Improving Bispecific CD20/CD19 CAR T-cell Therapy to Overcome Resistance Mechanisms in B-cell Malignancies
Nirav ShahMD, MSHP
Medical College of Wisconsin
Project Term: July 1, 2022 - June 30, 2027
The objective of this proposal is to improve bispecific anti-CD20/anti-CD19 CAR T-cell activity and persistence by understanding impact of cell manufacturing parameters on final engineered CAR-T product and determining resistance mechanisms in relapsing patients. We will analyze patient apheresis, final CAR-T product, and peripheral blood samples from subjects enrolled on an ongoing clinical trial (NCT04186520). Data from these studies will advance CAR T-cell therapies for lymphoma patients.
Chimeric Antigen Receptor (CAR) modified T-cells are an exciting new form of immunotherapy that involves the genetic modification of one’s own T-cells to redirect them against proteins on cancer cells. This therapy is most advanced in blood cancers, specifically B-cell lymphomas and leukemias, with multiple FDA approved CAR T-cells treatments targeting the CD19 protein now available. For those with relapsed aggressive B-cell lymphoma, anti-CD19 CAR T-cell therapy can achieve a long-term remission in 30-40% of patients. Despite effectiveness, most patients still fail to respond or relapse after administration of CAR T-cells. One proposed mechanism to explain the failure of single targeted CD19 CAR T-cell therapy is that tumors escape CAR T-cells by ridding itself of the CD19 protein.
To address that mechanism of relapse, we initiated a first-in-human trial of dual targeted anti-CD20, anti-CD19 CAR (CAR20.19) T-cells for B-cell malignancies. We hypothesized that targeting multiple antigens on tumor cells could be a more effective approach to minimize tumor antigen escape. Published results from this trial (Shah et al. Nature Medicine Oct 2020) documented a high overall response rate in patients with relapsed B-cell cancers. Notably, among patients who relapsed after CAR20.19 treatment, CD19 loss was not identified, suggesting that dual antigen targeting may inhibit the mechanism of antigen escape. Despite high initial response, relapse of cancer limited the long-term efficacy of this CAR product. To overcome the limitations we identified in this first trial, we launched a follow-up CAR20.19 trial that modifies the manufacturing process to optimize and enhance the final CAR20.19 T-cell product to improve the long-term remission rate. From this trial we plan to analyze the starting material used to make the CAR T-cells, the final product before infusion, and blood samples from the patients after administration to understand differences among long-term responders and non-responders. We are optimistic that through detailed analyses of the starting material and final CAR products we can identify specific mechanisms of treatment failure to dual targeted CAR T-cells and through an iterative process modify our manufacturing process to overcome these limitations and improve patient outcomes. Findings from this study would not only be applicable to those receiving CAR20.19 T-cells but have potential to enhance outcomes for any patient receiving cell therapy.