There is evidence from allogeneic hematopoietic stem cell transplantation [HSCT] that there is an immune response against leukemia-associated antigens in patients with either acute or chronic myeloid leukemia (AML, CML). However, an autologous anti-tumor cell response in AML is either not evident or actively suppressed due to replacement of the lymphohematopoietic space with rapidly growing malignant cells. We have shown that specific AML-reactive T cells can be generated and expanded from primary cultures of mononuclear cells from all newly diagnosed patients with AML using a novel cell culture method employing sequential modulation of growth factors. This culture induces potent antigen presentation by inducing dendritic cell differentiation in the presence of autologous lymphocytes. The sensitized lymphocytes are then expanded through the use of growth factors. Large numbers (109-1010) of CD8+ T cells that are myeloid leukemia-specific are generated in this manner. In this novel study, we will employ the novel culture method to conduct a multi-center Phase 1/2 clinical trial of adoptive autologous T cell therapy in patients who have recently received an autologous HSCT (AHSCT) for AML. Peripheral blood cells will be obtained from patients with AML at first diagnosis or relapse, who are deemed eligible for AHSCT. Mononuclear cells containing AML blasts and normal T cells will be cryopreserved. The patient will then be treated and at the time high dose therapy for AHSCT is administered the cell culture will be initiated in a central lab. The cultured T cells will then be tested for their ability to kill autologous AML cells and to ensure the absence of residual AML. The T cells will be infused into the patient approximately 5 weeks after AHSCT. Cohorts of patients will be observed for safety after infusion of graded numbers of T cells (primary endpoint) and all patients will be observed for 1 year to determine progression-free survival, compared with our large institutional database. This innovative protocol will determine whether cellular immunotherapy with autologous cytotoxic T cells is safe and has the potential for therapeutic benefit in patients with AML.

Public Health Relevance

This proposal involves a novel multi-center clinical trial testing the safety and efficacy of infusing autologous cytotoxic T cells in patients with acute myeloid leukemia who have recently undergone autologous stem cell transplantation. The autologous T cells will be generated through induction of dendritic cell differentiation of AML cells in cell cultures obtained at the time of diagnosis. We hypothesize that these autologous T cell infusions will be safe and effective at decreasing relapse rates following autologous stem cell transplantation.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Cancer Immunopathology and Immunotherapy Study Section (CII)
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Merritt, William D
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University of California San Diego
Internal Medicine/Medicine
Schools of Medicine
La Jolla
United States
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