Monthly Archives: April 2022

Abstract: Cell signaling induced cell fate determination is central to stem cell and developmental biology. Embryonic stem cells (ESC) are an attractive model for understanding the relationship between cell signaling and cell fates. Cultured mouse ESCs can exist in multiple cell states resembling distinct stages of early embryogenesis, such as Totipotent, Pluripotent, Primed and Primitive Endoderm. The signaling mechanisms regulating the Totipotent state acquisition and coexistence of these states are poorly understood. Here we identify BMP4 as an inducer of the Totipotent state. However, we discovered that BMP4-mediated induction of the Totipotent state is constrained by the cross-activation of FGF, TGF- and WNT pathways. We exploited this finding to enhance the proportion of Totipotent cells in ESCs by rationally inhibiting these cross-activated pathways using small molecules. Single-cell mRNA-sequencing further revealed that induction of the Totipotent state is accompanied by the suppression of both the Primed and Primitive Endoderm states. Furthermore, the reprogrammed Totipotent cells generated in culture have a molecular and functional resemblance to Totipotent cell stages of preimplantation embryos. Our findings reveal a novel BMP4 signaling mechanism in ESCs to regulate multiple cell states, potentially significant for managing stem cell heterogeneity in differentiation and reprogramming.

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Cross-activation of the FGF, TGF- and WNT pathways constrains BMP4-mediated induction of the Totipotent state in mouse embryonic stem cells. -...

This article was originally published here

Stem Cells Transl Med. 2022 Apr 18:szac011. doi: 10.1093/stcltm/szac011. Online ahead of print.

ABSTRACT

No effective therapy exists for the most common long-term side effect of radiation therapy for head and neck cancer (HNC)xerostomia. The objective was to evaluate safety and provide proof of concept for efficacy of allogeneic adipose tissue-derived mesenchymal stem/stromal cells (AT-MSCs) injected into the major salivary glands of irradiated patients. This open-label, first-in-human, phase 1b, and single-center trial was conducted with repeated measurements days 0, 1, 5, and 30 and 4 months. Eligible patients with objective and subjective signs of radiation-induced salivary gland damage after treatment of oropharyngeal squamous cell carcinoma stages I-II (UICC 8) were enrolled. Twenty-five million cryopreserved AT-MSCs were injected into each submandibular and 50 million AT-MSCs into each parotid gland. Data were collected on adverse events, unstimulated and stimulated whole saliva (UWS and SWS) flow rates and saliva composition, patient-reported outcomes (EORTC QLQ-H&N35 and Xerostomia Questionnaire [XQ]), blood samples and salivary gland scintigraphy. Data were analyzed using repeated measures linear mixed models. Ten patients (7 men, 3 women, 59.5 years [range: 45-70]) were treated in 4 glands. No treatment-related serious adverse events occurred. During 4 months, UWS flow rate increased from 0.13 mL/minute at baseline to 0.18 mL/minute with a change of 0.06 (P = .0009) mL/minute. SWS flow rate increased from 0.66 mL/minute at baseline to 0.75 mL/minute with a change of 0.09 (P = .017) mL/minute. XQ summary score decreased by 22.6 units (P = .0004), EORTC QLQ-H&N35 dry mouth domains decreased by 26.7 (P = .0013), sticky saliva 23.3 (P = .0015), and swallowing 10.0 (P = .0016). Our trial suggests treatment of the major salivary glands with allogenic AT-MSCs is safe, warranting confirmation in larger trials.

PMID:35435231 | DOI:10.1093/stcltm/szac011

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Intraglandular Off-the-Shelf Allogeneic Mesenchymal Stem Cell Treatment in Patients with Radiation-Induced Xerostomia: A Safety Study (MESRIX-II) -...

Molecular characteristics associated with resistance to CD19-directed chimeric antigen receptor T-cell therapy for pediatric acute lymphoblastic leukemia can hopefully improve patient selection and eligibility for therapy.

Researchers have identified molecular characteristics associated with resistance to CD19-directed chimeric antigen receptor (CAR) T-cell therapy for pediatric acute lymphoblastic leukemia (ALL), according to data presented at the American Association for Cancer Research 2022 Annual Meeting.1

Investigators observed 3 key features of leukemia cells that do not respond to CAR T-cell therapy: hypermethylation of DNA, a stem cell-like phenotype and inherent plasticity, and decreased antigen presentation. These are independent of CD19 status and leukemia subtype, indicating a new predictive biomarker.

Whats most important about this is we can detect it prior to therapy in patient samples, so this highlights its potential as a biomarker for response, Katherine E. Masih, BS, an NIH-Cambridge scholar in the Genetics Branch, Center for Cancer Research at the National Cancer Institute, said in a press conference. We hope that eventually this can improve patient selection and eligibility for CD19 CAR T-cell therapy.

CD19 is a common target of CAR T cells, and resistance to treatment can occur even if patients continue to show CD19 expression. The investigators explored primary non-response (PNR) to CAR T-cell therapy, which occurs in 10% to 20% of patients and whose causes are not fully understood. Known reasons for non-response to CAR T cells include collection of dysfunctional T cells and decreased death cell receptors on the cell surface.2,3

The investigators used bone marrow samples from 14 participants in the PLAT-02 trial (NCT02028455) of CD19-directed CAR T-cell therapy for relapsed/refractory pediatric ALL.1 These samples included those of 7 patients who had a complete response to therapy and 7 who had no response. Non-response was defined as not achieving and maintaining minimal residual disease negativity at 63 days.

