and LDA score >2). P values by linear discriminant analysis for Bifidobacterium and Butyricicoccus before CAR-T were 0.003 and 0.027, respectively; P values by linear discriminant analysis for Leuconostoc, Bifidobacterium, Lactococcus, and Enhydrobacter after CAR-T were 0.016, 0.029, 0.0029, and 0.037, respectively. b Mean bacterial abundance in MM patients with different CRS grades before and during occurrence of CRS (n=43). Red stars indicate significant difference between Grade 1 CRS and Grade 3 CRS group by all three methods in panel a. P values for Bifidobacterium by maSigPro was 8.9e-08, by generalized linear-mixed model were 9.75e-06 and 1.42e-08 before and after CAR-T, by linear discriminant analysis were 0.003 and 0.029 before and after CAR-T, respectively; P values for Leuconostoc by maSigPro was 1.29e-14, by generalized linear-mixed model and linear discriminant analysis were 3.14e-11 and 0.016 after CAR-T, respectively. Boxplots indicate the median (thick bar), first and third quartiles (lower and upper bounds of the box, respectively), lowest and highest data value within 1.5 times the interquartile range (lower and upper bounds of the whisker). c Network representing correlations between gut microbes (gray nodes), immune cells and inflammatory markers (green nodes) at FDR<0.05. Correlations were measured by repeated measure correlation analysis (rmcorr). Red edges indicate positive correlations and blue edges negative correlations. Edge width is proportional to correlation coefficient () calculated by Spearman correlation test. Only genera identified as associated with clinical response and CRS grade were included in correlation analysis. d Top 2 positive and negative correlations in repeated measure correlation analysis. Data are presented as meanSEM.

To determine if gut microbial functions correlated with CAR-T therapy, we first inferred community function of MM patients using Phylogenetic Investigation of Communities by Reconstruction of Unobserved State (PICRUSt2). By applying time-course differential analysis, we identified differential pathways related to fatty acid metabolism, glutathione metabolism, quinone biosynthesis and glycan degradation (Supplementary Fig.10) in the MM cohort. Further, we compared pathways across different CRS groups. Microbial function of fecal samples from patients with severe CRS had high metabolism or biosynthesis related to inflammatory compounds, including several pathways associated with phosphonate and its metabolism, amino acid metabolism, lipoic acid metabolism, amino sugar, and nucleotide sugar metabolism and antibiotic synthesis (Supplementary Fig.11).

Likewise, we performed differential analysis of PICRUSt2 predicted functions in the 38 validation MM cohort. Comparing PR with CR, differential pathways concerning glutamate (d-Glutamine and d-glutamate metabolism), glycan (Glycan biosynthesis and metabolism), arginine, proline (d-Arginine and d-ornithine metabolism, Arginine and proline metabolism) and phenylalanine (phenylpropanoid biosynthesis) were revealed (Supplementary Fig.12a), among which the pathways related to glutamate and phenylalanine metabolism were endorsed in differential analysis of predicted KEGG pathways between PR and CR groups in the discovery MM sample (Supplementary Fig.10a). Lipopolysaccharide and steroid biosynthesis pathways were also consistently found to be differ between the CR and PR group by differential analysis of predicted pathways (Supplementary Fig.10a) and metabolites (Supplementary Fig.12a). Referring to the CRS grade-related pathway, difference in glycerolipid metabolism pathway was reproducible detected in both the discovery (Supplementary Fig.11a) and validation MM samples (Supplementary Fig.12c).

