Genotype of immune response inhibitory molecules as predictors of clinical outcome after CAR T-cell therapy: a prospective-multicenter cohort study

Abstract

Background: CAR T-cell therapy represents a breakthrough in cancer treatment as a cell-based emerging immunotherapy with unprecedented success in relapsed or refractory hematological

malignancies such as lymphoma, certain types of leukemia, and multiple myeloma. Patients’ own T- lymphocytes are genetically engineered to express a chimeric antigen receptor to harness and

reactivate cancer antigen-specific recognition in an HLA-unrestricted manner and thus, destroy malignant cells. Current targets are CD19 and BCMA antigens, with 6 approved CAR T-cell products. No evidence exists on biomarkers predictive of clinical response, overall survival, and/or toxicity following CAR T-cells infusion. Polymorphisms identified on the genes encoding for immune inhibitory molecules, – also referred to as checkpoints –, have been described to predispose to cancer development and relapse after allogeneic hematopoietic stem cell transplantation, the current treatment of choice for several hematologic cancers. Despite CAR T-cell therapy’s massive therapeutic potential, significant challenges remain to be overcome for better and broader applications, including unwanted potential toxicity, systemic immunogenicity, slow and complex manufacturing, and high cost. Objectives: To determine if the genotypes of CTLA-4, PD-1, LAG-3, BTLA, and CD200 immune inhibitory checkpoints are associated with the incidence of Cytokine Release Syndrome (CRS) and Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS) and can be predictive of overall survival, disease-free survival, and response after CAR T-cell therapy. Design & Methods: A prospective-multicenter cohort study, framed in the Spanish Group Terapia Avanzada CAR T (TACART), setting up a collection of samples shipped to Girona from authorized CAR T Spanish hospitals. DNA is extracted and stored at the IdIBGi Biobank and genotyping is performed using RT-PCR. Univariate and multivariate analyses are performed. Participants: Patients with aggressive hematological malignancies after ≥ 2 lines of treatment that are candidates to undergo CAR T-cell immunotherapy in Spanish hospitals