A central theme of the research projects in this program is that the growth of myeloma tumor cells is modulated through multiple and functionally diverse interactions with the tumor cell microenvironment. Many of these interactions involve elements of innate and adaptive immunity that can either promote or inhibit the growth of myeloma cells in vivo. A better understanding of both negative and positive immune system interactions can lead to the development of innovative therapies for patients with myeloma. This is a goal of each of the 3 research projects and this core will support each project by providing a centralized laboratory resource for immune monitoring and manufacturing immune cells for adoptive cellular therapy. For patients with myeloma who receive conventional therapies as well as those enrolled on specific clinical trials supported by this program, we have established procedures for obtaining samples of myeloma tumor cells and normal immune cells for research studies (described in Core A). Bone marrow aspirates and biopsies and well as peripheral blood cells are obtained after informed consent and viable cells, plasma and serum are cryopreserved at regular intervals. Using these samples Core C will provide a detailed analysis of immune function using a variety of methods that provide a quantitative assessment of specific populations as well as their level of maturation and function. Quantitative analysis of circulating immune cells as well as bone marrow cells and myeloma cells is determined by multi-parameter flow cytometry with a panel of fluorochrome-conjugated monoclonal antibodies. Cytokine production by distinct subsets of immune cells is also determined by flow cytometry. Levels of individual cytokines are measured by bead-based multiplex assays or by ELISA. Reconstitution of T cell receptor repertoire is examined by TCR VB spectratyping. Thymic function is evaluated by quantitative PCR for T-cell receptor excision circles (TREC). T cell immunity to specific target antigens such as CMV and EBV or to myeloma-associated tumor antigens such as MUC-1 is determined by ELISPOT or with fluorescent-HLA-peptide-conjugates. Results of these assays are correlated with other parameters of immune function as well as with clinical outcomes. For patients enrolled on the clinical trials of myeloma/DC fusion vaccine and T cell infusions described in Project 3, this core will have the additional responsibility for clinical scale manufacturing of large numbers of autologous T cells for adoptive T cell infusions.
The specific aims of this core are listed below: 1. To provide phenotypic and functional measurements of immune function and response to immune therapies. 2. Manufacture patient T cells for adoptive immune therapy
Cells of the immune system represent an important component of the myeloma tumor microenvironment. This core facility will support each of the research projects in the measurement of immune function in patients with myeloma and in response to therapy. This core facility will also manufacture large numbers of T cells reactive with patient myeloma cells for infusion after autologous stem cell transplantation in Project 3.
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|Ray, Arghya; Ravillah, Durgadevi; Das, Deepika S et al. (2016) A novel alkylating agent Melflufen induces irreversible DNA damage and cytotoxicity in multiple myeloma cells. Br J Haematol 174:397-409|
|An, Gang; Acharya, Chirag; Feng, Xiaoyan et al. (2016) Osteoclasts promote immune suppressive microenvironment in multiple myeloma: therapeutic implication. Blood 128:1590-603|
|Tagde, Ashujit; Rajabi, Hasan; Bouillez, Audrey et al. (2016) MUC1-C drives MYC in multiple myeloma. Blood 127:2587-97|
|Jiang, H; Acharya, C; An, G et al. (2016) SAR650984 directly induces multiple myeloma cell death via lysosomal-associated and apoptotic pathways, which is further enhanced by pomalidomide. Leukemia 30:399-408|
|GullÃ , Annamaria; Di Martino, Maria Teresa; Gallo Cantafio, Maria Eugenia et al. (2016) A 13 mer LNA-i-miR-221 Inhibitor Restores Drug Sensitivity in Melphalan-Refractory Multiple Myeloma Cells. Clin Cancer Res 22:1222-33|
|Tai, Yu-Tzu; Acharya, Chirag; An, Gang et al. (2016) APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment. Blood 127:3225-36|
|Bommarito, Davide; Martin, Allison; Forcade, Edouard et al. (2016) Enhancement of tumor cell susceptibility to natural killer cell activity through inhibition of the PI3K signaling pathway. Cancer Immunol Immunother 65:355-66|
|Ohguchi, Hiroto; Hideshima, Teru; Bhasin, Manoj K et al. (2016) The KDM3A-KLF2-IRF4 axis maintains myeloma cell survival. Nat Commun 7:10258|
|Bae, J; Prabhala, R; Voskertchian, A et al. (2015) A multiepitope of XBP1, CD138 and CS1 peptides induces myeloma-specific cytotoxic T lymphocytes in T cells of smoldering myeloma patients. Leukemia 29:218-29|
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