In addition, we applied metabolic Liquid Chromatography Mass Spectrometry (LC-MS) to quantify concentration of fecal metabolites during CRS. Intermediates (Choline, l-Cysteine, S-Sulfo-l-cysteine, Rosmarinic acid, l-Phenylalanine, and 2-Phenylacetamide) involved in multiple amino acid metabolism pathways were differentially abundant between CP and PR group when during CRS (p-value<0.05). We also identified metabolites concerning phosphonate and phosphonate metabolism (Bialaphos) and steroid biosynthesis (Desoxycortone) to be differ between CR and PR (Supplementary Fig.13). In differential analysis between CRS groups, we identified phosphocreatine which annotated to arginine and proline metabolism (Supplementary Fig.14). Moreover, three abovementioned pathways (i.e., tyrosine metabolism, phenylalanine metabolism, phosphonate, and phosphonate metabolism) were also indicated to have differentially abundances between the CR and PR group in the predicted pathway analysis (Supplementary Fig.10). Two pathways (tyrosine metabolism and phenylalanine metabolism) were also differed among patients with different CRS grades (Supplementary Fig.11). Additionally, we performed pathway enrichment analysis of differentially abundant metabolites between the CR and PR subjects to reveal distinction on metabolic functions (Supplementary Fig.15a). Two pathways (Phenylalanine, tyrosine and tryptophan biosynthesis; Riboflavin metabolism) reached marginal significance (p=0.07). These concordant findings strengthened the results of functional prediction analysis and highlighted the importance of amino acid metabolism during the CAR-T therapy.

Primary inflammatory markers of CRS are cytokines, such as IL-6, IL-2, IL-10, interferon gamma (IFN-), and tumor necrosis factor- (TNF-). Various cytokines are elevated in the serum of patients experiencing CRS after CAR-T cell infusion29. By assessing serum cytokine concentrations and immune cell numbers during CAR-T, we observed significantly increased amounts of serum inflammatory cytokines (IL-6, CRP, IFN-, D-dimer, ferritin) but low numbers of immune cells (monocytes, lymphocytes, neutrophils, leukocytes) in severe CRS (Fig.5c). We also compared serum cytokine concentrations and immune cell numbers in CR and PR, observing significant differences for many of them (see Supplementary Fig.16).

To explore further associations between the gut microbiome and CRS during CAR-T therapy, we determined whether serum cytokine concentrations and numbers of PB immune cells correlated with the abundance of gut microorganisms (Fig.5d). By assessing common within-individual correlation for repeated measures30, we constructed correlation network between gut microbes, cytokines, and immune cells (Fig.5c). The top significant correlation pairs were MCP-1 and Lactobacillus, lymphocyte and Clostridium, IL-15 and Lactobacillus, leukocyte and Veillonella (Fig.5d). In addition, serum level of lymphocyte was negatively correlated with 11 genera, including multiple genera related to CRS level such as Bifidobacterium, Butyricimona and Oscillospira. M1 and M2 macrophages, which play a key role in CRS initiation, did not show significant correlation with any microbes.

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AP Top Stories September 12 A

Here's the latest for Monday September 12th: Blackouts in Ukraine after power stations attacked; Queen Elizabeth II mourned in Scotland; Devastating floods in Pakistan; California wildfire growing.

AP

The 10th annual Blood, Sweat & Tears run will take place on Sept. 24 after taking a pause during the COVID-19 pandemic.

Participants have the option to run or walk through a 5-mile, 10-mile or 5K course. All courses begin and end at the same line on Timber Road. Proceeds from the run will benefit the Emily Whitehead Foundation, dedicated to raising awareness and funding less-toxic cures for childhood cancer.

The organization supports families fighting childhood cancer and connects them to clinical trials for CAR T-Cell therapy, the life-saving treatment that Emily Whitehead received 10 years ago during her battle with leukemia.

This years run will also honor the memory of Mike McCauley, an ultramarathoner who ran the Blood, Sweat & Tears event and worked closely with the Emily Whitehead Foundation to raise awareness of pediatric cancer.

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Snitz Creek Restoration: North Cornwall Township chair slams watershed association for threats of protest

Emily Whitehead was only 5 years old when she was first diagnosed with cancer. She initially received treatment at Hershey Medical Center. After exhausting all treatment possibilities and relapsing twice, doctors only gave her weeks to live.

Tom and Kari Whitehead, Emilys parents, refused to give up and began researching more unconventional means of treatment.

They discovered that the Childrens Hospital of Philadelphia was conducting a clinical trial for CAR T-Cell therapy, a treatment involving the collection of a patients T-Cells, reprogramming them, and infusing them back into the body.

