Immunotherapy has the potential to allow selective elimination of tumor cells in patients and the development of long-term protection against outgrowth of tumor variants. As knowledge of the immune system improves, there has been an increased enthusiasm for treating cancer with immune modulating therapies.
The aim of this proposal is the development of a new mechanism to deliver selective immune activation against ovarian carcinomas. We propose to transduce T cells with chimeric NK cell receptors that can recognize tumor cells as NK cells do and directly activate T cells. These chimeric receptors are produced by fusing the NKG2D gene with the signalling portion of CD3zeta to create a chimeric NKG2D receptor (chNKG2D). We hypothesize that chNKG2D based immunotherapy will provide both direct attack on ovarian carcinoma cells, produce cytokines to activate host immunity, and lead to long-term tumor free survival.
The specific aims of this proposal will address the following questions: 1. To what extent do murine chNKG2D T cells eliminate ovarian tumor cells in vivo and are there potential autoimmune responses of these T cells? 2. What are the key host immune mechanisms that chNKG2D T cells activate to eliminate ovarian tumor cells in vivo? 3. To what extent do chNKG2D T cells activate host T cells and lead to protection against tumor rechallenge? The chNKG2D receptor approach provides a novel means to invoke tumor-specific host responses using chimeric NK cell receptors to direct the immune response against tumor cells. We have combined the ligand specificity of the NKG2D receptor with the signaling domain of CD3? to create a receptor that allows CTLs to kill tumor cells and secrete proinflammatory cytokines. Due to the expression of ligands for NKG2D on tumors derived from many different tissues, this approach has the potential to be useful against a wide variety of cancers. The overall goal is to determine the effectiveness and mechanisms by which chimeric NKG2D receptors eliminate ovarian carcinomas and activate host immunity resulting in tumor-free survival. This proposal aims to understand the underlying function and effectiveness of a novel immunotherapy, called chimeric NKG2D receptors, that uses the tumor recognition of a natural killer cell with the function of killer T cells. We believe this cell-based therapy will provide a robust means to allow a person's immune cells to recognize and attack their own tumor and result in tumor elimination and long-term survival in ovarian cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA130911-05
Application #
8267726
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Muszynski, Karen
Project Start
2008-08-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$321,839
Indirect Cost
$120,564
Name
Dartmouth College
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Talebian, Laleh; Fischer, Dawn A; Wu, Jillian et al. (2014) The natural killer-activating receptor, NKG2D, on CD3+CD8+ T cells plays a critical role in identifying and killing autologous myeloma cells. Transfusion 54:1515-21
Sentman, Charles L; Meehan, Kenneth R (2014) NKG2D CARs as cell therapy for cancer. Cancer J 20:156-9
Spear, Paul; Wu, Ming-Ru; Sentman, Marie-Louise et al. (2013) NKG2D ligands as therapeutic targets. Cancer Immun 13:8
Zhang, Tong; Sentman, Charles L (2013) Mouse tumor vasculature expresses NKG2D ligands and can be targeted by chimeric NKG2D-modified T cells. J Immunol 190:2455-63
Sentman, Charles L (2013) Challenges of creating effective chimeric antigen receptors for cancer therapy. Immunotherapy 5:783-5
Spear, Paul; Barber, Amorette; Rynda-Apple, Agnieszka et al. (2013) NKG2D CAR T-cell therapy inhibits the growth of NKG2D ligand heterogeneous tumors. Immunol Cell Biol 91:435-40
Iyori, Mitsuhiro; Zhang, Tong; Pantel, Haddon et al. (2011) TRAIL/DR5 plays a critical role in NK cell-mediated negative regulation of dendritic cell cross-priming of T cells. J Immunol 187:3087-95
Zhang, Tong; Sentman, Charles L (2011) Cancer immunotherapy using a bispecific NK receptor fusion protein that engages both T cells and tumor cells. Cancer Res 71:2066-76
Barber, A; Meehan, K R; Sentman, C L (2011) Treatment of multiple myeloma with adoptively transferred chimeric NKG2D receptor-expressing T cells. Gene Ther 18:509-16
Talebian, Laleh; Wu, Jia Yan; Fischer, Dawn A et al. (2011) Novel mobilization strategies to enhance autologous immune effector cells in multiple myeloma. Front Biosci (Elite Ed) 3:1500-8

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