Phase I Trial of MCARH109, a G Protein-Coupled Receptor Class C Group 5 Member D (GPRC5D)-Targeted Chimeric Antigen Receptor T-Cell Therapy for Multiple Myeloma: An Updated Analysis.

MCARH109 is a first-in-class G protein-coupled receptor, class C, group 5, member D (GPRC5D)-targeted chimeric antigen receptor (CAR) T-cell therapy for patients with relapsed/refractory multiple myeloma. This phase I clinical trial included 17 patients and determined that MCARH109 is safe at a maximum tolerated dose of 150 × 10 CAR T cells. In this updated analysis, no new serious adverse events were reported at a median follow-up of 37 months.

CD19 CAR T-cell therapy and prophylactic anakinra in relapsed or refractory lymphoma: phase 2 trial interim results.

In preclinical models, anakinra, an IL-1 receptor antagonist (IL-1Ra), reduced immune effector cell-associated neurotoxicity syndrome (ICANS) without compromising anti-CD19 chimeric antigen receptor (CAR) T-cell efficacy. We initiated a phase 2 clinical trial of anakinra in patients with relapsed/refractory large B-cell lymphoma and mantle cell lymphoma treated with commercial anti-CD19 CAR T-cell therapy. Here we report a non-prespecified interim analysis reporting the final results from cohort 1 in which patients received subcutaneous anakinra from day 2 until at least day 10 post-CAR T-cell infusion.

Validation of a High-Sensitivity Assay for Detection of Chimeric Antigen Receptor T-Cell Vectors Using Low-Partition Digital PCR Technology.

Although in vivo engraftment, expansion, and persistence of chimeric antigen receptor (CAR) T cells are pivotal components of treatment efficacy, quantitative monitoring has not been implemented in routine clinical practice. We describe the development and analytical validation of a digital PCR assay for ultrasensitive detection of CAR constructs after treatment, circumventing known technical limitations of low-partitioning platforms. Primers and probes, designed for detection of axicabtagene, brexucabtagene, and Memorial Sloan Kettering CAR constructs, were employed to validate testing on the Bio-Rad digital PCR low-partitioning platform; results were compared with Raindrop, a high-partitioning system, as reference method.

Programming CAR T Cell Tumor Recognition: Tuned Antigen Sensing and Logic Gating.

Unlabelled: The success of chimeric antigen receptor (CAR) T cells targeting B-cell malignancies propelled the field of synthetic immunology and raised hopes to treat solid tumors in a similar fashion. Antigen escape and the paucity of tumor-restricted CAR targets are recognized challenges to fulfilling this prospect. Recent advances in CAR T cell engineering extend the toolbox of chimeric receptors available to calibrate antigen sensitivity and combine receptors to create adapted tumor-sensing T cells.

Unraveling barriers to iPSC-derived CAR-T cell differentiation.

The generation of off-the-shelf CAR-T cells from TiPSCs has been hindered by the difficulty to recapitulate adaptive T cell development and lower therapeutic efficacy compared to peripheral blood CAR-T cells. Ueda et al. address these issues in a triple-engineering strategy, combining optimized CAR expression with cytolytic and persistence enhancements.

Replication competent retrovirus testing (RCR) in the National Gene Vector Biorepository: No evidence of RCR in 1,595 post-treatment peripheral blood samples obtained from 60 clinical trials.

The clinical impact of any therapy requires the product be safe and effective. Gammaretroviral vectors pose several unique risks, including inadvertent exposure to replication competent retrovirus (RCR) that can arise during vector manufacture. The US FDA has required patient monitoring for RCR, and the National Gene Vector Biorepository is an NIH resource that has assisted eligible investigators in meeting this requirement.

GPRC5D-Targeted CAR T Cells for Myeloma.

Background: B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapies have generated responses in patients with advanced myeloma, but relapses are common. G protein-coupled receptor, class C, group 5, member D (GPRC5D) has been identified as an immunotherapeutic target in multiple myeloma. Preclinical studies have shown the efficacy of GPRC5D-targeted CAR T cells, including activity in a BCMA antigen escape model.

Generation of T-cell-receptor-negative CD8αβ-positive CAR T cells from T-cell-derived induced pluripotent stem cells.

The production of autologous T cells expressing a chimaeric antigen receptor (CAR) is time-consuming, costly and occasionally unsuccessful. T-cell-derived induced pluripotent stem cells (TiPS) are a promising source for the generation of 'off-the-shelf' CAR T cells, but the in vitro differentiation of TiPS often yields T cells with suboptimal features. Here we show that the premature expression of the T-cell receptor (TCR) or a constitutively expressed CAR in TiPS promotes the acquisition of an innate phenotype, which can be averted by disabling the TCR and relying on the CAR to drive differentiation.

Gut microbiome correlates of response and toxicity following anti-CD19 CAR T cell therapy.

Anti-CD19 chimeric antigen receptor (CAR) T cell therapy has led to unprecedented responses in patients with high-risk hematologic malignancies. However, up to 60% of patients still experience disease relapse and up to 80% of patients experience CAR-mediated toxicities, such as cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. We investigated the role of the intestinal microbiome on these outcomes in a multicenter study of patients with B cell lymphoma and leukemia.

