Wednesday, April 24, 2024
4/24/2024
Abstract For the last 30 years, the 5-year survival rate of small cell lung cancer (SCLC) has been less than 7% despite the addition of immune checkpoint inhibitors as treatment options. Therapies like immune checkpoint inhibitors that aim to reengage an immune response may not succeed for SCLC as previous studies have shown downregulation of MHC molecules, low PD-L1 expression and limited immune infiltration. However, SCLC is often associated with autoantibody-driven Paraneoplastic Syndromes, providing evidence for the immunogenicity of SCLC. We propose that chimeric antigen receptor T cells (CAR-Ts) as a novel approach for SCLC immunotherapy that overcomes impediments to endogenous immunity. CAR-Ts are synthetically engineered to fuse antibody ligand binding domains with costimulatory components that activate T cells after engagement of cell surface antigens, and have had considerable success in leukemia, lymphoma, and multiple myeloma. The microenvironment of SCLC is phenotypically closer to CAR-T responsive lymphoma than many solid tumors where CAR-Ts have thus far had limited success. A challenge for CAR-T cells in many solid tumors is the identification of target antigens that are tumor-specific. We have identified 13 novel cell surface antigen and here will prioritize 3 with high prevalence in SCLC. Each of these antigens have post-translational modifications that act as neoantigens and lead to autoantibody production in a high percentage of SCLC cases. We will capture these neoantigen-autoantibodies from SCLC patient-derived B cells, sequence the tumor specific binding sequences, and design and test CARs constructed from the single chain variable fragments (scFvs). The benefit of isolating autoantibodies from SCLC patients to detect tumor-specific neoantigens is three-fold: 1. The antigens identified have already proven to be immunogenic; 2. The variable regions of these human autoantibodies can be directly engineered into ligand binding domains of CAR-T cells; and 3. Autoantibodies can be detected in the blood of patients and serve as tissue surrogate biomarkers to guide CAR-T cell target selection. The CAR-T cells we develop will be rigorously tested in multiple preclinical models that address complementary but non-overlapping therapeutic barriers. These include testing CAR-T cell tumor infiltration, efficacy and toxicity in a library of genetically diverse SCLC patient derived xenografts and identifying, then overcoming, immunosuppressive mechanisms in the immune competent Rb/p53 genetically engineered mouse model. Our team of experts in lung cancer, autoantibody biomarkers, immunology and CAR-T cells is well equipped to execute the development of novel immunotherapies that are desperately needed in SCLC.
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