Clinical investigation to improve efficacy of CAR-T Cell Therapy for Large B Cell Lymphoma
Frederick Locke
MDH. Lee Moffitt Cancer Center & Research Institute
Project Term: January 1, 2021 - December 31, 2025
We are investigating new interventions that could improve the effectiveness of CAR T-cell therapy for lymphoma. A clinical trial will test radiation immediately followed by CAR-T. Larger lymphoma tumors are less likely to respond to CAR-T and we expect that radiation could reduce the amount of tumor, leading to improvement in responses. We will also conduct a series of trials to determine the effectiveness of vaccinations before and after CAR T cell therapy, and if anti-cancer vaccines could improve outcomes.
The overall goal of this project is to improve the efficacy of Chimeric Antigen Receptor (CAR) T cell therapy in Large B cell Lymphoma (LBCL). CAR T cell therapy involves removing the patient’s T cells from their blood and then inserting the CAR gene into the T cells in the laboratory. These CAR T cells are reprogrammed to target a protein called CD19 on the surface of all the LBCL tumor cells. After manufacture, the CAR T cells are infused into the patient’s vein, like a blood transfusion, and they seek out and destroy LBCL. There are now several CD19-directed CAR T cell therapies approved for treatment of LBCL, including the first called axicabtagene ciloleucel (axi-cel). We were instrumental in the pivotal international multicenter clinical trial that led to FDA approval of axi-cel. Complete responses at 2 years were seen in 58% of patients resistant to chemotherapy. Alternatively, additional chemotherapy would have instead led to a complete response in <10% of these patients. However, 60% of patients do not achieve durable responses. We hypothesize that clinical interventions prior to axi-cel infusion can safely increase the number of patients that have long term remissions. First, we will prospectively evaluate the impact of radiation therapy (XRT) prior to axi-cel. Our preliminary data reveal that 1) high volume of tumor, quantified by PET scan, is associated with decreased likelihood of long-term remission following axi-cel and 2) mathematical modeling and in silico testing predict that reduction in tumor size using XRT will reduce relapses before day 180. We will determine if XRT overcomes the poor prognosis of patients with large LBCL tumors and validate the predictive capacity of our mathematical modeling. Second, we will test if induction of anti-tumor immunity by vaccination against a tumor antigen augments axi-cel efficacy. Our preliminary data show that 1) pre-existing anti-tumor immunity against tumor antigens is associated with response to axi-cel and 2) a Moffitt-created vaccine safely amplifies T cell responses against a tumor antigen called “surviving.” We will verify the optimal timing of vaccination before and after axi-cel to safely induce immune responses. Laboratory studies will determine if axi-cel therapy imparts a ‘vaccine effect’ and if relapsing tumors evolve to evade this immune response.