Tumors actively suppress immune response against themselves. This creates a fundamental barrier to successful immunotherapy, but the underlying molecular mechanisms are still poorly understood. This proposal builds upon the novel discovery that three key molecular pathways - indoleamine 2,3-dioxygenase (IDO), CD40/CD40L and CTLA-4 - all become tightly linked in tumor-bearing hosts, functioning together as a single integrated regulatory network. This innovative model is supported by important new discoveries made during the previous period of support, including the role of IDO in activating highly suppressive Tregs in tumor-bearing hosts;and identification of a novel subset of "reprogrammable" Foxp3+ Tregs that is capable of converting into pro-inflammatory, CD40L-expressing helper T cells under suitable conditions. The current proposal will use informative mouse preclinical models to develop clinically-applicable, mechanistically-based immunotherapy regimens. These regimens will incorporate the first-in human IDO-inhibitor drug 1-methyl-D-tryptophan (1MT), now in Phase I clinical trials, in combination with chemotherapy and active immunotherapy.
Aim 1 will test the hypothesis that the highly suppressive Tregs in tumor-draining lymph nodes (TDLNs) can be de-activated and rendered non-suppressive by simultaneously blocking IDO and providing a strong proinflammatory signal through the CD40/CD40L pathway.
Aim 2 will test the hypothesis that DCs in TDLNs can be licensed for robust and effective cross-presentation of endogenous tumor antigens by preventing the tolerogenic DC phenotype that is induced by IDO-activated Tregs via the CTLA-4/B7/FOXO3 pathway, and simultaneously driving the DC-activating/licensing CD40/CD40L pathway.
Aim 3 will test the hypothesis that the late stages of the CD8+ cytotoxic T cell response (clonal expansion, effector differentiation, and long-term memory formation) can be markedly enhanced by blocking the cell-intrinsic inhibitory effect of CTLA-4 on the CD8+ cells, and that this cell-intrinsic effect of CTLA-4 different from - and acts synergistically with - the upstream cell-extrinsic effects of interrupting the IDO/CTLA-4 loop during the initial priming stage.
These Specific Aims continue the project's strongly translational and pre-clinical therapeutic focus. The overall goal of the current proposal is to develop novel high-potency combination regimens that leverage the synergy of IDO-inhibitor drugs in combination with CD40 agonist antibodies, chemotherapy, and CTLA-4 blockade. The strategies proposed are timely, high-impact, and have a clear path to the clinic. The proposed studies bring new mechanistic insights to bear on the difficult and important clinical problem of identifying highly potent and synergistic multi-aget immunotherapy regimens, and provide testable outcome measures at the molecular level to evaluate whether each proposed strategic intervention is hitting its hypothesized target.

Public Health Relevance

Clinical strategies that use the body's own immune system to kill cancer cells are now poised to enter mainstream cancer therapy. The current proposal addresses a key unmet need in this field, asking what is the best way to combine powerful immunologic therapies so that they take advantage of the natural synergies between the complementary mechanisms and pathways, while minimizing the degree of toxicity to the patient.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA096651-11
Application #
8508861
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Yovandich, Jason L
Project Start
2002-07-01
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
11
Fiscal Year
2013
Total Cost
$226,477
Indirect Cost
$75,492
Name
Georgia Regents University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Sharma, Madhav D; Huang, Lei; Choi, Jeong-Hyeon et al. (2013) An inherently bifunctional subset of Foxp3+ T helper cells is controlled by the transcription factor eos. Immunity 38:998-1012
Divanovic, Senad; Sawtell, Nancy M; Trompette, Aurelien et al. (2012) Opposing biological functions of tryptophan catabolizing enzymes during intracellular infection. J Infect Dis 205:152-61
Ravishankar, Buvana; Liu, Haiyun; Shinde, Rahul et al. (2012) Tolerance to apoptotic cells is regulated by indoleamine 2,3-dioxygenase. Proc Natl Acad Sci U S A 109:3909-14
Baban, Babak; Chandler, Phillip R; Johnson 3rd, Burles A et al. (2011) Physiologic control of IDO competence in splenic dendritic cells. J Immunol 187:2329-35
Makala, Levi H C; Baban, Babak; Lemos, Henrique et al. (2011) Leishmania major attenuates host immunity by stimulating local indoleamine 2,3-dioxygenase expression. J Infect Dis 203:715-25
Sharma, Madhav D; Hou, De-Yan; Baban, Babak et al. (2010) Reprogrammed foxp3(+) regulatory T cells provide essential help to support cross-presentation and CD8(+) T cell priming in naive mice. Immunity 33:942-54
Munn, David H (2010) Lineage-specific transcription factors in unexpected places. Eur J Immunol 40:315-7
Johnson 3rd, Burles A; Kahler, David J; Baban, Babak et al. (2010) B-lymphoid cells with attributes of dendritic cells regulate T cells via indoleamine 2,3-dioxygenase. Proc Natl Acad Sci U S A 107:10644-8
Ding, Zhi-Chun; Blazar, Bruce R; Mellor, Andrew L et al. (2010) Chemotherapy rescues tumor-driven aberrant CD4+ T-cell differentiation and restores an activated polyfunctional helper phenotype. Blood 115:2397-406
Baban, Babak; Chandler, Phillip R; Sharma, Madhav D et al. (2009) IDO activates regulatory T cells and blocks their conversion into Th17-like T cells. J Immunol 183:2475-83

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