ZIA SC 004020 (ZIA) | |||
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Title | Antigen-specific T-cell Activation, Application to Vaccines for Cancer and AID | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Berzofsky, Jay | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $3,223,418 | Project Dates | null - null |
Fiscal Year | 2018 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Digestive Diseases (15.0%) Interferon (10.0%) Metastasis (30.0%) Childhood Cancers (2.0%) |
Breast (20.0%) Cervical Cancer (5.0%) Lung (10.0%) Melanoma (15.0%) Ovarian Cancer (10.0%) Prostate (25.0%) |
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Research Type | |||
Vaccines Systemic Therapies - Discovery and Development |
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Abstract | |||
The strategies above involve 5 steps that together comprise a push-pull approach, to optimize antigen structure, improve quantity and quality of the response, & remove regulatory barriers. Regulation of tumor immunity by NKT cells. NKT cells are true T cells restricted by a non-classical class I MHC molecule, CD1d, which presents glycolipid antigens. We discovered a novel immunoregulatory pathway in which NKT cells suppress tumor immunosurveillance, using IL-13 to induce myeloid cells to make TGF-b that suppresses immunity. Translating, we completed a phase I trial of anti-TGF-b as a new checkpoint blocker with clinical benefit in several melanoma patients. We discovered synergy between TGF-b blockade and 2 types of cancer vaccines in mice. We found that blockade of TGF-b1 and 2 (without 3) is sufficient to enhance immunosurveillance and vaccine efficacy and that this was further amplified by PD-1 blockade. However, type I (invariant TCR) NKT cells promote tumor immunity, whereas we found that type II (diverse TCR) NKT cells suppressed tumor immunity. These subsets cross-regulate each other, defining a new immunoregulatory axis. We are investigating the relationship between this novel NKT regulatory axis & other regulatory cells and molecules, including Treg cells, MDSCs and PD-1. Recently we found that both type II NKT cells and Treg cells can suppress tumor immunity concurrently, but type I inhibit type II NKT cells and leave Tregs as the dominant suppressor unless type I NKT cells are blocked or absent. Thus, the balance between 2 regulatory cells is determined by a 3rd cell that regulates the regulators. Moreover, we found different regulatory mechanisms in the same tumor in the lung and skin, even in the same mouse. The effector cells also cross between tissues in one direction only. Thus, tissue context determines cancer immunity even for the same tumor, implying that immunotherapy for primary tumors & metastases in different tissues may need to be different. We are performing structure-function studies of synthetic lipids to characterize ones that activate type I vs type II NKT cells. Further, we succeeded in making sulfatide-loaded CD1d tetramers that detect a subset of type II NKT cells in the liver & lung and have extensively characterized these cells, showing differences in surface markers, transcription factors & RNA expression profile. We are also testing the ability of sulfatide analogues to activate or inhibit type II NKT cell activities, both to understand function and to seek a specific antagonist to inhibit type II NKT cells. We identified a new class of agonist for type I NKT cells, b-ManCer, that inhibits tumors by a mechanism distinct from that of a-GalCer, requiring TNF-a and nitric oxide synthase instead of interferon (IFN)-g. This agonist also synergizes with a a-GalCer, is much less anergy-inducing than a-GalCer, and stimulates human NKT cells also. All of these studies are aimed to remove the negative regulatory roadblocks and/or improve the balance along the type I-II NKT axis to allow cancer vaccines to successfully induce tumor regression. Epitope enhancement and T-cell and antibody-based cancer vaccine strategies and translation to clinical trials. We carried out epitope enhancement (sequence modification to improve MHC binding) on an HLA-A2-binding epitope we discovered in a novel prostate and breast cancer antigen, TARP. The enhanced epitope induces human T cells that kill human tumor cells. We translated this to a phase I clinical trial of 2 peptides in stage D0 prostate cancer. 74% of vaccinees had a decreased PSA slope & tumor growth rate at 1 year (p = 0.0004). A randomized placebo-controlled phase II study is ongoing. We have studied a novel adenovirus-based HER-2 vaccine expressing the extracellular (EC) and transmembrane (TM) domains of rat neu (ErbB2), which prevents tumor growth in the neu-transgenic mice, and cures large established TUBO mammary tumors (2 cm) & large established lung m |