R01CA262629

Personalized Adoptive T-Cell Therapy for AML - Abstract/Project Summary

The development of strategies to expand and activate AML-specific T cells is of critical importance. We have developed a personalized cancer vaccine in which patient-derived tumor cells are fused with autologous dendritic cells (DCs), presenting a broad array of antigens that capture the heterogeneity of the leukemia cell population, including shared and neoantigens.

We have completed a Phase II clinical trial in which patients that achieve remission following chemotherapy undergo serial vaccination with DC/AML fusions. Remarkably, despite a median age of 63, 71% remained free of disease with a median follow-up of 5 years. Vaccination was associated with the expansion of T cells targeting both autologous AML cells and leukemia-associated antigens.

The DC/AML vaccine can be used as a platform to generate activated leukemia-specific T cells ex vivo for adoptive immunotherapy. In this way, effector cells may be generated that are leukemia-specific, capture tumor heterogeneity, and are activated ex vivo to achieve a functionally competent phenotype. We have demonstrated that vaccine stimulation in the context of IL7/IL-15 results in enhanced levels of central memory cells critical for long-term persistence of response.

While the generation of vaccine-stimulated leukemia-specific T cells ex vivo represents a promising strategy to effectively target AML cells in vivo, the immunosuppressive nature of the tumor microenvironment remains a barrier to the development of a memory response and long-term protection. We performed transcriptome analysis in the remission bone marrow at the time of vaccination to identify biomarkers that were predictive of durable response as compared to early relapse following vaccination with DC/AML fusions. Of note, decreased expression of TGF-β in the bone marrow microenvironment was associated with durable remission. These results are consistent with prior reports suggesting TGF-β as a negative regulator of tumor immunogenicity, T cell activation, and infiltration into the tumor bed. As such, there is a strong rationale to target TGF-β to enhance vaccine efficacy.

In the present study, we will create a novel strategy for adoptive T cell therapy generated by vaccine-mediated stimulation, selection of antigen-specific T cells, and ex vivo expansion. Functional characteristics will be examined in an immunocompetent murine leukemia model. We will then examine the effect of TGF-β inhibition on vaccine response and TGF-β inhibition within vaccine-stimulated T cells by silencing of the downstream effector SMAD2.

In the second aim, the T cell product will be characterized with respect to targeting of shared and neo-antigen targets, oligoclonal expansion and diversity of the repertoire, expression of markers of activation, exhaustion, senescence, and chemokines needed for migration into the tumor bed.

In the third aim, we will conduct a Phase I study in which patients with AML who achieve complete remission will undergo adoptive therapy with vaccine-stimulated T cells.

Beth Israel Deaconess Medical Center

TO DEVELOP THE MEANS TO CURE AS MANY CANCER PATIENTS AS POSSIBLE AND TO CONTROL THE DISEASE IN THOSE PATIENTS WHO ARE NOT CURED. CANCER TREATMENT RESEARCH INCLUDES THE DEVELOPMENT AND EVALUATION OF IMPROVED METHODS OF CANCER TREATMENT THROUGH THE SUPPORT AND PERFORMANCE OF BOTH FUNDAMENTAL AND APPLIED LABORATORY AND CLINICAL RESEARCH. RESEARCH IS SUPPORTED IN THE DISCOVERY, DEVELOPMENT, AND CLINICAL TESTING OF ALL MODES OF THERAPY INCLUDING: SURGERY, RADIOTHERAPY, CHEMOTHERAPY, AND BIOLOGICAL THERAPY INCLUDING MOLECULARLY TARGETED THERAPIES, BOTH INDIVIDUALLY AND IN COMBINATION. IN ADDITION, RESEARCH IS CARRIED OUT IN AREAS OF NUTRITIONAL SUPPORT, STEM CELL AND BONE MARROW TRANSPLANTATION, IMAGE GUIDED THERAPIES AND STUDIES TO REDUCE TOXICITY OF CYTOTOXIC THERAPIES, AND OTHER METHODS OF SUPPORTIVE CARE THAT MAY SUPPLEMENT AND ENHANCE PRIMARY TREATMENT. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.395 - Cancer Treatment Research

National Cancer Institute (NCI) [HHS - NIH]

Boston, Massachusetts 022155400 United States

Single Zip Code

National Cancer Institute's Investigator-Initiated Early Phase Clinical Trials for Cancer Treatment and Diagnosis (R01 Clinical Trials Required) (PAR-18-560)

Amendment Since initial award the End Date has been extended from 06/30/26 to 12/31/26 and the total obligations have increased 376% from $762,763 to $3,628,945.