The strategies above involve 5 steps that together comprise a push-pull approach, to optimize antigen structure, improve quantity & 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 & 2 types of cancer vaccines in mice. We found that blockade of TGF-b1 & 2 (without 3) is sufficient to enhance immunosurveillance & vaccine efficacy and this was further amplified by PD-1 blockade. 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 NKT regulatory axis & other regulatory cells & molecules, including Treg cells, MDSCs & PD-1. We found that both type II NKT cells & Treg cells can suppress tumor immunity concurrently, but type I inhibit type II NKT cells, leaving 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 cells dominate in the same tumor in the lung & skin. 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, not widely recognized by oncologists. We succeeded in making sulfatide-loaded CD1d tetramers that detect a subset of type II NKT cells in the liver & lung and have characterized these cells, showing differences in markers, transcription factors & RNA expression. We are also testing the ability of sulfatide analogues to activate or inhibit type II NKT cell activities. One sulfatide analog that stimulates type II NKT cells reduces tumors instead of promoting them & may be a clinically useful antagonist of 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 & nitric oxide synthase instead of interferon (IFN)-g. This agonist also synergizes with a-GalCer, is much less anergy-inducing than a-GalCer, & stimulates human NKT cells also. All of these studies are aimed to remove the roadblocks and/or improve the balance along the type I-II NKT axis to allow cancer vaccines to successfully induce tumor regression. Epitope enhancement, cancer vaccine strategies & 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 & 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. All 6 vaccinated patients in the safety lead-in had flat or reduced PSA slope. 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) & established lung metastases. The therapeutic effect in mice is purely antibody mediated, through inhibiting ErbB-2 function, unlike trastuzumab, which is FcR dependent, so may work in trastuzumab failures. We are carrying out a phase I/II trial of a human version of this vaccine. In Part 1, in HER2+ cancer in patients naive to HER2 therapy, at the 2nd & 3rd dose levels, 5/10 (50%) evaluable patients showed clinical benefit and complete safety, allowing starting Part 2 in HER2 3+ breast cancer patients who had progressed on HER2 therapy. In Part 2, so far 1/4 evaluable patients showed stable disease for 24 weeks. We also carried out a CRADA-collaborative study in mice of an intratumoral therapy that we found induces a T cell response necessary for full regression and results in long-term memory & resistance to rechallenge. Cytokines as vaccine adjuvants and induction of high avidity T cells. Our earlier work showed that high avidity T cells were more effective at clearing viral infections & cancers, and we found ways to induce them with cytokines & TLR ligands. The quality of response proved more important than the quantity. We recently found, using a novel adjuvant, CAF09, that we could lower the vaccine dose sufficiently to induce higher avidity CD4 T cells to better clear virus infection. We also found that IL-1b induces Th17 helper cells that do not work well to help Tc1 CD8 T cells that protect against vaccinia virus. Rather, they skew the CD8 response to Tc17 cells that make IL-17 & do not protect. TGF-b blockade can prevent this problem. We also found that IL-21 synergizes with IFN-g to induce IFN-stimulated genes & clear Citrobacter colitis through an effect on STAT1. Mucosal immunity, microbiome & HIV/SIV vaccines. About 85% of HIV transmission is mucosal. We found that a mucosal T cell vaccine can impact the initial mucosal nidus of infection. We are studying induction & trafficking of T cells, DCs, & MDSCs among mucosal compartments to optimize mucosal vaccine efficacy. In mice, we found that T cells could be directly primed in the vaginal mucosa, despite lack of organized lymphoid structures, contrary to textbook dogma. We also discovered that colonic DCs can imprint CD8 T cells to home back to the colon preferentially, based on differential retinoic acid expression vs. small intestine DCs. We discovered that altering a cathepsin S cleavage site could protect an immunodominant epitope of gp120 from degradation in endosomes during cross-presentation, providing proof of concept for a novel mechanism of virus escape for viruses like HIV that infect mostly non-APCs. Using NHP models, we found that activated mucosal T cells determine susceptibility to infection (transmission), eclipse time prior to systemic viral detection, & acute viral load. We found that even in naive animals, gut microbiota can strongly affect susceptibility to transmission, by affecting immune activation, and also affect vaccine efficacy. Further, we found that vaccines can induce MDSCs that counteract vaccine protection, and infection can affect trafficking of MDSCs. We also demonstrated for the first time that MDSCs could be infected by SHIV in vivo. We have translated our oral nanoparticle (NP) approach to macaque SIV vaccines and have found reduced risk against SHIV rectal acquisition in 2 studies. Surprisingly, we discovered that protection against SIV acquisition in 3 studies can occur without anti-envelope antibodies. While T cell immunity was induced, it did not correlate with protection. Rather, protection correlated with trained innate immunity, involving monocyte memory for SIV in induction of cytokines. In addition, we are combining an SIV vaccine & mucosal NP boost to increase mucosal immunity with a microbicide to reduce the viral inoculum in an OAR-funded study.

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National Cancer Institute (NCI)
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O'Konek, Jessica J; Ambrosino, Elena; Bloom, Anja C et al. (2018) Differential Regulation of T-cell mediated anti-tumor memory and cross-protection against the same tumor in lungs versus skin. Oncoimmunology 7:e1439305
Paquin-Proulx, Dominic; Greenspun, Benjamin C; Pasquet, Lise et al. (2018) IL13R?2 expression identifies tissue-resident IL-22-producing PLZF+ innate T cells in the human liver. Eur J Immunol 48:1329-1335
Jin, Ping; Chen, Wenjing; Ren, Jiaqiang et al. (2018) Plasma from some cancer patients inhibits adenoviral Ad5f35 vector transduction of dendritic cells. Cytotherapy 20:728-739
Frey, Blake F; Jiang, Jiansheng; Sui, Yongjun et al. (2018) Effects of Cross-Presentation, Antigen Processing, and Peptide Binding in HIV Evasion of T Cell Immunity. J Immunol 200:1853-1864
Kato, Shingo; Berzofsky, Jay A; Terabe, Masaki (2018) Possible Therapeutic Application of Targeting Type II Natural Killer T Cell-Mediated Suppression of Tumor Immunity. Front Immunol 9:314
Maeng, Hoyoung; Terabe, Masaki; Berzofsky, Jay A (2018) Cancer vaccines: translation from mice to human clinical trials. Curr Opin Immunol 51:111-122
Dzutsev, Amiran; Hogg, Alison; Sui, Yongjun et al. (2017) Differential T cell homing to colon vs. small intestine is imprinted by local CD11c+ APCs that determine homing receptors. J Leukoc Biol 102:1381-1388
Castiello, Luciano; Sabatino, Marianna; Ren, Jiaqiang et al. (2017) Expression of CD14, IL10, and Tolerogenic Signature in Dendritic Cells Inversely Correlate with Clinical and Immunologic Response to TARP Vaccination in Prostate Cancer Patients. Clin Cancer Res 23:3352-3364
Terabe, Masaki; Robertson, Faith C; Clark, Katharine et al. (2017) Blockade of only TGF-? 1 and 2 is sufficient to enhance the efficacy of vaccine and PD-1 checkpoint blockade immunotherapy. Oncoimmunology 6:e1308616
Speir, M; Authier-Hall, A; Brooks, C R et al. (2017) Glycolipid-peptide conjugate vaccines enhance CD8+ T cell responses against human viral proteins. Sci Rep 7:14273

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