CAR T cells and checkpoint inhibition for the treatment of glioblastoma

Immune-based treatment strategies, such as checkpoint inhibition and chimeric antigen receptor (CAR) T cells, have started a new frontier for treatment in non-Hodgkin lymphoma (NHL). Checkpoint inhibition has been most successful in Hodgkin lymphoma, where higher expression of PD-L1 is correlated with better overall response rate. Combinations of checkpoint inhibition with various chemotherapy or biologics are in clinical trials, with initially promising results and manageable safety profiles. CAR T-cell therapies that target CD19 are a promising and attractive therapy for B-cell NHLs, with a product approved by the US Food and Drug Administration in 2017. Changes in the target, hinge, or costimulatory domain can dramatically alter the persistence and efficacy of the CAR T cells. The ZUMA trials from Kite used CD19-(CD28z) CAR T cells, whereas the TRANSCEND studies from Juno and the JULIET studies from Novartis used CD19-(4-1BBz) CARs. Despite the recent successes with CAR T-cell clinical trials, major concerns associated with this therapy include cytokine release syndrome, potential neurotoxicities, B-cell aplasia, loss of tumor antigen leading to relapse, and cost and accessibility of the treatment. Although first-generation CAR T-cell therapies have failed in solid malignancies, newer second- and third-generation CAR T cells that target antigens other than CD19 (such as mesothelin or B-cell maturation antigen) are being studied in clinical trials for treatment of lung cancer or multiple myeloma. Overall, immune-based treatment strategies have given oncologists and patients hope when there used to be none, as well as a new basket of tools yet to come with further research and development.

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Contextual reprogramming of CAR-T cells for treatment of HER2+ cancers

Journal of Translational Medicine ◽

10.1186/s12967-021-03132-6 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Zhifen Yang ◽

Lingyu Li ◽

Ahu Turkoz ◽

Pohan Chen ◽

Rona Harari-Steinfeld ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Growth Factor Receptor ◽

Checkpoint Inhibition ◽

Single Chain ◽

Tev Protease ◽

Car T Cells ◽

Car T

Abstract Background Adoptive transfer of chimeric antigen receptor (CAR)-engineered T cells combined with checkpoint inhibition may prevent T cell exhaustion and improve clinical outcomes. However, the approach is limited by cumulative costs and toxicities. Methods To overcome this drawback, we created a CAR-T (RB-340-1) that unites in one product the two modalities: a CRISPR interference-(CRISPRi) circuit prevents programmed cell death protein 1 (PD-1) expression upon antigen-encounter. RB-340-1 is engineered to express an anti-human epidermal growth factor receptor 2 (HER2) CAR single chain variable fragment (scFv), with CD28 and CD3ζ co-stimulatory domains linked to the tobacco etch virus (TEV) protease and a single guide RNA (sgRNA) targeting the PD-1 transcription start site (TSS). A second constructs includes linker for activation of T cells (LAT) fused to nuclease-deactivated spCas9 (dCas9)-Kruppel-associated box (KRAB) via a TEV-cleavable sequence (TCS). Upon antigen encounter, the LAT-dCas9-KRAB (LdCK) complex is cleaved by TEV allowing targeting of dCas9-KRAB to the PD-1 gene TSS. Results Here, we show that RB-340-1 consistently demonstrated higher production of homeostatic cytokines, enhanced expansion of CAR-T cells in vitro, prolonged in vivo persistence and more efficient suppression of HER2+ FaDu oropharyngeal cancer growth compared to the respective conventional CAR-T cell product. Conclusions As the first application of CRISPRi toward a clinically relevant product, RB-340-1 with the conditional, non-gene editing and reversible suppression promotes CAR-T cells resilience to checkpoint inhibition, and their persistence and effectiveness against HER2-expressing cancer xenografts.

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YIA19-005: Immunotherapy for Prostate Cancer Combining CAR-Engineered T Cells with Targeted Immune Checkpoint Inhibition

Journal of the National Comprehensive Cancer Network ◽

10.6004/jnccn.2018.7213 ◽

2019 ◽

Vol 17 (3.5) ◽

pp. YIA19-005

Author(s):

Saul J. Priceman ◽

Stephen J. Forman ◽

◽

Keyword(s):

Prostate Cancer ◽

T Cells ◽

T Cell ◽

Immune Checkpoint ◽

Antitumor Immunity ◽

Checkpoint Inhibition ◽

Car T Cells ◽

Car T ◽

Engineered T Cells ◽

Checkpoint Receptors

Repairing defects in antitumor immunity has been a longstanding challenge in prostate cancer, and in recent years cellular immunotherapy has emerged as a promising approach for controlling advanced disease. To date, therapies including tumor vaccine and adoptive T-cell immunotherapy have made remarkable headway in solid cancers. Several validated prostate-specific tumor antigens are available as targets for T-cell therapy, including prostate stem cell antigen (PSCA), which is overexpressed in metastatic disease. We are in late-stage preclinical development of PSCA-specific chimeric antigen receptor (CAR)-engineered T cells with plans to initiate a clinical trial early 2019 for the treatment of metastatic castration-resistant prostate cancer. Immune checkpoint pathways, including the programmed cell death protein-1 (PD-1) and the cytotoxic T lymphocyte-associated protein-4 (CTLA4), have emerged as critical drivers of immunosuppression in solid cancers, by limiting both adaptive antitumor immunity as well as adoptive T-cell therapies. Unfortunately in prostate cancer, checkpoint inhibition has led to underwhelming responses, likely due to the low mutational load and immunologically “cold” tumor microenvironment. We hypothesize that antitumor activity of PSCA-CAR T cells will elicit checkpoint pathways that dampen antitumor immune responses and reduce overall clinical outcomes. Herein, we utilize an shRNA approach to knockdown checkpoint receptors as a rational combinatorial strategy that targets checkpoint pathways to improve overall therapy with PSCA-CAR T cells for metastatic prostate cancer. We have successfully developed a multiple shRNA knockdown approach to simultaneously disrupt 3 pathways that may hamper CAR T-cell activity in the tumor. These CAR T cells with shRNA knockdown of checkpoint receptors will be directly compared with checkpoint pathway inhibitor antibody therapies in xenograft models of prostate cancer, with the hope that next generation CARs will resist this break on the immune system in solid tumors.

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