The intent of this project is to develop an effective dendritic cell (DC) vaccine for solid tumors. While DC vaccines can induce potent peripheral T-cell immunity, their antitumor effects have been limited. This is most likely due to the presence of immunosuppressive cells within the tumor, such as regulatory T cells (Tregs), as well as tumor sporting stroma. While vaccine strategies targeting Tregs or cancer associated fibroblasts (CAFs, the major component of tumor stroma) have produced complete responses in animal models, tumors inevitably recur, as effector T-cell functions are eroded and/or subverted. We now hypothesize that by targeting not only the tumor and Tregs, but also CAFs, T-cell effector function will be retained for longer and the local 'tumor promoting heaven'will be destroyed resulting in sustained tumor remissions. We further hypothesize that the potent immunostimulatory environment created in the tumor will result in epitope spreading as newly activated antigen presenting cells within the tumor stroma 'cross-present'dying tumor cells. To test these hypotheses we will take advantage of our preliminary studies in which we have demonstrated that silencing the negative regulator A20 in DC can overcome Treg mediated immune suppression resulting in potent antitumor responses in the B16 model. In addition, we have shown that an A20-silenced DC vaccine can induce potent immune responses against fibroblast activating protein (FAP) expressed on the cell surface of CAFs. Using the B16 model, we will evaluate in Aim 1 if a DC vaccine coexpressing A20-shRNA, FAP and TRP2 (DC-shA20-FAP-TRP2) reverses the suppressive tumor microenvironment and facilitates T-cell infiltration into tumors, and determine in Aim 2 the potency of our vaccine to induce bystander T-cell responses (epitope spreading), leading to elimination of tumor antigen loss variants.
In Aim 3 we will then evaluate the efficacy and safety of our vaccine in a spontaneous murine Hgf-Cdk4R24c melanoma model. The proposed study is highly innovative since it will test for the first time the ability of genetically modified DCs to induce T-cell responses against cancer cells and their supporting stroma, while concomitantly overcoming Treg-mediated immunosuppression in a single vaccine formulation. If this pre-clinical approach is successful and clinical validation appears justified, we have the resources to prepare vector and cellular components that conform to the appropriate Good Manufacturing Practices safety standards, and will seek separate funding for such a study.

Public Health Relevance

The body's immune defenses against cancers often fail because malignancies actively inhibit the immune system. The immune system is not only suppressed by the cancer cells but also by the surrounding none cancerous cells. We propose to develop a vaccine that attacks cancer cells and the immunosuppressive surrounding cells. The effect of the vaccine will be evaluated in animal models.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA148748-04
Application #
8704114
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Muszynski, Karen
Project Start
2011-09-01
Project End
2016-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77030
DeRenzo, Christopher; Gottschalk, Stephen (2016) Genetically Modified T-cell Therapy for the Treatment of Osteosarcoma: An Update. J Clin Cell Immunol 7:
Mata, Melinda; Gottschalk, Stephen (2016) Man's Best Friend: Utilizing Naturally Occurring Tumors in Dogs to Improve Chimeric Antigen Receptor T-cell Therapy for Human Cancers. Mol Ther 24:1511-2
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Song, Xiao-Tong (2014) Genetic modification of dendritic cells with RNAi. Methods Mol Biol 1139:119-30
Yu, Feng; Wang, Xingbing; Guo, Z Sheng et al. (2014) T-cell engager-armed oncolytic vaccinia virus significantly enhances antitumor therapy. Mol Ther 22:102-11
DeRenzo, Christopher; Gottschalk, Stephen (2014) Genetically modified T-cell therapy for osteosarcoma. Adv Exp Med Biol 804:323-40
Gottschalk, Stephen; Yu, Feng; Ji, Minjun et al. (2013) A vaccine that co-targets tumor cells and cancer associated fibroblasts results in enhanced antitumor activity by inducing antigen spreading. PLoS One 8:e82658
Song, Xiao-Tong (2013) Combination of virotherapy and T-cell therapy: arming oncolytic virus with T-cell engagers. Discov Med 16:261-6

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