Adoptive Cellular Therapy of T Cell Lymphoma

项目总结

PROJECT SUMMARY Peripheral T cell lymphomas (PTCL) are a highly heterogeneous group of neoplasms that account for 10-30% of all Non-Hodgkin Lymphomas. Of these, angioimmunoblastic T cell lymphoma (AITL), PTCL NOS (not otherwise specified), and Sezary syndrome (SS) are particularly aggressive with 5-year survivals of <30%. Thus, aggressive chemotherapy, targeted agents and stem cell transplantation have limited efficacy. In fact, as many as 26-59% of patients never even reach transplantation due to early relapse or primary refractoriness. Novel therapies that can cure, or at least subside disease to allow transplant, are urgently needed. AITL and a subset of PTCL NOS share a T-follicular helper cell phenotype, and along with nearly half of SS, they all express the chemokine receptor CXCR5. For AITL, CXCR5 signaling may contribute to its pathogenesis, making it a particularly good target. Chimeric Antigen Receptor (CAR) T cells targeting CD19 have shown remarkable efficacy in treating B cell leukemias and lymphomas. In preliminary work, we have developed a novel Chimeric Antigen Receptor (CAR) that targets CXCR5. Importantly, cytotoxic CD8+ T cells used to express the CXCR5 CAR, are negative for CXCR5 themselves, thus avoiding fratricide. Our central hypothesis is that CXCR5 CART will be highly effective for the treatment of malignant T cell clones in a large subset of patients with PTCL. To test this hypothesis, in aim 1 we will assess the efficacy of our CXCR5 CAR on multiple models of PTCL in vitro, ex vivo, and in vivo. Building upon recent observations that affinity optimization improves CAR activity and reduces side effects, in aim 2 we will compare the efficacy of CXCR5 CARs with a range of affinities. In preliminary work, we have developed a phage screening platform that has identified CXCR5 binders with different affinities. In aim 3 we will test the synergistic cytotoxicity of simultaneously activating the intrinsic pathway of apoptosis with Venetoclax, along with the extrinsic pathway of apoptosis by the CXCR5 CAR. To maximize synergy and protect the CAR-T cells from Venetoclax, we will additionally fortify the CXCR5 CAR T cells with an anti-apoptotic BCL-2 family member. To avoid potential complications of expressing an anti-apoptotic gene in a T cell, it will be introduced in a transient fashion as an mRNA molecule. mRNA reprogramming has numerous advantages over DNA including, among others, the ability to introduce multiple genes in a single rapid step and to carefully calibrate cytotoxicity to the required dose. This study integrates successful approaches from pharmacology, genetics, immunology and apoptosis to develop a novel therapy that could meaningfully improve patient outcomes, through either an improved bridge to transplant or an eventual cure.