Session: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Poster II
Hematology Disease Topics & Pathways:
Biological, Diseases, AML, Therapies, immunotherapy, Clinically relevant, Myeloid Malignancies, vaccines
Here we report immune monitoring studies, exploring quality of vaccines and specificity and persistence of T cell responses. DC vaccines produced in batch lots were cryopreserved in multiple aliquots for thaw prior to application. Extensive characterization showed DCs to be of mature phenotype, with high levels of positive co-stimulatory molecules and fewer negative regulatory molecules. Antigen-loading by electroporation of in vitro transcribed RNA, led to full length intracellular protein expression in most cells. Chemokine-directed migration was measured for all DC preparations. A novel dual-color ELISpot assay showed that DCs of each patient secreted IL-12 but not IL-10 after CD40 ligand stimulation. Despite extensive chemotherapy and impaired hematopoiesis, high quality DC vaccines with essential functions were easily generated from monocytes of these patients.
T cell responses to target antigens were assessed with two assays. Intracellular interferon-gamma production was measured in PBL acquired at various time points during treatment. Standard ELISpot assays independently confirmed T cell responses to both antigens. In addition, responses to non-immunizing antigens (hTERT and survivin) were detected in some cases, demonstrating antigen-spreading during treatment. T cell responses to one or both targets were found in 4/5 patients; thus, both self-antigens were immunogenic when presented by polarized mDCs. Persistent vaccination allowed maintenance of T cell responses over extended periods of time in 4/5 patients. Interestingly, antigen-specific responses to over-lapping peptides were only found in two patients when anti-PD-1 blocking antibody was present in the stimulation cultures, thereby enabling T cells to produce cytokine after antigen-specific stimulation.
To date 3/5 patients are alive without current signs of relapse. Two patients received DC vaccines for 22 and 30 months and have been followed for 53 and 41 months respectively, since completion of chemotherapy. The third patient had signs of relapse and vaccination was halted after 10 months. This individual was then given allogeneic SCT and remains in CR after 35 months. The two remaining patients are deceased. One patient who showed no T cell activity relapsed after 12 months of vaccination and died at month 20 during chemotherapy. The fifth patient was vaccinated for 24 months without signs of relapse but died due to unrelated heart disease. The ongoing clinical study using extended DC vaccination will provide more information whether persistent vaccination against these self-antigens contributes to immune responses that prevent disease relapse in AML patients.
Disclosures: Eckl: Medigene Immunotherapies GmbH: Employment. Geiger: Medigene Immunotherapies GmbH: Employment. Schendel: Medigene Immunotherapies GmbH: Employment, Patents & Royalties: DC Vaccines.
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