Immunology & Cancer Immunotherapy Program Activities and Selected Scientific Reports
The Cancer Immunotherapy Program at Norris Cotton Cancer Center is located at Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire. Mary Jo Turk, PhD and Kenneth R. Meehan, MD are the leaders of this program, which is one of six foundational research programs at the Norris Cotton Cancer Center. The twenty-five members of Cancer Immunotherapy come from five departments across the Geisel School of Medicine, the Dartmouth-Hitchcock Medical Center, and the Thayer School of Engineering at Dartmouth College.
The program's members meet monthly to exchange ideas and research updates. On an annual basis, Cancer Immunotherapy gathers for a retreat specific to immunology. As appropriate, program members plan topical meetings to address particular issues in great depth. The lively Dartmouth campus provides many other opportunities for scientific involvement and members from Cancer Immunotherapy are regular participants in both the Microbiology & Immunology, and Immunology Seminar Series. Similarly, symposia are organized, such as the Annual Dartmouth Immunology & Immunotherapy Symposium.
Education and mentoring are top priorities of our Program. In cooperation with Dartmouth’s NIH-funded SYNERGY Clinical and Translational Science Institute, senior ICIP members provide formal mentorship for program junior clinician-scientists in designing clinical trials, and securing grant funding in cancer immunotherapy. Our faculty are heavily involved in the training of fellows, residents, and medical students, as well as classroom instruction for medical, graduate, and undergraduate students across the Dartmouth campus and the Dartmouth-Hitchcock Medical Center.
2017-2018 Research Highlights
VISTA; a novel negative immune checkpoint in cancer
Dr. Noelle and his team reported the discovery of a novel negative checkpoint regulator for cancer; V-domain Ig suppressor of t cell activation (VISTA). The VISTA research program at NCCC has grown steadily during the past 5 years, now involving ten current ICIP members, collaborative members from other programs (CM and CIR), and multiple industry partners.
In 2014, Dr. Noelle showed that the administration of a VISTA mAb as monotherapy significantly suppresses the growth of transplantable and inducible tumors (Le Mercier, Cancer Res 2014, 24691994). This study also demonstrated synergy between VISTA blockade and vaccination to impair the growth of established melanoma tumors. The importance of VISTA for MDSCs suppression was further illustrated by Dr. Green, in collaboration with Dr. Noelle, who used an oncogenic immunodeficiency-inducing retroviral model to demonstrate that VISTA blockade interferes with MDSC suppression of B cell responses (Green J. Virol. 2015, 26157131). While this early work was done in mice, a study from Dr. Noelle, in collaboration with historic ICIP members Ernstoff and Wang, further established VISTA as a negative checkpoint regulator in human T cells (Lines, Cancer Research 2014, 24691993). This study reported the structure of human VISTA and showed its expression predominantly within the myeloid lineage in the tumor microenvironment. The above studies, combined with additional unpublished work from Drs. Noelle and Turk, resulted in the funding of a multi-PI R01 to Drs. Noelle and Turk, beginning in 2016 (R01CA214062), to study the mechanisms by which VISTA blockade eradicates large, established anti-PD-1/CTLA-4 resistant tumors. Specific aims include mechanistic mouse studies as well as the analysis of human colorectal cancers, led by Co-I’s Stan and Barth (CIR), and bioinformatic studies, led by Co-I Dr. Cheng (CM).
In 2016, Dr. Fiering discovered that intratumoral injection of cowpea mosaic viral nanoparticles generates systemic immunity against metastatic melanoma (Lizotte, Nat Nanotechnol 2016, 26689376). In collaboration with Dr. Nicole Steinmetz (UCSD), the Fiering laboratory further established the potency of combining plant viral nanoparticles with standard cancer chemotherapy (Lee et. al. Nano Lett. 2017, 28650644). The efficacy of this approach was displayed against an aggressive murine model of ovarian cancer (Patel ACS Omega 2018, 29732445). In cross-programmatic collaboration with Dr. Hoopes (CIR), this project was rapidly translated to clinical studies in canine animals at NCCC. Drs. Fiering and Hoopes (CIR) have recently reported the successful treatment of canine oral melanoma by intratumoral injection of plant viral nanoparticles, in conjunction with either magnetic nano-particle based hyperthermia (Hoopes et. al. Proc SPIE Int Soc Opt Eng 2017, 29203951), or with local radiation therapy (Hoopes et. al. Mol Pharm 2018, 29613803). This project has led to a large collaborative multi-institutional NCI program grant (U01CA218292) awarded in 2017, which is led by Dr. Steinmetz at the NCI-designated UCSD Moores Cancer Center, with Dr. Fiering as a project leader and Dr. Hoopes (CIR) as a Co-I. The goal of these studies is to delineate the underlying mechanisms of immune activation primed by plant viral-like particles and to gain further insights into mechanisms of action and efficacy through further study of companion dogs with oral melanoma.
ICIP continues to greatly benefit from collaborations with the Thayer School of Engineering at Dartmouth. Dr. Margie Ackerman became a formal member of ICIP in 2018, following several years of collaboration with program members. Dr. Ackerman is an expert in antibody engineering, and most recently has optimized the design of B7H6-targeted receptors for Dr. Sentman’s new CAR T cell platform. As mouse single chain variable fragments have the potential to induce host anti-CAR responses, Drs. Ackerman and Sentman developed unique CARs against B7H6 based on human scFv’s (Hua et. al. Protein Eng Des Sel 2017). They subsequently showed that these novel human CARS preferentially trigger the cytotoxic function of T cells against B7H1-expressing cancer cells (Gacerez et al. Cancer Immunol Immunother 2018, 29453518). Optimization of CAR constructs continues to be a focus of Drs. Sentman and Ackerman’s ongoing research.
Memory T cell responses to cancer
Studies published by Dr. Turk, in collaboration with Drs. Huang, and Angeles, revealed that resident memory CD8 T cells in the skin are required for durable protection against melanoma (Malik et. al. Science Immunol, 2017). Building on prior work in the Turk laboratory, this study also showed that autoimmune vitiligo provides a hospitable niche for the long-term maintenance of tumor-specific CD8 T cells in the skin of mice, and identifies CD103 as a T cell-intrinsic requirement for TRM generation. In her role as PI of a clinical protocol, Dr. Angeles has begun to accrue patients to study TRM responses in the skin of melanoma survivors with vitiligo and other skin adverse events. This clinical study was supported by a Dartmouth SYNERGY Clinical Investigator Fellowship Award to Dr. Angeles, in collaboration with Drs. Turk, Barth (CIR), Shirai, Chapman, and Ernstoff (now at Roswell Park). A Munck-Pfefferkorn award to Drs. Turk, Huang, Usherwood, Pioli, and Cheng (CM) with new capabilities developed in Dr. Tomlinson’s Genomics Shared Resource, has separately enabled successful single-cell deep sequencing of anti-tumor TRM cells from mice. This project has resulted in the funding of an NCI R01 to Dr. Turk in 2018, with Drs. Huang, Angeles, Cheng (CM) and Gui (CEB). These translational studies have been among the first to characterize resident memory T cell responses to cancer.