Enhancing CAR T cell therapy for multiple myeloma
Perelman School of Medicine at the University of Pennsylvania
Project Term: July 1, 2019 - June 30, 2024
My overall focus is to improve CAR T cell therapy for multiple myeloma. Our clinical trial uses CAR T cells targeting BCMA as first line therapy for high-risk multiple myeloma to assess whether early use of CAR T cells is safer and more effective than use in patients with relapsed disease. Half of patients will also receive CAR T cells targeting CD19 to assess whether this can improve the duration of response to anti-BCMA CAR T cells. Our goal is to evaluate whether early use of CAR T cells is a safer and more effective way to use CAR T cells for multiple myeloma patients.
Multiple myeloma is generally incurable. New medications developed over the last 20 years have steadily improved survival, but nearly all patients eventually relapse. No therapy has yet been able to break the cycle of serial relapses that leads to treatment-resistant and eventually fatal myeloma complications. Our objective is to develop new treatment approaches utilizing chimeric antigen receptor (CAR) T cells that prevent relapse in patients who respond to standard multiple myeloma therapies. CAR T cell therapy entails harvesting T cells (a type of immune system cell) from patients, genetically modifying them to express a CAR that specifically recognizes a molecule on the surface of the cancer cell, and infusing the modified cells into the patient. The infused cells have the potential to kill cancer cells and provide long-term surveillance against relapse. The FDA has approved CAR T cells targeting CD19 for some blood cancers and patients have achieved long-term remissions and potentially cures in some patients who previously had no curative treatment option. We and others tested CAR T cells targeting the BCMA molecule in patients with relapsed multiple myeloma and in patients who stopped responding to therapy. We found that anti-BCMA CARs are effective in many patients, but most patients eventually relapse after initial responses. We are initiating a clinical trial that tests several new approaches to reduce the risk of relapse after CAR T cell therapy in myeloma patients. First, we will administer CAR T cells to patients who are responding to therapy rather than patients who have relapsed through many therapies; we hypothesize that T cells from these less advanced patients will be healthier and allow production of CAR T cells that can provide more durable immune surveillance against relapse. Second, we will combine anti-BCMA CAR T cells with anti-CD19 CAR T cells; we hypothesize that addition of anti-CD19 CAR T cells will target a minor subset of CD19-expressing myeloma cells that may be important for seeding relapses after response to anti-BCMA CAR T cells. Finally, we will examine whether immune responses against the transcription factor Sox2 can reduce risk of myeloma relapse after CAR therapy. Since prior studies suggest that Sox2 helps myeloma cells regrow after therapy, we aim to develop a new immunotherapy targeting Sox2 that specifically eliminates the myeloma cells responsible for relapse.