EXPERTISE:1) Genomic and Immunological Predisposition to CD20/CD19 Bi-specific CAR T cell Therapy: Bi-specific anti-CD20/CD19 Chimeric Antigen Receptor (CAR, 4-1BB-CD3zLV20.19)-transduced T cell therapy provides an effective approach to treat relapsed and refractory B cell malignancies. Yet a significant number of patients relapse. Specifically, the genetic predisposition that leads to the failure of CAR+ T cell therapy has not been explored. We performed single-cell and bulk RNA sequencing on pre-PBMCs, CAR+ T cell infusion product, recovered CAR+ T cells from patients. We identify a previously unknown insertional mutation in a kinase causing a predisposed condition for the non-responders. We are targeting this kinase to rescue the CAR-T cell functions and augment T cell responses. 2) Sensitizing TME for CAR T cell Therapy in PDAC Patients: Pancreatic adenocarcinoma remains one of the deadliest malignancies. To advance the mechanistic understanding of the immune response, we are evaluating the host immune response in pancreatic cancer and the subsequent changes induced by two different types of radiation therapy. This evaluation will leverage an ongoing Phase II trial at MCW. To identify methods to convert the immunosuppressive TME into pro-immune, we are defining the transcriptomic alterations using single-cell and bulk RNA seq. This work is done in collaboration with Dr. Hall MD, Dept Surgery, MCW.3. Genome instability caused by dysfunctional R-loops as the basis for malignant transformation in Fanconi Anemia Patients: Using WGS, single-cell, and bulk RNA sequencing of FANC-G patients, we have identified a panel of pathogenic mutations. We hypothesize that the locations of these mutations are deterministic and not stochastic. Towards this, we have found a significant concordance between the locations of R-loops and mutations. This work is done in collaboration with Dr. Myers MD, Cincinnati Children’s; Dr. Runaas MD HemOnc, Medicine, MCW; and Dr. Thakar MD, Seattle Children.
Listed skills include Immunology, Cell Culture, Cell Signaling, Cell, and 10 others.