Emily became the first pediatric patient in the world to receive CAR T-Cell therapy. Since then, she has received national media attention, including a full-length documentary titled "Of Medicine and Miracles," which debuted at the Tribeca Film Festival earlier this year.

The attention has allowed for the Whiteheads to help families in similar circumstances in getting in any support they need, including connecting them with clinical trials for the T-Cell Therapy.

T-Cell Therapy is currently only available to patients with certain kinds of cancer, who have run out of treatment options, and often only available through clinical trials. Even with strict accessibility, the treatment has been able to help countless families facing pediatric cancer across the country.

Once such family was the Goras, from Duncannon, whose experience with pediatric cancer mirrored the Whiteheads'.

Every time I watch him, Im just amazed at what the CART team has done for him, Stan Gora said, (They) saved his life, allowed him to grow up and be a boy and do the things we boys did. Every day its a blessing.

Ayden was only 2 years old when he was first diagnosed with leukemia. He spent three years in and out hospitals, spending much of it at Hershey Medical Center. Six months before the end of his treatment, he relapsed.

Thats when the Goras began to explore other treatment options, talking to other parents who had gone through the same thing, and discovered that T-Cell therapy treatments were an option.

It wasnt until his options ran out that we realized like, Oh my gosh, thats us, too,' Stan Gora said. That trial, that type of therapy, is something we might have to rely on, because nothing else is working.

The family visited CHOP to get a second opinion on Aydens condition, which eventually evolved into him participating in the trial. Gora said that while getting things moving on the trial was a bit logistically complex, the process of signing up went smoothly.

Gora said that he spoke with Tom Whitehead for advice on the therapy, on a father-to-father level, because he felt like he was walking into the ordeal blindly.

Because Aydens body had already been put under immense pressure from previous treatments, the doctors warned that recovery after the T-Cells had been re-introduced into his body might be difficult, and once the therapy was done, Ayden had to be placed in the ICU for two weeks.

Our initial response was like, what the hell did we do? Did we do the right thing? Gora said. He was fighting cancer, but now he was maybe still fighting cancer, and now they put him on the ventilator. As a parent, thats kind of scary.

Gora said they experienced a moment of clarity about 30 days after the treatment when Aydens test results came back that the cancer was completely undetectable in his body. They knew that they had made the right choice.

Looking back, Gora clarified that no matter what happened, going through with the treatment was always the right choice, because the alternative was to do nothing.

Ayden begins his first year back to in-school learning since the pandemic and is currently obsessed with hip hop dancing, Gora said.

Hes a little clumsy sometimes, Gora said. Maybe he wouldnt be like that before all this, who knows, but hes growing up.

Registration for the event is available at bloodsweatandtearsfivemiler.weebly.com.

For more information on the course and questions regarding registration, contact Tom Garrett at tgarrett7@msn.com.

More information on the Emily Whitehead Foundation can be found at emilywhiteheadfoundation.org.

Original post:
Blood, Sweat & Tears run returns for its 10th year - Lebanon Daily News

Melissa Barnett, OD, from the University of California, Davis Eye Center, Sacramento and Davis, CA, described new strategies, technologies, and drug classes to treat chronic conditions that include myopia, Demodex infestation, meibomian gland dysfunction, glaucoma drug delivery, advancements in corneal and cataract surgeries, and presbyopia

Every medical breakthrough in history was born through research, and eyecare is at the zenith of research today. Melissa Barnett, OD, from the University of California, Davis Eye Center, Sacramento and Davis, CA, described new strategies, technologies, and drug classes to treat chronic conditions that include myopia, Demodex infestation, meibomian gland dysfunction, glaucoma drug delivery, advancements in corneal and cataract surgeries, and presbyopia. Here are some of the highlights.

Currently, a record-breaking number of myopia cases are being diagnosed, and patients have several different treatment options to choose from that include spectacle multifocals, contact lens multifocals, MiSight soft lenses (CooperVision), and Ortho-K lenses (Euclid).

Atropine drops and atropine derivatives are another approach being tested that work by reducing the progression of myopia.

