Vaccination of AML patients with leukemia cells fused to dendritic cells (AML/DC vaccine) has been shown to induce leukemia-specific T cell responses in peripheral blood. To test the effect of checkpoint blockade following vaccine, Stroopinsky et al. used a murine AML model. Mice treated with checkpoint blockade alone had modestly prolonged survival, while vaccine alone prevented tumor growth in a subset of mice. Combination therapy resulted in 100% survival, protective memory responses, expanded tumor reactive T cells, and enhanced diversity and clonal expansion of TCRs. Clinical studies have been initiated using PD-1 blockade in combination with AML/DC vaccine.
Contributed by Margot O’Toole
ABSTRACT: We have developed a personalized vaccine whereby patient derived leukemia cells are fused to autologous dendritic cells, evoking a polyclonal T cell response against shared and neo-antigens. We postulated that the dendritic cell (DC)/AML fusion vaccine would demonstrate synergy with checkpoint blockade by expanding tumor antigen specific lymphocytes that would provide a critical substrate for checkpoint blockade mediated activation. Using an immunocompetent murine leukemia model, we examined the immunologic response and therapeutic efficacy of vaccination in conjunction with checkpoint blockade with respect to leukemia engraftment, disease burden, survival and the induction of tumor specific immunity. Mice treated with checkpoint blockade alone had rapid leukemia progression and demonstrated only a modest extension of survival. Vaccination with DC/AML fusions resulted in the expansion of tumor specific lymphocytes and disease eradication in a subset of animals, while the combination of vaccination and checkpoint blockade induced a fully protective tumor specific immune response in all treated animals. Vaccination followed by checkpoint blockade resulted in upregulation of genes regulating activation and proliferation in memory and effector T cells. Long term survivors exhibited increased T cell clonal diversity and were resistant to subsequent tumor challenge. The combined DC/AML fusion vaccine and checkpoint blockade treatment offers unique synergy inducing the durable activation of leukemia specific immunity, protection from lethal tumor challenge and the selective expansion of tumor reactive clones.
Author Info: (1) Beth Israel Deaconess Medical Center, Harvard Medical School. dstroopi@bidmc.harvard.edu. (2) Beth Israel Deaconess Medical Center, Harvard Medical School. (3) Beth Israel Deac
Author Info: (1) Beth Israel Deaconess Medical Center, Harvard Medical School. dstroopi@bidmc.harvard.edu. (2) Beth Israel Deaconess Medical Center, Harvard Medical School. (3) Beth Israel Deaconess Medical Center, Harvard Medical School. (4) Beth Israel Deaconess Medical Center, Harvard Medical School. (5) Beth Israel Deaconess Medical Center, Harvard Medical School. (6) Beth Israel Deaconess Medical Center, Harvard Medical School. (7) Beth Israel Deaconess Medical Center, Harvard Medical School. (8) Beth Israel Deaconess Medical Center, Harvard Medical School. (9) Beth Israel Deaconess Medical Center, Harvard Medical School. (10) Beth Israel Deaconess Medical Center, Harvard Medical School. (11) Beth Israel Deaconess Medical Center, Harvard Medical School. (12) Beth Israel Deaconess Medical Center, Harvard Medical School. (13) Beth Israel Deaconess Medical Center, Harvard Medical School. (14) Beth Israel Deaconess Medical Center, Harvard Medical School. (15) Beth Israel Deaconess Medical Center, Harvard Medical School. (16) Beth Israel Deaconess Medical Center, Harvard Medical School. (17) Beth Israel Deaconess Medical Center, Harvard Medical School. (18) Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School. (19) Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School. (20) Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School. (21) Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School. (22) Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School. (23) Beth Israel Deaconess Medical Center, Harvard Medical School. (24) Beth Israel Deaconess Medical Center, Harvard Medical School.
