A variety of approaches have been developed in recent years to recruit CD8+ T cells for the control of cancer due to their recognized potency to destroy tumor cells. One of the most promising approaches to date is the use of adoptive T cell transfer, with particular success in metastatic melanoma patients. Recent progress has been made toward defining the mechanisms that promote effective adoptive T cell-based immunotherapy of cancer. However, the variables that determine success versus failure, particularly for cancers beyond melanoma, remain poorly defined. The broad objective of this proposal is to identify mechanisms that promote CD8+ T cell-mediated elimination of established autochthonous tumors using adoptive T cell-based immunotherapies. The hypothesis driving this study is that the effectiveness of T cell- based adoptive immunotherapy of cancer will vary with the distinct histological origin of the tumor and the CD8+ T cell epitope targeted due to differential effects on the tumor microenvironment. The following specific aims will be pursued.
Specific Aim 1. Define the mechanisms that promote regression of established autochthonous brain tumors following radiation-enhanced adoptive immunotherapy.
Specific Aim 2. Evaluate the sensitivity of tumors from unique tissue origins to adoptive T cell immunotherapy.
Specific Aim 3. Identify mechanisms critical for adoptive T cell immunotherapy targeting a weak tumor-associated determinant. In this study, mice that express the SV40 large T antigen oncoprotein from tissue-specific promoters will be used to investigate mechanisms that regulate effective adoptive T cell immunotherapy toward tumors that arise in distinct tissues. This will include models of brain, pancreas and prostate cancer. The SV40 T antigen system provides a powerful model to address these issues due to the availability of multiple well-established transgenic mouse tumor models and the large array of reagents available to monitor T antigen-specific CD8+ T cell responses to multiple determinants derived from the same protein antigen. Localized versus systemic effects of radiation associated with successful T cell-mediated tumor regression will be defined in order to more specifically design immunotherapies for established tumors. In addition, the efficacy of radiation-enhanced adoptive T cell transfer to control tumors of unique histological origin will be assessed by defining changes in the T cell phenotype and tumor microenvironments that are associated with successful immunotherapy. Finally, we will identify approaches that overcome the limitations of targeting a weak tumor-associated determinant by adoptive immunotherapy in order to broaden the repertoire of available targets. By testing these approaches in a tumor system where the antigen and the effectors'T cell population are held constant, the results of these studies should reveal tumor-specific mechanisms that promote and/or inhibit successful adoptive T cell-based immunotherapy. This new knowledge should provide insight for increasing the success of translational adoptive T cell-based immunotherapy approaches against diverse cancers.

Public Health Relevance

The results of this study will further our understanding of how adoptive T cell-based immunotherapies can be applied to established cancers. The ability to apply this approach to multiple cancer types will be investigated and will provide insight for enhancement of this promising approach for the treatment of cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA025000-31A1
Application #
7782476
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Mccarthy, Susan A
Project Start
1978-06-01
Project End
2014-11-30
Budget Start
2009-12-04
Budget End
2010-11-30
Support Year
31
Fiscal Year
2010
Total Cost
$386,069
Indirect Cost
Name
Pennsylvania State University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Ward-Kavanagh, Lindsay K; Kokolus, Kathleen M; Cooper, Timothy K et al. (2018) Combined sublethal irradiation and agonist anti-CD40 enhance donor T cell accumulation and control of autochthonous murine pancreatic tumors. Cancer Immunol Immunother 67:639-652
Li, Guangfu; Liu, Dai; Cooper, Timothy K et al. (2017) Successful chemoimmunotherapy against hepatocellular cancer in a novel murine model. J Hepatol 66:75-85
Memarnejadian, Arash; Meilleur, Courtney E; Shaler, Christopher R et al. (2017) PD-1 Blockade Promotes Epitope Spreading in Anticancer CD8+ T Cell Responses by Preventing Fratricidal Death of Subdominant Clones To Relieve Immunodomination. J Immunol 199:3348-3359
Cozza, Eugene M; Cooper, Timothy K; Budgeon, Lynn R et al. (2015) Protection from tumor recurrence following adoptive immunotherapy varies with host conditioning regimen despite initial regression of autochthonous murine brain tumors. Cancer Immunol Immunother 64:325-36
Ward-Kavanagh, Lindsay K; Zhu, Junjia; Cooper, Timothy K et al. (2014) Whole-body irradiation increases the magnitude and persistence of adoptively transferred T cells associated with tumor regression in a mouse model of prostate cancer. Cancer Immunol Res 2:777-88
Rytelewski, Mateusz; Meilleur, Courtney E; Yekta, Maryam Atef et al. (2014) Suppression of immunodominant antitumor and antiviral CD8+ T cell responses by indoleamine 2,3-dioxygenase. PLoS One 9:e90439
Goodwin, Erin M; Zhong, Qing; Abendroth, Catherine S et al. (2013) Anaplastic renal carcinoma expressing SV40 T antigen in a female TRAMP mouse. Comp Med 63:338-41
Wilson, Jarad J; Pack, Christopher D; Lin, Eugene et al. (2012) CD8 T cells recruited early in mouse polyomavirus infection undergo exhaustion. J Immunol 188:4340-8
Watson, Alan M; Mylin, Lawrence M; Thompson, Megan M et al. (2012) Modification of a tumor antigen determinant to improve peptide/MHC stability is associated with increased immunogenicity and cross-priming a larger fraction of CD8+ T cells. J Immunol 189:5549-60
Maleki Vareki, S; Harding, M J; Waithman, J et al. (2012) Differential regulation of simultaneous antitumor and alloreactive CD8(+) T-cell responses in the same host by rapamycin. Am J Transplant 12:233-9

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