The success of gene therapy for cancer will eventually depend on delivering genes specifically to tumor cells in vivo. However, systemic administration of viral stocks has not so far achieved therapeutic targeting of metastatic disease, due to low titres, immune inactivation, non-specific adhesion and loss of viral paticles in the circulation. It would, therefore, be valuable if vectors could be carried to local sites of tumor growth and be released in response to externally applied signals (such as drugs) or environmental cues supplied by the biological properties of the tumor itself. Several cell types could serve as tumor homing cell carriers of vectors, including tumor antigen specific T cells. We have recently shown that systemic delivery of surface targeted T cells, engineered to produce a transcriptionally tumor targeted retroviral vector upon recognition by the T cell of a specific tumor antigen, generated highly significant therapeutic effects in a model of metastatic disease. However, our T cell studies used human T cells lacking cytolytic effector functions, in mice lacking a functional immune system. We now propose to expand the concept of T cell carriers for the gene therapy of cancer. As summarized in Figures 18 and 19 we will 1: Demonstrate that antigen specific, murine cytotoxic T cells can be converted into retroviral producer cells in vitro, that they can be adoptively transferred in vivo to tumor bearing hosts and that they can traffick to and specifically transduce antigen positive tumors in the presence of a fully intact immune system: 2: Characterise the therapeutic enhancement produced by combining tumor localized production of cytotoxic retrovirus with the T cells' natural effector functions (target cell killing and cytokine release) in a protocol of adoptive T cell therapy in an immunocompetent murine model of malignant melanoma: and 3; Investigate the potential of antigen specific T cell based retroviral vector production at the tumor site to enhance the recruitment of further doses of adoptively transferred T cells and the recruitment/activation of endogenous anti tumor immune effectors. Clinically, these experiments should rapidly lead to improved patient trials for adoptive T cell therapy of cancer and they will develop the potential of cell-based carriers for in vivo gene delivery to metastatic disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA107082-01A2
Application #
6965589
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Welch, Anthony R
Project Start
2005-07-01
Project End
2009-04-30
Budget Start
2005-07-01
Budget End
2006-04-30
Support Year
1
Fiscal Year
2005
Total Cost
$294,275
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Rajani, Karishma; Parrish, Christopher; Kottke, Timothy et al. (2016) Combination Therapy With Reovirus and Anti-PD-1 Blockade Controls Tumor Growth Through Innate and Adaptive Immune Responses. Mol Ther 24:166-74
Blanchard, Miran; Shim, Kevin G; Grams, Michael P et al. (2015) Definitive Management of Oligometastatic Melanoma in a Murine Model Using Combined Ablative Radiation Therapy and Viral Immunotherapy. Int J Radiat Oncol Biol Phys 93:577-87
Zaidi, Shane; Blanchard, Miran; Shim, Kevin et al. (2015) Mutated BRAF Emerges as a Major Effector of Recurrence in a Murine Melanoma Model After Treatment With Immunomodulatory Agents. Mol Ther 23:845-856
Alonso-Camino, Vanesa; Rajani, Karishma; Kottke, Timothy et al. (2014) The profile of tumor antigens which can be targeted by immunotherapy depends upon the tumor's anatomical site. Mol Ther 22:1936-48
Jennings, V A; Ilett, E J; Scott, K J et al. (2014) Lymphokine-activated killer and dendritic cell carriage enhances oncolytic reovirus therapy for ovarian cancer by overcoming antibody neutralization in ascites. Int J Cancer 134:1091-101
Ilett, Elizabeth; Kottke, Timothy; Donnelly, Oliver et al. (2014) Cytokine conditioning enhances systemic delivery and therapy of an oncolytic virus. Mol Ther 22:1851-63
Rommelfanger, Diana M; Compte, Marta; Grau, Marta C et al. (2013) The efficacy versus toxicity profile of combination virotherapy and TLR immunotherapy highlights the danger of administering TLR agonists to oncolytic virus-treated mice. Mol Ther 21:348-57
Boisgerault, Nicolas; Kottke, Timothy; Pulido, Jose et al. (2013) Functional cloning of recurrence-specific antigens identifies molecular targets to treat tumor relapse. Mol Ther 21:1507-16
Kottke, Timothy; Boisgerault, Nicolas; Diaz, Rosa Maria et al. (2013) Detecting and targeting tumor relapse by its resistance to innate effectors at early recurrence. Nat Med 19:1625-1631
Kaluza, Karen M; Vile, Richard (2013) Improving the outcome of adoptive cell transfer by targeting tumor escape. Oncoimmunology 2:e22059

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