Acute Myeloid Leukemia (AML) is a lethal hematological malignancy for which standard therapy is rarely curative. We have developed a personalized AML vaccine in which patient derived leukemia cells are fused with autologous DCs such that a broad array of antigens are presented in the context of DC mediated costimulation. The vaccine effectively targets clonal diversity including the LSC compartment and induces responses against neoantigen targets generated from the patient specific mutational events. We are completing a phase II study in which patients with AML who achieve remission following standard therapy undergo serial vaccination with DC/AML fusions. Vaccination resulted in the dramatic expansion of AML specific lymphocytes in the peripheral blood and bone marrow. Remarkably, despite a median age of 60 with predominant intermediate and high risk disease, 75% of patients remain in remission at a median of 4 years of follow up. The goals of the present study are to more fully examine the DCAML fusion vaccine and confirm these dramatic clinical findings in the context of a randomized trial design. A fundamental challenge to developing sustained anti-leukemia immunity and durable disease response is overcoming the immunosuppressive milieu by which tumor cells evade host immunity and re-introduce tolerance. In the present study, we will also examine the potential synergy of vaccine mediated T cell expansion with PDL1 blockade to prevent the reestablishment of tolerance. Each of the treatment arms will be assessed with respect to the expansion of T cells targeting whole AML cells, LSCs, and leukemia associated antigens. Based on analysis of the AML mutational events, a neo-antigen profile will be generated for each patient and their functional relevance will be interrogated by assessing the native immune response following exposure to the whole cell vaccine. To define biomarkers predictive of response, the immune landscape of the bone marrow microenvironment, presence of AML driver mutations, gene signature for LSCs and immunoregulatory pathways, and noncoding RNAs regulating antigen presentation and costimulation will be interrogated with respect to their correlation with immune response and clinical outcome.

Public Health Relevance

In the present study, we will conduct a clinical trial evaluating an autologous DC/AML fusion cell vaccine alone and in combination with an anti-PDL1 antibody, evaluating immune response and 2 year relapse free survival. Based on analysis of the AML mutational events, a neo-antigen profile will be generated for each patient and their functional relevance will be interrogated by assessing the native immune response following exposure to the whole cell vaccine. To define biomarkers predictive of response, the immune landscape of the bone marrow microenvironment, presence of AML driver mutations, and noncoding RNAs regulating antigen presentation and costimulation will be interrogated with respect to their correlation with immune response and clinical outcome.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA212649-02
Application #
9395905
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Merritt, William D
Project Start
2016-12-09
Project End
2021-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215