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Dr. Avigan - Fusion Cell Vaccination in Conjunction with Stem Cell Transplantation Is Well Tolerated, Induces Anti-Tumor Immunity and Is Associated with Responses in Patients with Multiple Myeloma
David Avigan, MD
Beth Israel Deaconess Medical Center
Boston Massachusetts
USA
12.30.08


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David Avigan, MD, Jacalyn Rosenblatt, MD, Baldev Vasir, PhD, Zekui Wu, MD, Adam Bissonnette, Poorvi Somaiya, Claire MacNamara, Lynne Uhl, MD, Irit Avivi, MD, Tami Katz, Ph.D, Corrine Zarwan, MD, Robin Joyce, MD, James D. Levine, MD, Vassiliki Boussiotis, MD, Dimitrios Tzachanis, MD, Karen Lowe, RN, Dilani Dombagoda, Nancy Giallombardo, NP, Jamie Mortellite, NP, Katharine Conway, NP, Donna Fitzgerald, PA, Paul Richardson, MD, Kenneth Anderson, MD, Nikhil C. Munshi, MD, Michal Tsumer, Lina Bisharat, Jacob Rowe, MD and Donald Kufe, MD

ABSTRACT: Autologous stem cell transplantation results in tumor cytoreduction and improved disease outcomes in patients with multiple myeloma (MM), but patients ultimately relapse from persistent disease. A promising area of investigation is the development of cancer vaccines that educate host immunity to target and eliminate myeloma cells and can be used to eradicate residual disease following autologous stem cell transplantation. The early post-transplant period is characterized by a transient reversal of tumor mediated tolerance due to the reduction in disease bulk, the depletion of regulatory T cells. We have developed a cancer vaccine model in which DCs are fused to autologous MM cells resulting in the presentation of multiple tumor antigens with the capacity to elicit a broad anti-tumor response.  We are conducting a study in which patients with MM undergo stem cell transplantation followed by post-transplant vaccination with 3 doses of DC/MM fusions. DCs were generated from adherent mononuclear cells cultured with GM-CSF and IL-4 for 5-7 days and matured with TNFα.   DCs strongly expressed costimulatory and maturation markers.  Myeloma cells were isolated from bone marrow aspirates and were identified by their expression of CD38, CD138, and/or MUC1.  DC and MM cells were fused with polyethylene glycol and fusion cells were quantified by determining the percentage of cells that coexpress unique DC and myeloma antigens. To date, 26 patients have been enrolled.  All patients have undergone successful vaccine generation. Mean yield of the DC and myeloma preparations was 171x106 and 70x106 cells, respectively.  Mean fusion efficiency was 40% and the mean cell dose generated was 4x106 fusion cells. Mean viability of the DC, myeloma, and fusion preparations was 88%, 86%, and 78%, respectively.  As a measure of their potency as antigen presenting cells, fusion cells potently stimulated allogeneic T cell proliferation in vitro.  Mean stimulation indexes were 12, 57, 31 for T cells stimulated by myeloma cells, DCs, and fusion cell preparations at an APC: T cell ratio of 1:10.  Adverse events judged to be potentially vaccine related were mild, and included injection site reactions, pruritis, myalgias, fever, chills, headache, fatigue and tachycardia. To date 14 patients have completed vaccinations and initial follow up of which 8 have achieved a complete remission and 6 a partial remission. Of note, 4 patients achieved complete remission only after undergoing post-transplant vaccination.  We are examining the effect of transplant and vaccination on measures of cellular immunity, anti-tumor immunity and levels of activated as compared to regulatory T cells.  T cell responses to PHA mitogen and tetanus toxoid were transiently depressed post-transplant.  Similarly, DTH responses to candida antigen were absent post-transplant in all but 1 patient.  In contrast, a significant increase was noted post-transplant in circulating tumor reactive lymphocytes as determined by T cell expression of IFNγ by CD4 and CD8 cells following ex vivo coculture with autologous myeloma cell lysate (Mean percentage of tumor reactive CD8 cells was 0.9 and 11 pre and post-transplant, respectively p=0.01; mean percentage of CD4 cells was 0.7 and 2.7; p=0.02).  A further amplification of tumor reactive lymphocytes was seen with vaccination in a subset of patients (mean percentage of CD4 and CD8 tumor reactive T cells was 4.9 and 15, respectively).  A decrease in the median levels of circulating regulatory T cells and a relative increase in the ratio of activated (CD4/CD25low)/regulatory (CD4/CD25high) cells was observed following transplantation.  This finding suggests that although nonspecific T cell responses are muted in the early post-transplant period, there is a greater capacity to recognize tumor antigens, potentially due to the depletion of regulatory T cells and the decline in tumor mediated immune suppression.  In summary, fusion cell vaccination in conjunction with stem cell transplantation was well tolerated, induced anti-tumor immunity and clinical responses in patients with MM.  The post-transplant period is characterized by increased levels of activated as compared to regulatory T cells and enhanced levels of T cells with the capacity to respond to myeloma cells. The increase in tumor reactive T cells post-transplant is further amplified following exposure to the DC/MM fusion vaccine.

 


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