Vaccine and immunotherapy strategies for cancer and viruses causing cancer

Division Of Clinical Sciences - Nci

Investigators

Linked publications & trials

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, and remove regulatory barriers. Regulation of tumor immunity by NKT cells: NKT cells are true T cells recognizing glycolipid antigens presented by CD1d. 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. We completed a phase I trial of anti-TGF-b with clinical benefit in melanoma patients. We discovered synergy between TGF-b blockade and cancer vaccines in mice. Blockade of TGF-b1 / 2 (without 3) was sufficient to enhance vaccine efficacy, 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 suppress tumor immunity. We discovered these subsets cross-regulate each other, defining a new immunoregulatory axis. We are investigating relationships with other regulatory cells/ molecules. Both type II NKT cells and 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 distinct regulatory cells dominate in the same tumor in the lung and skin. Thus, tissue context determines cancer immunity for the same tumor, implying that immunotherapy for primary tumors and metastases in different tissues may unexpectedly need to be different. We are performing a structure-function study of sulfatide analogs to activate or inhibit type II NKT cell activities. One sulfatide analog stimulates type II NKT cells when not processed, but type I NKT cells when processed by DCs , and under that condition can prevent instead of promote cancers. Endosomal processing by arylsulfatase A converts sulfatide to b-GalCer, not expected to be active, but which turned out to be a strong type I NKT cell stimulant. This is the first case of glycolipid processing that changes cell tropism and reverses function. 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, synergizes with a-GalCer, is much less anergy-inducing than a-GalCer, and stimulates human NKT cells also. Studies using structure-specific antibodies showed that b-ManCer could assume a structure resembling a-GalCer. All of these studies are aimed to remove the roadblocks to allow cancer vaccines to successfully induce tumor regression. Epitope enhancement in cancer vaccine strategies and translation to clinical trials: We first devised and 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 and tumor growth rate at 1 year (p = 0.0004). We studied preclinically and published 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) and 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 translated to a clinical autologous DC vaccine transduced with an Ad5f35 expressing the EC and TM domains of human HER2 and have now published a phase I/II trial of this human vaccine. At vaccine doses of 10-40 million DCs, 7/21 (33%) evaluable patients showed clinical benefit (CR, PR, or SD) and complete safety. A new study combining this vaccine with checkpoint inhibitors (anti-PD-1, a VEGFR inhibitor, and an enhanced IL-15) in endometrial cancer is under review. We also found preliminary data for synergy among anti-TGFb, anti-LAG3, anti-TIGIT and anti-PDL1. Without the vaccine, the checkpoint inhibitors don't work without anti-TGFb. We also found vaccine efficacy enhancement by blockade of PD-L1 and TIGIT, a combination further enhanced by CD4 T cell depletion. Based on DTR-Foxp3 Knock-in mice, the enhancement was due to removal of Foxp3+ CD4 Treg cells. Thus, inhibitors of negative regulation amplify the vaccine efficacy. Moreover, we are defining signature expression profiles of different tumors that allow prediction of which combination of inhibitors will be most effective for each. We invented a new modified a-GalCer (PLS-a-GalCer) that is more potent in treating mouse tumors, and are investigating the mechanism, involving targeting a scavenger receptor by PLS. We also carried out a CRADA-collaborative study in mice of an intratumoral therapy that we found induces a T cell response necessary for regression. This has been translated to the clinic by our collaborators. We are examining the effects of cholesterol and omega-3 lipids in regulating tumor growth in mice. Tumor growth is slowed in mice that genetically make more omega-3 lipids, and cancer vaccine efficacy is enhanced. Indeed, DCs from the transgenic mice are more effective vaccine vehicles, and the effect can be mimicked by growing DCs in lipid-containing media. We also initiated a CRADA with BriaCell to test the ability of semi-allogeneic DCs to act as more effective cancer vaccine vehicles by recruiting allogeneic help, and have now shown proof of concept. Also, we opened a CRADA with Portage Biotech to examine the ability of their agents that block RAGE or adenosine receptors, and activate the STING pathway to enhance cancer vaccine efficacy. Cytokines as vaccine adjuvants for induction of high avidity T cells: Our earlier work showed that high avidity T cells were more effective at clearing viral infections and cancers. We discovered ways to induce them with cytokines and TLR ligands and a novel adjuvant, CAF09. The quality of response proved more important than the quantity. We also found that IL-1b induces Th17 helper cells that do not help Tc1 CD8 T cells that protect against virus. Rather, they skew the T cells to Tc17 that make IL-17 and do not protect. TGF-b blockade can prevent this problem. We also examined combinations of cytokines and TLR ligands as vaccine adjuvants and found greatest efficacy of IL-15 + TLR3 and TLR9 agonists, followed by IL-12 + GM-CSF. Mucosal immunity, microbiome: We are also examining the effect of the gut microbiome on cancer, and of NKT cells on the gut microbiome and the downstream effect on cancer. We have bred Ja18 knockout (KO) mice that lack type I NKT cells only, and CD1d KO mice that lack both type I and type II NKT cells, along with wild type B6 mice that have both types in the same facility. We collected their gut microbiome samples at ages 14, 23, 30, 60 and 90 days, and did 16S RNA sequencing with the CCR Microbiome Core. We cohoused mice pairwise from day 30 to day 90 and examined the ability of microbes to be transferred. We are finding microbes that grow selectively in mice lacking or retaining different subsets of NKT cells. This could provide an indirect mechanism by which the presence or absence of different types of NKT cells can affect cancer growth through altering the microbiome.