This ectoparasite, the most common one in humans, has a prevalence rate of 100% in patients 70 years and older. The current treatmenttea tree oil at a concentration of 100%has the most rapid kill time compared to all other treatments that include 100% caraway oil, 100% alcohol, 10% povidone-iodine, and 4% pilocarpine. The most common side effects associated with tea tree oil are burning and stinging. The oil also is associated with the risk of corneal damage.

Topical and oral ivermectin also can be used to treat Desmodex. The topical form in conjunction with daily eyelid scrubs was more effective than lid hygiene alone.

This is associated with most cases of dry eye. The current treatments are meibomian gland obstruction, anti-inflammatories, and mechanical devices.

Two drugs, minocycline (Meizuvo, Hovione) showed a positive clinical effect in almost three-quarters of clinical trial patients and perfluorohexyloctane (NOV03, Novaliq) prevented excessive tear evaporation and helps restore tear film balance.

The push in glaucoma therapy is the development of alternative drug delivery systems to conventional drops.

Microdose latanoprost (Eyenovia) is currently under evaluation in a phase 2 trial. Using the microdose design, substantial intraocular pressure reductions were observed as with conventional drops; however, the big advantage is that this approach is associated with a 75% reduction in drugs and preservatives, which cause toxicity of the ocular surface.

Punctal plug delivery systems deliver both latanoprost (Evolute, Mati Therapeutics)and travoprost (OTX-TP, Ocular Therapeutix) and are promising for glaucoma and ocular hypertension and are minimally invasive.

An intracanalicular insert is bioresorbable and provides sustained-release of preservative-free travoprost.

Bimatoprost SR (Durysta, Allergan) is an FDA-approved 10-microgram bimatoprost sustained-release implant for patients with open-angle glaucoma and ocular hypertension.

The travoprost intraocular implant (iDose, Glaukos) is positioned in the anterior chamber and anchored behind the trabecular meshwork. The 36-month data showed superior IOP-lowering capability in higher percentages of patients compared with timolol.

Travoprost intracameral implant (OTX-TIC, Ocular Therapeutix) is a bioresorbable sustained-release implant injected into the anterior chamber.It currently is in a phase 1 prospective clinical trial.

Omidenepag Isopropyl (Eybelis, OMDI), is a new topical glaucoma medication that is a selective, non-prostaglandin, prostanoid EP2 receptor, that has the advantage of no prostaglandin side effects. The drug is currently in the phase 3 AYAME Study.

Descemetorhexis without endothelial keratoplasty is a procedure in which Descemets membrane is removed but not followed by endothelial transplantation to treat Fuchs dystrophy. Surgical candidates include those with central guttae and a clear peripheral cornea. The procedure is controversial but may cause fewer adverse events compared with Descemet membrane endothelial keratoplasty. The recovery time is a mean of 3 months.

IOTA cell therapy (Aurion Biotech) is an injectable corneal endothelial cell therapy that may have the potential to restore sight in some patients.

A new treatment for neurotrophic keratitis, dHGF (deleted form of hepatocyte growth factor) (CSB-001, Claris Biotherapy), is being evaluated. The technology, which is an anti-fibrotic, neurotrophic, and anti-inflammatory, accelerates healing of the affected corneal tissue.

Cataract care advancements include more sophisticated intraocular lens (IOL) trifocal technology, a Light Adjustable lens (RxSight), modular IOL systems, small aperture lens designs, and accommodating IOLs (Juvene, LensGen; FluidVision PowerVision/Alcon; and Lumina, Akkolens International).

A couple of drugs are being developed to address presbyopia, i.e., phentolamine ophthalmic solution 0.75% that inhibits the iris dilator muscle; the drug, instilled at night, results in moderate pupil reduction, and low-dose pilocarpine (0.4%) a daytime drop that works on the sphincter and ciliary muscle.

Other novel technologies under development include contact lenses for drug delivery to treat seasonal allergic conjunctivitis (Johnson & Johnson Vision with etafilcon A contact lenses with 0.019 mg ketotifen), latanoprost and prostaglandins for glaucoma (Leo Lens) and dexamethasone for inflammation, and anti-inflammatory and antibiotic agents (OcuMedic ).