CD19-directed chimeric antigen receptor T cell therapy in Waldenström macroglobulinemia: a preclinical model and initial clinical experience.

Background: Waldenström macroglobulinemia (WM) is an incurable disease and, while treatable, can develop resistance to available therapies and be fatal. Chimeric antigen receptor (CAR) T cell therapy directed against the CD19 antigen has demonstrated efficacy in relapsed or refractory B lymphoid malignancies, and is now approved for B cell acute lymphoblastic leukemia and certain B cell lymphomas. However, CAR T therapy has not been evaluated for use in WM.

HLA-independent T cell receptors for targeting tumors with low antigen density.

Chimeric antigen receptors (CARs) are receptors for antigen that direct potent immune responses. Tumor escape associated with low target antigen expression is emerging as one potential limitation of their efficacy. Here we edit the TRAC locus in human peripheral blood T cells to engage cell-surface targets through their T cell receptor-CD3 complex reconfigured to utilize the same immunoglobulin heavy and light chains as a matched CAR.

Lentiviral globin gene therapy with reduced-intensity conditioning in adults with β-thalassemia: a phase 1 trial.

β-Thalassemias are inherited anemias that are caused by the absent or insufficient production of the β chain of hemoglobin. Here we report 6-8-year follow-up of four adult patients with transfusion-dependent β-thalassemia who were infused with autologous CD34 cells transduced with the TNS9.3.

Depletion of high-content CD14 cells from apheresis products is critical for successful transduction and expansion of CAR T cells during large-scale cGMP manufacturing.

With the US Food and Drug Administration (FDA) approval of four CD19- and one BCMA-targeted chimeric antigen receptor (CAR) therapy for B cell malignancies, CAR T cell therapy has finally reached the status of a medicinal product. The successful manufacturing of autologous CAR T cell products is a key requirement for this promising treatment modality. By analyzing the composition of 214 apheresis products from 210 subjects across eight disease indications, we found that high CD14 cell content poses a challenge for manufacturing CAR T cells, especially in patients with non-Hodgkin's lymphoma and multiple myeloma caused by the non-specific phagocytosis of the magnetic beads used to activate CD3 T cells.

A Phase I Trial of Regional Mesothelin-Targeted CAR T-cell Therapy in Patients with Malignant Pleural Disease, in Combination with the Anti-PD-1 Agent Pembrolizumab.

Malignant pleural diseases, comprising metastatic lung and breast cancers and malignant pleural mesothelioma (MPM), are aggressive solid tumors with poor therapeutic response. We developed and conducted a first-in-human, phase I study of regionally delivered, autologous, mesothelin-targeted chimeric antigen receptor (CAR) T-cell therapy. Intrapleural administration of 0.

CAR T cells: Building on the CD19 paradigm.

Spearheaded by the therapeutic use of chimeric antigen receptors (CARs) targeting CD19, synthetic immunology has entered the clinical arena. CARs are recombinant receptors for antigen that engage cell surface molecules through the variable region of an antibody and signal through arrayed T-cell activating and costimulatory domains. CARs allow redirection of T-cell cytotoxicity against any antigen of choice, independent of MHC expression.

Preclinical Efficacy and Safety of a Human Embryonic Stem Cell-Derived Midbrain Dopamine Progenitor Product, MSK-DA01.

Parkinson's disease is characterized by the loss of dopaminergic neurons in the substantia nigra leading to disabling deficits. Dopamine neuron grafts may provide a significant therapeutic advance over current therapies. We have generated midbrain dopamine neurons from human embryonic stem cells and manufactured large-scale cryopreserved dopamine progenitors for clinical use.

Toxicity and response after CD19-specific CAR T-cell therapy in pediatric/young adult relapsed/refractory B-ALL.

Chimeric antigen receptor (CAR) T cells have demonstrated clinical benefit in patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We undertook a multicenter clinical trial to determine toxicity, feasibility, and response for this therapy. A total of 25 pediatric/young adult patients (age, 1-22.

CD19 CAR T cells following autologous transplantation in poor-risk relapsed and refractory B-cell non-Hodgkin lymphoma.

High-dose chemotherapy and autologous stem cell transplantation (HDT-ASCT) is the standard of care for relapsed or primary refractory (rel/ref) chemorefractory diffuse large B-cell lymphoma. Only 50% of patients are cured with this approach. We investigated safety and efficacy of CD19-specific chimeric antigen receptor (CAR) T cells administered following HDT-ASCT.

BCMA-Targeted CAR T-cell Therapy plus Radiotherapy for the Treatment of Refractory Myeloma Reveals Potential Synergy.

We present a case of a patient with multiply relapsed, refractory myeloma whose clinical course showed evidence of a synergistic abscopal-like response to chimeric antigen receptor (CAR) T-cell therapy and localized radiotherapy (XRT). Shortly after receiving B-cell maturation antigen (BCMA)-targeted CAR T-cell therapy, the patient required urgent high-dose steroids and XRT for spinal cord compression. Despite the steroids, the patient had a durable systemic response that could not be attributed to XRT alone.