Multiple myeloma is an incurable tumor with modest treatment options. It is an attractive model to study immune tumor interactions, as both the primary tumor and the infiltrating immune T cells can be readily isolated without the need for ex vivo culture. Our preliminary studies show that transformation of preneoplastic gammopathy to clinical myeloma is associated with a progressive decline in tumor reactive innate and adaptive immune effector function in the tumor bed. We have also found that dendritic cells (DCs) can acquire antigen from autologous tumor cells and lead to the generation of tumor specific killer T cells. Here, we test the hypothesis that injection of tumor loaded dendritic cells will lead to enhancement of antitumor immunity, which can be assessed at the level of the tumor microenvironment. Our long term goal is to optimize the ability of DCs to boost anti-tumor immunity in patients. Herein, we propose to 1) optimize the presentation of tumor antigens from autologous myeloma cells by dendritic cells; 2) examine the feasibility and tolerability of injection of tumor loaded DCs in patients with persistent / high risk myeloma; 3) assess immune responses to tumor specific vaccination and compare responses in blood versus tumor bed; and 4) assess changes in the expression of interferon-y responsive genes in tumor cells following vaccination. These studies may not only provide the basis of a novel approach to boost anti-tumor immunity in myeloma, but also yield insights into the role of tumor microenvironment in assessing the efficacy of anti-tumor vaccination.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA109465-02
Application #
7046857
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Howcroft, Thomas K
Project Start
2005-04-01
Project End
2010-02-28
Budget Start
2006-04-01
Budget End
2007-02-28
Support Year
2
Fiscal Year
2006
Total Cost
$325,932
Indirect Cost
Name
Rockefeller University
Department
Microbiology/Immun/Virology
Type
Other Domestic Higher Education
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
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Sehgal, Kartik; Ragheb, Ragy; Fahmy, Tarek M et al. (2014) Nanoparticle-mediated combinatorial targeting of multiple human dendritic cell (DC) subsets leads to enhanced T cell activation via IL-15-dependent DC crosstalk. J Immunol 193:2297-305
Richter, Joshua; Neparidze, Natalia; Zhang, Lin et al. (2013) Clinical regressions and broad immune activation following combination therapy targeting human NKT cells in myeloma. Blood 121:423-30
Dhodapkar, Madhav V (2013) Personalized immune-interception of cancer and the battle of two adaptive systems--when is the time right? Cancer Prev Res (Phila) 6:173-6
Dhodapkar, Madhav V; Dhodapkar, Kavita M (2011) Vaccines targeting cancer stem cells: are they within reach? Cancer J 17:397-402
Dhodapkar, Madhav V; Dhodapkar, Kavita M (2011) Spontaneous and therapy-induced immunity to pluripotency genes in humans: clinical implications, opportunities and challenges. Cancer Immunol Immunother 60:413-8
Dhodapkar, Madhav V; Richter, Joshua (2011) Harnessing natural killer T (NKT) cells in human myeloma: progress and challenges. Clin Immunol 140:160-6
Dhodapkar, Kavita M; Feldman, Darren; Matthews, Phillip et al. (2010) Natural immunity to pluripotency antigen OCT4 in humans. Proc Natl Acad Sci U S A 107:8718-23
Dhodapkar, Madhav V (2010) Immunity to stemness genes in human cancer. Curr Opin Immunol 22:245-50

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