Scleral lenses are useful for treating persistent epithelial defects, corneal infiltrates, corneal neovascularization, and chemical burns.

Originally posted here:
Eye care therapies on the move: What's in the pipeline - Optometry Times

This week: Kyverna Therapeutics appoints new Senior Vice President, Nucleus Biologics obtains ISO 13485:2016 Certification for manufacture and distribution of cell and gene therapy media, rare pediatric disease designation granted to iECUREs investigational gene editing product candidate for OTC deficiency and construction completed on Sheffield Gene Therapy Innovation and Manufacturing Centre.

The cell therapy company focusing on regenerative treatment of serious autoimmune diseases, Kyverna Therapeutics (CA, USA),has appointed Tom Van Blarcom as Senior Vice President, Head of Research. Kyvernas therapeutic platform utilizes advanced T-cell engineering and synthetic biology techniques to suppress and eliminate the autoreactive immune cells responsible for inflammatory and autoimmune diseases.

President and CEO of Kyverna, Dominic Borie stated, We are excited to welcome Tom to the Kyverna team. His broad experience in cell therapy research across a wide range of diseases will be invaluable in supporting our work developing engineered T-cell therapies for the treatment of autoimmune diseases. Toms leadership and extensive industry experience will be a critical pillar of our company as we advance our Regulatory T-cell platform and CAR-T programs to achieve our mission of bringing curative living medicines to life to free patients from the siege of autoimmune disease.

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Nucleus Biologics (CA, USA) announced that it has received an ISO 13485:2016 certification from the British Standards Institution (London, UK) for the manufacture and distribution of media for the cell and gene therapy industry. ISO 13485 is the industry standard for quality management systems regulating medical devices and associated services and ensures that the design, development and production of a product consistently fulfils customer and regulatory requirements.

David Sheehan, CEO and Founder of Nucleus Biologics acknowledged, This milestone is the result of years of effort to extend our leadership in custom cell culture media for the cell and gene therapy market. Now, therapy developers have one partner that can offer everything from formulation development support to cGMP 2,000-liter media manufacturing all governed by strict adherence to the ISO 13485 level quality system. Our history of product innovations, quality and collaborations will only expand as we help our customers speed the time from discovery to cure.

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iECURE (PA, USA) reported that the US FDA has granted rare pediatric disease designation to GTP-506 for treatment of Ornithine Transcarbamylase (OTC) deficiency, the most common urea cycle disorder. iECURE is a gene editing company developing mutation-agnostic in vivo gene insertion therapies to treat liver disorders with significant unmet need. GTP-506 is a potential single dose dual vector gene editing product candidate, designed to restore metabolic function through cleavage of the PCSK9 gene locus and insertion of a functional OTC gene into the cleavage site.

Joe Truitt, CEO of iECURE stated, Receiving Rare Pediatric Disease Designation for GTP-506 for the treatment of OTC deficiency highlights the dire need for new treatment options for this devastating pediatric disease. GTP-506 is a potentially transformative therapy for babies born with OTC deficiency and we expect to file an investigational new drug application with the FDA for our first-in-human clinical trial in mid-2023.

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The University of Sheffield (UK) announced the completion of construction for The Sheffield Gene Therapy Innovation and Manufacturing Centre (GTIMC). The state-of-the-art center will provide translational and regulatory support in conjunction with training and skills programs in good manufacturing practice. The GTIMC is one of three innovative centers in a new 18 million network funded by LifeArc (London, UK) and the Medical Research Council (London, UK), with support from the Biotechnology and Biological Sciences Research Council (Swindon, UK).

Mimoun Azzouz, Director of the GTIMC and Chair of Translational Neuroscience at the University of Sheffield stated, Sheffield has emerged as one of the leading players in cell and gene therapy and this national network of partners, facilities and training programs will allow us to stay at the cutting edge of translational discoveries for new and potentially life changing treatments. Seeing the construction work completed is an exciting milestone for the team. It brings us closer to being fully operational and able to progress new and exciting discoveries, which will benefit patients and families worldwide.

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Original post:
Cell therapy weekly: Kyverna Therapeutics appoints new Senior Vice President - RegMedNet