We have developed a tumor vaccine in which patient-derived myeloma cells are chemically fused with autologous dendritic cells (DCs) such that a broad spectrum of myeloma-associated antigens are presented in the context of DC-mediated costimulation. We have completed a phase 1 study in which patients with multiple myeloma underwent serial vaccination with the DC/multiple myeloma fusions in conjunction with granulocytemacrophage colony-stimulating factor. DCs were generated from adherent mononuclear cells cultured with granulocyte-

Background A multiple myeloma (MM) vaccine has been developed whereby patient derived tumor cells are fused with autologous dendritic cells (DCs), creating a hybridoma that stimulates a broad anti-tumor response. We report on the results of a phase II trial in which patients underwent vaccination following autologous stem cell transplantation (ASCT) to target minimal residual disease. Methods Twenty-four patients received serial vaccinations with DC/myeloma fusion cells following post-transplant hematopoietic recovery. A second cohort of 12 patients received a pre-transplant vaccine followed by post-transplant vaccinations. DCs generated from adherent mononuclear cells cultured with GM-CSF, IL-4 and TNFα were fused with autologous bone marrow-derived MM cells using polyethylene glycol (PEG). Fusion cells were quantified by determining the percentage of cells that co-express DC and MM antigens. Findings The post-transplant period was associated with reduction in general measures of cellular immunity; however, an increase in CD4 and CD8+ myeloma specific T cells was observed after ASCT that was significantly expanded following post-transplant vaccination. Seventy-eight percent of patients achieved a best response of CR+VGPR and 47% achieved a CR/nCR. Remarkably, 24% of patients who achieved a partial response following transplant were converted to CR/nCR after vaccination and at over 3 months post-transplant, consistent with a vaccine-mediated effect on residual disease. Interpretation The post-transplant period for patients with multiple myeloma provides a unique platform for cellular immunotherapy in which vaccination with DC/MM fusions resulted in the marked expansion of myeloma specific T cells and cytoreduction of minimal residual disease.

Myeloid-derived suppressor cells (MDSCs) play a critical role in promoting immune tolerance and disease growth. The mechanism by which tumor cells evoke the expansion of MDSCs in acute myeloid leukemia (AML) has not been well described. We have demonstrated that patients with AML exhibit increased presence of MDSCs in their peripheral blood, in comparison with normal controls. Cytogenetic studies demonstrated that MDSCs in patients with AML may be derived from leukemic or apparently normal progenitors. Engraftment of C57BL/6 mice with TIB-49 AML led to an expansion of CD11b Gr1 MDSCs in bone marrow and spleen. Coculture of the AML cell lines MOLM-4, THP-1 or primary AML cells with donor peripheral blood mononuclear cells elicited a cell contact-dependent expansion of MDSCs. MDSCs were suppressive of autologous T-cell responses as evidenced by reduced T-cell proliferation and a switch from a Th1 to a Th2 phenotype. We hypothesized that the expansion of MDSCs in AML is accomplished by tumor-derived extracellular vesicles (EVs). Using tracking studies, we demonstrated that AML EVs are taken-up myeloid progenitor cells, resulting in the selective proliferation of MDSCs in comparison with functionally competent antigen-presenting cells. The MUC1 oncoprotein was subsequently identified as the critical driver of EV-mediated MDSC expansion. MUC1 induces increased expression of c-myc in EVs that induces proliferation in the target MDSC population via downstream effects on cell cycle proteins. Moreover, we demonstrate that the microRNA miR34a acts as the regulatory mechanism by which MUC1 drives c-myc expression in AML cells and EVs.

No abstract

No abstract