A multiomic analysis of the bone marrow included whole-exome sequencing, RNA sequencing of the bulk cells, single-cell RNA sequencing, array-based methylation analysis, and ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing).

In patients who went on to have PNR, investigators discovered epigenetic markers including 238 regions of hypermethylated DNA, which is associated with inactivated genes (P = 8.15 10-25). These regions are known to be activated in stem cells.

The ATAC-seq analysis showed increased accessibility of chromatin at regions linked to stem cell proliferation (normalized enrichment score [NES] = 2.31; P < .0001) and cell cycling (NES = 2.27; P < .0001), indicating inherent plasticity that may allow leukemia cells to adapt to resist CAR T-cell therapy.

Investigators found that the epigenetic differences did not lead to differences in phenotype of B cells between primary sensitive and PNR patients. However, PNR cells did show an increase in regions associated with hematopoietic stem cells and myeloid and lymphoid progenitors. In addition, investigators observed decreased antigen presentation and processing that could lead to lack of response in cells that still express CD19 (P = .0001).

These factors characterized a potential novel biomarker associated with PNR that investigators named Stem-Cell Epigenome with Multi-Lineage Potential (SCE-MLP). Masih acknowledged that the sample size of 14 patients was small and more research on SCE-MLPs link to PNR is needed. We would love to see this validated in a larger cohort with more cases of PNR that exist around the country, she said.

Another potential use of SCE-MLP could be to find ways to overcome resistance to CAR T-cell therapy by combining it with targeted therapies that disrupt these epigenetic factors for resistance.

Currently, the investigators hope that this research will be used to shape patient selection for CAR T-cell therapy and alternative therapies.

If we can reliably identify responders, perhaps through screening for SCE-MLP, we can prioritize less toxic targeted therapies for our patients and overall improve outcomes for children with this devastating disease, Masih said.

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Epigenetic Biomarker Predicts Resistance to CAR T-Cell Therapy in ALL - Targeted Oncology

Magenta Therapeuticsannounced that it is reducing its workforce by 14% in a revised operating plan to prioritize research and development. The plan also includes reductions in spending related to general and administrative expenses and investments in its research platform.

Changes in Magentas operating procedures stem from its recent success in a Phase I/II targeted conditioning clinical trial of therapeutic MGTA-117. MGTA-117 is Magentas lead targeted conditioning product candidate and is an antibody-drug conjugate (ADC) designed to selectively deplete hematopoietic stem cells (HSCs) from patients.

The drug specifically targets the CD117 receptor, which is highly expressed in HSCs and leukemia cells. By depleting HSCs from patients with certain types of cancers, patients can successfully receive treatment with healthy stem cells or other HSC-based gene therapies designed to eliminate cancers.

Magenta has shared encouraging early data from its trials studying MGTA-117 in patients with relapsed/refractory acute myeloid leukemia and myelodysplasia-excess blasts, a condition in which early forms of blood cells are increased in the bone marrow and blood. Based on preliminary analyses, Magenta has stated that the data suggest early signals of positive pharmacodynamic activity and are well-tolerated amongst patients dosed with no reported drug-related adverse events.

MGTA-117 has the potential to reduce or eliminate the need for high-dose or high-intensity chemotherapeutic agents prior to beginning gene therapy. The company plans to disclose a summary of clinical observations from its initial cohort in May 2022, which areanticipatedto evaluate MGTA-117s ability to selectively target CD117, potently deplete CD117-expressing cells and rapidly clear them from the body with a well-tolerated profile.

Based on Magentas positive experience with MGTA-117 and uncertain capital market environments for biotech companies, the company is deprioritizing other portfolio investments, including certain MGTA-145 investments and planned clinical trials. MGTA-145 is a chemokine receptor 2 (CXCR2) agonist protein developed to enhance stem cell mobilization in sickle cell disease. Clinical data from a Phase II trial of the drug in combination with plerixafor mobilized a sufficient number of stem cells for transplantation in 88% of patients, and all patients had successful engraftment.

Source: BioSpace

We are encouraged by our progress in the MGTA-117 clinical trial and want to proactively address our resource allocation to ensure focus on creating value for patients and all of our stakeholders, Jason Gardner, president and CEO of Magenta Therapeutics, said in a statement. We have the utmost respect and appreciation for our departing employees and their contribution to advancing our programs. The workforce reduction allows the company to extend its cash runway into 2024.

The company also plans to continue pursuing studies surrounding CD45-ADC, which is designed to selectively target and deplete stem cells and lymphocytes in autoimmune and blood cancer patients to avoid the use of chemotherapy prior to stem cell transplant. In March, Magentastatedthat data from a dose-ranging toxicology study of the drug was expected in the second half of 2022.

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Magenta Therapeutics Cuts Workforce by 14%, Shifts Focus to R&D - PharmaLive