Acute myelogenous leukemia (AML) arises from leukemia stem cells that serve as a reservoir for disease relapse. A promising area of investigation is the development of immunotherapeutic approaches that stimulate the immune system to eliminate leukemia stem cells. We have developed a cancer vaccine in which dendritic cells (DC) are fused to tumor cells. T cells stimulated by DC/AML fusions target leukemia stem cells in vitro. In clinical studies, vaccination with DC/tumor fusions stimulates antitumor immunity in most patients, but only a subset demonstrate disease regression. An important element contributing to tumor mediated immune suppression involves the PD-1/PDL-1 pathway. PD-L1 has been shown to exert a significant role in promoting T cell tolerance by binding PD-1 on activated T cells and suppressing their capacity to secrete stimulatory cytokines. We have demonstrated that blockade of this pathway using antibodies directed against PD-L1 or PD-1 results in enhanced capacity of DC/tumor fusions to stimulate T cell proliferation ex vivo. Similarly, blockade of the PD1 pathway resulted in an increase in T cell expressing granzyme B as a measure of enhanced cytolytic capacity. A clinical grade antibody to PD-1, CPT-11, has been developed by Teva Pharmaceuticals which has been shown to potently induce anti-tumor immunity in murine models. In reversing a key element of tumor mediated immune suppression, we hypothesize that therapy with CT-011 will provide an ideal platform for the expansion of tumor reactive memory effector cells following induction chemotherapy. We hypothesize that the addition of tumor specific immunotherapy using the DC/AML fusion vaccine will further expand tumor specific T cells. In the proposed study, we will examine toxicity, immunologic effect and clinical efficacy of DC/AML fusion vaccination following induction chemotherapy for patients with AML. We will then examine these endpoints in patients undergoing combined therapy with the vaccine and CT-011.
Acute myelogenous leukemia (AML) arises from leukemia stem cells that are difficult to eradicate and serve as a reservoir for disease relapse following chemotherapy. A promising area of investigation is the development of immunotherapeutic approaches that stimulate the immune system to recognize leukemia stem cells as foreign and eliminate them. In this clinical trial, patients are treated with a tumor vaccine alone or in combination with CT-O11, an antibody that may augment response to vaccination;this immunotherapy may help to control leukemic cells that are resistant to chemotherapy and prevent disease recurrence.
|Rosenblatt, Jacalyn; Stone, Richard M; Uhl, Lynne et al. (2016) Individualized vaccination of AML patients in remission is associated with induction of antileukemia immunity and prolonged remissions. Sci Transl Med 8:368ra171|