Potentiating T Cell Activity Against Multiple Myeloma Through SUMOylation Inhibition
Abstract
This proposal addresses the fiscal year 2022 (FY22) Peer Reviewed Cancer Research Program (PRCRP) Topic Area of Myeloma and the FY22 PRCRP Military Health Focus Areas of Environmental exposure risk factors associated with cancer and Gaps in cancer research that may affect mission readiness. Multiple myeloma (MM), the second most common blood cancer, is characterized by abnormal growth of a type of white blood cells, called plasma cells, in the bone marrow. In the United States, more than 34,470 new patients are expected to be diagnosed with MM in 2022, and more than 12,640 patients will die of the disease. MM is currently incurable, and the survival rate is low: around 55% of patients survive for 5 years after the cancer is found. For patients for whom all other treatments have failed, chimeric antigen receptor (CAR) T cell therapy remains a last promising option that may offer hope. CAR T cells are manufactured by harvesting T cells from a patient, inserting a gene for a specific receptor into their T cells, which reprograms the cells to recognize and kill cancer cells, and infusing them back into the patient like a blood transfusion. CAR T cell therapy has shown impressive results for treating MM. We have tested two types of CAR T cells that have been reprogrammed to target proteins called B-cell maturation antigen (BCMA) or CS1 on the surface of MM cancer cells. Although CAR T therapy is quite effective, less than half of treated patients achieve long-term responses. Thus, there is an urgent need to improve CAR T cell therapy. We have shown that inhibiting SUMOylation, a process of protein modification inside cells, is a novel therapy with the potential to address this need. We found a Small Ubiquitin-like MOdifier (SUMO) inhibitor drug called TAK-981, which effectively killed MM in mouse models of the disease. TAK-981 could kill MM cancer cells directly and could kill MM cancer cells indirectly by promoting immune cells to kill MM. Specifically, TAK-981 helped normal T cells function better and prevented T cell exhaustion. T cell exhaustion is a loss of T cell immune function, which is a major barrier for improving CAR T cell therapy. Our data also showed that TAK-981 treatment enhanced the ability of BCMA-CAR T and CS1-CAR T cells to kill MM cells grown in the laboratory. More importantly, TAK-981 strengthened CS1-CAR T cell MM killing in a mouse model of MM, and mice treated with TAK-981 + CS-1 CAR T cells lived significantly longer than mice treated with CS1-CAR T cells alone. Based on our promising preliminary data, we hypothesize that inhibiting SUMOylation improves the ability of CAR T cells to kill MM cancer cells by enhancing CAR T function and preventing exhaustion. We will: (1) Measure the ability of TAK-981 + CAR T cells to kill MM cells grown in the laboratory and in a mouse model made with human tumor cells from a patient with MM, and assess safety of the drug in the mice; (2) Inhibit SUMOylation during CAR T cell manufacturing and measure how much it improves the function of CAR T cells. We expect our study to show that SUMOylation inhibition improves CAR T cell killing of MM and to reveal the cellular mechanisms that cause this effect. BCMA-CAR T cells are a U.S. Food and Drug Administration-approved therapy for MM treatment. CS1-CAR T cells were developed by our team and are currently in a phase 1 trial, and TAK-981 is in a phase 1/2 clinical trial for MM patients; thus, all three treatments have sufficient safety and efficacy clinical information. Our study will build new combination therapies (TAK-981+BCMA-CAR T and TAK-981+CS1-CAR T) with the potential for rapid translation into MM clinical in the near-term. We expect to achieve a patient-related outcome in 2-3 years. Our new combination therapy will be used for patients with relapsing MM who have failed all other treatments. Because SUMOylation inhibition can prevent CAR T exhaustion and strengthen CAR T function, patien
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310658
Entities
People
- Steven D. Rosen
Organizations
- Beckman Research Institute of City of Hope
- United States Army