This year in the U.S. ~40,000 new cases of renal cell carcinoma (RCC) will be diagnosed and >13,000 deaths are expected from RCC. Metastatic RCC carries a median survival of 8 months and ~30% of RCC patients are diagnosed with advanced metastatic disease. Localized RCC is treated surgically through resection;however, there is no efficacious therapy currently available for metastatic disease. Adaptive immunity to RCC plays a critical role in tumor surveillance, with both CD8+ and CD4+ T cells contributing to tumor regression. One of the major sites of RCC metastasis is the lung, an environment that is known to be immunosuppressive even in the absence of tumor outgrowth. Therefore, if novel immunotherapies against metastatic RCC are to move forward into clinical trials, the effect of the lung environment on the generation and maintenance of protective T cell responses, compared to the primary tumor site, must be understood. We previously described the development of a recombinant adenoviral vector encoding the human TNF-related apoptosis-inducing ligand (TRAIL;Ad5-TRAIL) cDNA. More recently, our studies have focused on using a similar recombinant adenovirus encoding full-length murine TRAIL (Ad5-mTRAIL) in immunocompetent mice bearing experimental renal cell carcinoma (Renca) tumors. Antigens derived from Ad5-mTRAIL-killed Renca cells could be cross- presented to CD8+ T cells in vitro, and Ad5-mTRAIL used alone minimally prolonged survival and induced a low level of CTL activity in vivo. To enhance DC efficiency we combined Ad5-mTRAIL with CpG oligonucleotides (CpG), which significantly augmented in vivo antigen-specific T cell proliferation and CTL activity, as well as prolonged survival of Renca tumor-bearing mice. Interestingly, CD4+ or CD25+ cell depletion prior to therapy further enhanced survival and in vivo CTL activity, and CD4+ cell-depleted, tumor-free mice also rejected a subsequent challenge of Renca cells, but not MHC-matched prostate tumor cells, showing the existence of tumor-specific immunologic memory. While the effects of CD4+ cell depletion were striking, survival did not reach 100%, suggesting the presence of additional immunosuppressive mechanisms. In this renewal application, we propose the following specific aims to investigate the hypothesis that localized Ad5-TRAIL administration, when used in conjunction with therapies designed to overcome tumor- derived immunosuppression, will lead to protective antitumor immunity in the lungs of mice with experimental metastatic RCC:
Aim 1) Ascertain the extent to which intratumoral Ad5-mTRAIL/CpG administration at the primary RCC tumor site impacts the magnitude of CD8+ effector T cell responses against experimental lung metastases;
Aim 2) Examine the effect of CD4+ T cell subsets, specifically CD4+CD25+ Treg and Th17, on the quality and quantity of the CD8+ T cell-mediated antitumor response against RCC lung metastases;
and Aim 3) Examine the impact of tumor-infiltrating myeloid cell populations on the lung antitumor immune response during Ad5-mTRAIL/CpG immunotherapy - focusing on the stimulatory versus suppressive capacities of these cells. The current proposal reflects our commitment to develop novel immunotherapies for RCC that can eliminate both primary tumors and distal metastases, thereby prolonging the survival of patients with advanced RCC.

Public Health Relevance

There is great need to continue to develop innovative treatment strategies for patients with progressive metastatic renal cell carcinoma (RCC). Data generated during the previous funding period showing that tumor- specific systemic immunity can be induced using the combination of a recombinant adenovirus encoding the cDNA sequence for full-length murine TNF-related apoptosis-inducing ligand (TRAIL;Ad5-mTRAIL) and immunostimulatory CpG oligonucleotides constitutes the rationale behind the current proposal, where we will investigate the hypothesis that that localized Ad5-mTRAIL administration and the ensuing tumor cell apoptosis, combined with therapies designed to overcome tumor-derived immunosuppression, will lead to systemic protective antitumor immunity in the lungs of mice containing experimental RCC metastases. We will utilize these findings to better devise in vivo approaches for tumor immunotherapy and to understand not only the mechanism of direct action of Ad5-mTRAIL on tumor cells, but to understand some of the fundamental tenets behind the regulation of systemic antitumor immune responses and how tumor cell apoptosis and antigen cross-presentation can be used to stimulate antitumor immunity.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA109446-11
Application #
8484212
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Welch, Anthony R
Project Start
2004-06-15
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
11
Fiscal Year
2013
Total Cost
$242,926
Indirect Cost
$78,632
Name
University of Minnesota Twin Cities
Department
Urology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Amarante-Mendes, Gustavo P; Griffith, Thomas S (2015) Therapeutic applications of TRAIL receptor agonists in cancer and beyond. Pharmacol Ther 155:117-31
Brincks, Erik L; Kucaba, Tamara A; James, Britnie R et al. (2015) Triptolide enhances the tumoricidal activity of TRAIL against renal cell carcinoma. FEBS J 282:4747-65
Murphy, Katherine A; James, Britnie R; Guan, Yue et al. (2015) Exploiting natural anti-tumor immunity for metastatic renal cell carcinoma. Hum Vaccin Immunother 11:1612-20
Wald, Gal; Barnes, Kerri T; Bing, Megan T et al. (2014) Minimal changes in the systemic immune response after nephrectomy of localized renal masses. Urol Oncol 32:589-600
Anderson, Kristin G; Mayer-Barber, Katrin; Sung, Heungsup et al. (2014) Intravascular staining for discrimination of vascular and tissue leukocytes. Nat Protoc 9:209-22
James, Britnie R; Anderson, Kristin G; Brincks, Erik L et al. (2014) CpG-mediated modulation of MDSC contributes to the efficacy of Ad5-TRAIL therapy against renal cell carcinoma. Cancer Immunol Immunother 63:1213-27
Rodrigue-Gervais, Ian Gaël; Labbé, Katherine; Dagenais, Maryse et al. (2014) Cellular inhibitor of apoptosis protein cIAP2 protects against pulmonary tissue necrosis during influenza virus infection to promote host survival. Cell Host Microbe 15:23-35
James, Britnie R; Brincks, Erik L; Kucaba, Tamara A et al. (2014) Effective TRAIL-based immunotherapy requires both plasmacytoid and CD8α dendritic cells. Cancer Immunol Immunother 63:685-97
James, Britnie R; Tomanek-Chalkley, Ann; Askeland, Eric J et al. (2012) Diet-induced obesity alters dendritic cell function in the presence and absence of tumor growth. J Immunol 189:1311-21
Norian, Lyse A; Kresowik, Timothy P; Rosevear, Henry M et al. (2012) Eradication of metastatic renal cell carcinoma after adenovirus-encoded TNF-related apoptosis-inducing ligand (TRAIL)/CpG immunotherapy. PLoS One 7:e31085

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