Autologous stem cell transplantation for multiple myeloma (MM) results in effective cytoreduction but patients subsequently relapse. A promising area of investigation is the development of cancer vaccines that educate host immunity to selectively target and eliminate MM cells and can be used to eradicate residual disease following autologous stem cell transplantation. We have developed a cancer vaccine in which dendritic cells (DC) are fused to autologous tumor cells resulting in the presentation of multiple tumor antigens with the capacity to elicit a broad anti-tumor response. In a clinical trial of patients with advanced MM, vaccination with autologous DC/MM fusions induced anti-tumor immunity in a majority of patients, and disease stabilization ranging from 10 weeks to 36 months. In an ongoing trial of MM patients undergoing DC/tumor fusion vaccination in conjunction with stem cell transplantation, we have demonstrated a marked expansion of myeloma reactive T cells with the concomitant eradication of post-transplant residual disease following vaccination. To overcome the intrinsic immunosuppressive environment and regulatory T ceils that limit vaccine response, we are developing strategies to incorporate adoptive immunotherapy with MM reactive T cell clones. One approach is the use of vaccination prior to stem cell collection such that educated lymphocytes are infused at the time of transplant and further expanded in vivo by post-transplant vaccination. Alternatively, adoptive immunotherapy may be further optimized by ex-vivo generation of MM specific T cells with an activated phenotype. We have found that ligation of CD3/CD28 following ex vivo stimulation with DC/MM fusion vaccine results in the dramatic expansion of activated tumor reactive T cells while minimizing the presence of regulatory T cells. Our hypothesis is that combining transplant mediated cytoreduction and regulatory T cell depletion with the infusion of activated tumor reactive lymphocytes and boosting vaccination with DC/MM fusions offers the ideal platfomn for optimized cellular immunotherapy in MM. To address this hypothesis the Specific Aims are: 1) To evaluate toxicity, cellular and humoral antitumor immunity, and clinical response of a combined DC/MM vaccination and adoptive transfer of in vivo primed T cells;2) To optimize strategies for the ex vivo expansion of myeloma specific T cells using sequential stimulation with DC/MM fusions and anti-CD3/CD28 ex vivo;and 3) To define the toxicity, immunologic response and clinical effect of ex vivo generated and expanded myeloma specific T cells administered in conjunction with pre and post-transplant vaccination with DC/MM fusions.
Multiple myeloma is an incurable malignancy. The proposed work involves the further development of a vaccine for the treatment of multiple myeloma. These studies have the potential to advance therapy for patients with this disease.
|Tai, Yu-Tzu; Lin, Liang; Xing, Lijie et al. (2018) APRIL signaling via TACI mediates immunosuppression by T regulatory cells in multiple myeloma: therapeutic implications. Leukemia :|
|Bae, J; Hideshima, T; Zhang, G L et al. (2018) Identification and characterization of HLA-A24-specific XBP1, CD138 (Syndecan-1) and CS1 (SLAMF7) peptides inducing antigens-specific memory cytotoxic T lymphocytes targeting multiple myeloma. Leukemia 32:752-764|
|Pyzer, Athalia Rachel; Stroopinsky, Dina; Rajabi, Hasan et al. (2017) MUC1-mediated induction of myeloid-derived suppressor cells in patients with acute myeloid leukemia. Blood 129:1791-1801|
|Cholujova, Danka; Bujnakova, Zdenka; Dutkova, Erika et al. (2017) Realgar nanoparticles versus ATO arsenic compounds induce in vitro and in vivo activity against multiple myeloma. Br J Haematol 179:756-771|
|Yin, Li; Tagde, Ashujit; Gali, Reddy et al. (2017) MUC1-C is a target in lenalidomide resistant multiple myeloma. Br J Haematol 178:914-926|
|Harada, T; Ohguchi, H; Grondin, Y et al. (2017) HDAC3 regulates DNMT1 expression in multiple myeloma: therapeutic implications. Leukemia 31:2670-2677|
|Hideshima, Teru; Cottini, Francesca; Nozawa, Yoshihisa et al. (2017) p53-related protein kinase confers poor prognosis and represents a novel therapeutic target in multiple myeloma. Blood 129:1308-1319|
|Ohguchi, H; Harada, T; Sagawa, M et al. (2017) KDM6B modulates MAPK pathway mediating multiple myeloma cell growth and survival. Leukemia 31:2661-2669|
|Feng, Xiaoyan; Zhang, Li; Acharya, Chirag et al. (2017) Targeting CD38 Suppresses Induction and Function of T Regulatory Cells to Mitigate Immunosuppression in Multiple Myeloma. Clin Cancer Res 23:4290-4300|
|Bar-Natan, Michal; Stroopinsky, Dina; Luptakova, Katarina et al. (2017) Bone marrow stroma protects myeloma cells from cytotoxic damage via induction of the oncoprotein MUC1. Br J Haematol 176:929-938|
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