Abstract
Engineered T cells that express chimeric antigen receptors (CARs) have been a promising therapy for hematologic malignancies. The optimization of CAR structure using different signaling domains can alter a wide range of CAR-T cell properties, including anti-tumor activity, long-term persistence, and safety. In this study, we developed a novel CAR structure based on KIRS2/Dap12 for B cell acute lymphoblastic leukemia (B-ALL) antigen CD19 and compared the anti-tumor efficacy and safety of this construct in transduced T cells with standard second-generation CAR-T cells targeting CD19 for B-ALL in vitro and in vivo and in adult relapsed/refractory (r/r) B-ALL patients. We discovered that KIRS2/Dap12 receptor infused with 4-1BB co-stimulation domain could enhance anti-tumor efficacy by remarkably increasing the production of pro-inflammatory interleukin-2 (IL-2), especially when co-cultured with antigen-positive tumor cells. In addition, CD19-KIRS2/Dap12-BB CAR-T cells showed the inspiring outcome that complete responses were seen in 4 of 4 (100%) patients without neurotoxicity and a high rate of severe cytokine release syndrome (CRS) after CAR-T infusion in a phase I clinical trial. Given these encouraging findings, CD19-KIRS2/Dap12-BB CAR-T cells are safe and can lead to clinical responses in adult patients with r/r B-ALL, indicating that further assessment of this therapy is warranted.
Highlights
To improve the safety of chimeric antigen receptors (CARs)-transduced T cells, we previously designed a natural multi-chain immunoreceptor CAR based on the DNAX-activating protein of 12 kDa (Dap12) signaling domain for the first time, which triggers antigen-specific cytotoxicity, cytokine production, and proliferation that is comparable with CD3z-based CARs ex vivo/in vitro for hematological malignancies.[9,10]
KIRS2/Dap12-BB CAR-T cells show efficacy in hematological malignancies and solid tumor models We evaluated the anti-tumor cytotoxicity of CD19-KIRS2/ Dap12-BB CAR-T cells compared with CAR-T cells engineered with a CD19-targeted 41BB-based second-generation CAR in Nalm[6] cell-derived xenograft tumors (Figure 3A)
KIRS2/DAP12 receptor with scFv triggered antigen-specific cytotoxicity, cytokine production, and proliferation that is comparable with second-generation CD3z-based CARs in a previous study
Summary
Adoptive T cell therapy (ACT) involves the manufacture of a patient’s T cells followed by infusion of these engineered T cells into the patient with cancer.[1,2] In recent years, chimeric antigen receptor (CAR) T cell immunotherapy, based on the infusion of engineered autologous T cells to recognize the tumor-associated antigens expressed on cancer cells, has changed the modality of treatment for hematological malignancies.[3,4] CAR-T cells targeting CD19 or B cell maturation antigen (BCMA) in treating B cell lymphoma, leukemia, and multiple myeloma have achieved unprecedented response rates.[5,6] Synonymous with the outstanding clinical outcome of CAR-T cell therapy in hematological malignancies have been severe toxicities, including cytokine-release syndrome (CRS), neurotoxicity syndrome, CAR-T cell-related encephalopathy syndrome (CRES), and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS).[7]. Considering the critical importance of co-stimulation for T cell activation and acquisition of effector function, we generated a panel of representative receptors through combining the KIRS2/Dap[12] with costimulatory molecule 41-BB in this study. To determine whether they are able to induce a more controlled T cell response and improved T cell activity, we evaluated functional characterization of diverse KIRS2/ Dap[12] CAR structure and found that KIRS2/Dap12-BB CARconferred T cells enhanced antitumor cytotoxicity and increased cytokine production. A phase I clinical trial using autologous T cells expressing CD19-specific CAR (CD19-KIRS2/Dap12-BB) in adult relapsed/refractory (r/r) B-ALL patients with lymphodepleting chemotherapy was conducted to evaluate the anti-tumor activity and safety of CD19-KIRS2/Dap12-BB CAR-T cells compared with second-generation CAR-T cells targeting CD19
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