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.
|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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