Blockade of PD-1 in Combination with Dendritic Cell/Myeloma Fusion Cell Vaccination Following Autologous Stem Cell Transplantation

Autologous stem cell transplantation (ASCT) for multiple myeloma (MM) offers a unique setting to explore the role of immunotherapy in eradicating residual disease. A challenge to developing an effective anti-tumor immune response is overcoming the suppressive effect of inhibitory pathways, including the PD-1/PDL1 pathway. We are conducting a clinical trial in which MM patients are treated with an anti-PD1 antibody (CT-011) alone (Cohort 1) and in combination with a dendritic cell/myeloma fusion cell vaccine (Cohort 2) following ASCT. To date, 27 patients have been enrolled into Cohort 1, in which patients receive three infusions of CT-011 at doses of 3mg/kg given at 6 week intervals beginning 1-3 months following ASCT. Mean age of the patients is 57 years; 61% are male. Twelve patients have received at least two infusions of CT-011. CT-011 has been well tolerated, with possibly related adverse events consisting of transient grade 1-2 leukopenia, diarrhea, fatigue, arthralgia, rash, and peri-orbital edema. One patient developed grade 3 neutropenia, which resolved after two days without growth factor. Immunologic response was determined by quantifying circulating tumor reactive T cells prior to each dose of CT-011 and at 1, 3, 6 months following the last infusion, as defined by the percentage of T cells expressing IFNg in response to ex vivo exposure to autologous tumor lysate.  Four patients have completed 6 months of follow up, and are evaluable for immune response. CT-011 was associated with the dramatic expansion of myeloma specific T cells. Mean percentage of circulating tumor reactive CD4+ and CD8+ T cells increased from 1.5 and 1.96 respectively prior to the first infusion of CT-011, to 4.26 and 8.28 respectively 1 month following the third infusion. As determined by tetramer staining in the subset of patients who are HLA A2.1, CT-011 resulted in a mean 9 fold expansion of T cells specific to the MUC1 antigen.  Notably, immunologic response to CT-011 persists at 6 months following completion of therapy. Clinical response, as determined by time to disease progression, will be determined with longer follow up. We have initiated enrollment to Cohort 2, in which patients will be vaccinated with an autologous DC/myeloma fusion vaccine 1 week prior to each dose of CT-011. These data demonstrate that CT-011 results in the expansion of tumor reactive lymphocytes in the early post-transplant period, providing an ideal platform for combination with a tumor vaccine.