Phase 1 Trial of P-PSMA-101 CAR-T Cells in Patients with Metastatic Castration Resistant Prostate Cancer (mCRPC).

Acute Kidney Injury After the CAR-T Therapy Tisagenlecleucel

CAR T-cell therapy for solid tumours

Safety and Antitumor Effects of CD19-Specific Autologous Chimeric Antigen Receptor-Modified T (CAR-T) Cells Expressing the Inducible Caspase 9 Safety Switch (iC9-CAR19 T Cells) in Adult Acute Lymphoblastic Leukemia (ALL)

primary analysis of Phase ib trial of duvelisib for cytokine release syndrome prophylaxis in patients undergoing chimeric antigen receptor T cell therapy for non-hodgkins lymphoma

Promoter usage regulating the surface density of CAR molecules may modulate the kinetics of CAR-T cells in vivo

Efficacy and Safety of P-Bcma-101 CAR-T Cells in Patients with Relapsed/Refractory (r/r) Multiple Myeloma (MM)

On-target off-tumor toxicity, cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS) are severe immune-related adverse events (irAEs) that are frequently associated with Chimeric Antigen Receptor (CAR) T-cell therapy. Current efforts to manage such therapy-related toxicities involve incorporation of an inducible suicide agent within CAR constructs, such as iCaspase-9 or herpes simplex virus type 1 thymidine kinase that can be selectively activated to produce toxic effects within CAR T cells and attenuate their activity. However, while activation of these agents helps to mitigate or overcome such unwarranted toxicities, the therapeutic benefit of CAR T cells anti-tumor activity is also compromised. Therefore, to continue maintenance of CAR T cells’ therapeutic function while minimizing irAEs, an ideal safety switch should 1) rapidly inhibit the activation and proliferation of CAR T cells exposed to the target antigen, 2) reversibly inhibit activity without inducing CAR T cell elimination and 3) be clinically translatable for safe application in patients. Our laboratory investigated one such safety switch to inhibit CAR T-cell activity while maintaining their therapeutic function. We showed that incorporating a mutant variant of c-KIT D816V (KITv) in the intracellular domain of mesothelin-targeting second-generation CAR T cells (M28z-KITv) improved efficacy in solid tumors with low antigen, or an immunosuppressive environment. Herein, we evaluate the use of Dasatinib, a clinically available multitarget (BCR, SRC, c-KIT) tyrosine kinase inhibitor (TKI), as a tunable safety switch to reversibly inhibit M28z-KITv CAR T-cell functional activity. In cohorts of mice established with lung adenocarcinoma, daily administration of Dasatinib starting on day 1 or day 3 after CAR T-cell administration stabilized tumor growth, which otherwise continued to regress in untreated mice, indicating inhibition of CAR T-cell functional activity. Upon discontinuation of Dasatinib, tumors regressed, indicating reversal of CAR T-cell functional activity. In an experiment conducted to investigate functional persistence of CAR T cells upon long-term exposure to Dasatinib (1 month), we noted uninhibited activity of CAR T cells to rechallenged tumors. Dasatinib, thus may act as a tunable safety switch to regulate M28z-KITv CAR T-cell activity without compromising its therapeutic function. Citation Format: Kyohei Misawa, Meriem Taleb, Srijita Banerjee, William-Ray Vista, Navin K. Chintala, Prasad S. Adusumilli. A tunable safety switch for solid tumor CAR T-cell therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3993.

CD7 chimeric antigen receptor T cells for relapsed/refractory T-cell lymphomas: Single-arm, open-label, phase I study

Cytokine Release Syndrome (CRS) Is Not Required for CAR-T Cell Efficacy in Aggressive Large B-NHL

Incidence of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), infections and cardiovascular events across different chimeric antigen receptor (CAR) T-cell therapy products in large B-cell lymphoma (DLBCL): A nationwide analysis

CLL-1 chimeric antigen receptor T-cells for the treatment of Acute Myeloid Leukemia: A phase 1 clinical trial

A Multi-Omic Single-Cell Landscape of Cytokine Release Syndrome in Multiple Myeloma Patients after Anti-BCMA CAR-T Cell Therapy

Real-time interleukin-6 (IL-6) kinetics predict cytokine release syndrome (CRS) in patients receiving chimeric antigen receptor (CAR) T-cell therapy for Relapsed/Refractory B-cell malignancies

Auto Hematopoietic Stem Cell Transplantation Combined with Another Target Humanized CAR-T Cells for Refractory/Relapsed B-Cell Non-Hodgkin Lymphoma after Failure of Murinized CD19-CAR-T Therapy

B-cell maturation antigen chimeric antigen receptor T-cell re-expansion in a patient with myeloma following salvage programmed cell death protein 1 inhibitor-based combination therapy.