- Theme 1: Identifying immune system mechanisms that regulate cancer initiation and progression
- Theme 2: Defining the role of the tumor microenvironment in cancer immunity
- Theme 3: Theme 3: Developing novel approaches to cancer immunotherapy and understanding the mechanisms underlying their efficacy and toxicities
Engineering therapeutic T-cells is a major direction in immunotherapy. Kole Roybal, PhD and Wendell Lim, PhD have developed a new system that allows for Notch-induced expression specific cytokines, antibodies, or other effector molecules by T cells only upon antigen-specific CAR engagement, published in Science and three separate manuscripts in Cell. In pre-clinical studies, they have introduced these elements into primary human CD4+ and CD8+ T cells and, using CAR that target HER2 or CD19, have shown specific production of the cytokines only after interaction of the T cells with tumors bearing the relevant target antigen.4 This system allows local delivery of effector molecules in the solid tumor site that would be toxic if administered systemically. Roybal and Lim are founders of a new biotech, Cell Design Labs, to take these fundamental discoveries into the clinic.
Theme 2: Defining the role of the tumor microenvironment in cancer immunity
Matthew Krummel, PhD and colleagues have identified distinct subsets of myeloid cells within the tumor microenvironment identified by CD103 in mice and CD141 in humans that can positively impact the anti-tumor effects of CD8+ T cells. Additionally, Krummel has developed an intravital two-photon lung imaging technique that has allowed his lab to visualize metastasis of lung cancer cells in the liver by circulating tumor cells and their initial interactions with myeloid cells in the lung. Krummel is founder of a new biotech, Pionyr, that is developing antibody-based therapeutics to interfere with the suppressive myeloid cells in the tumor microenvironment. Krummel and colleagues have established the UCSF ImmunoProfiler Consortium, with partnerships with pharmaceutical companies Amgen, BMS, and Abbvie, to analyze the immune cell composition and gene expression in human biopsy samples taken from cancer patients to understand the nature of the immune response in the tumor microenvironment.
New associate member Matthew Spitzer, PhD, working with Lawrence Fong, MD, has used mass cytometry to compare the leukocytes in the tumor microenvironment, secondary lymphoid tissues, and blood of mice bearing primary or transplantable tumors treated with immunotherapeutic drugs (Cell). This in-depth analysis revealed the unexpected finding that a systemic immune response, detectable in the circulation as well as in lymph nodes, was needed for tumor eradication. Further, a unique subset of peripheral CD4+ T cells was identified that were capable of conferring tumor protection when adoptively transferred into other breast-tumor-bearing mice, and similar T cells were observed in human melanoma patients successfully responding to PD-1 blockade therapy.8 In clinical studies, Adil Daud, MD; Krummel; and Michael Rosenblum, MD, PhD have collaborated to investigate the tumor-infiltrating leukocytes in melanoma patients receiving PD-1 blockade therapy and have defined a profile that predicts successful responses.
Valerie Weaver, PhD has pioneered the area of cell and tissue mechanics in cancer. The extracellular matrix (ECM) stiffening correlates with tumor invasion and metastasis. In a biophysical and biochemical assessment of stromal-epithelial interactions in noninvasive, invasive, and normal adjacent human breast tissue and in breast cancers of increasingly aggressive subtype, Weaver’s analysis revealed that human breast cancer transformation is accompanied by an incremental increase in collagen deposition and a progressive linearization and thickening of interstitial collagen and increased number of infiltrating tumor-associated macrophage. These findings show that collagen linearization and stromal stiffening are linked and implicate tissue inflammation as the cause. In collaboration with scientists at MD Anderson, Weaver found that human PDACs with impaired epithelial transforming growth factor-β (TGFβ) signaling develop stiff, matricellular-enriched fibrosis associated with high epithelial tension and shorter patient survival.
Zena Werb, PhD has shown that inhibition of the CSF-1 receptor on macrophages in particular offers a promising strategy to reduce directed cell migration and tumor dissemination and metastasis. There are currently clinical trials testing this approach in cancer (Nicholas Butowski, MD).
Theme 3: Developing novel approaches to cancer immunotherapy and understanding the mechanisms underlying their efficacy and toxicities
As detailed below, the Cancer Immunotherapy Research Clinic has also initiated numerous trials using new immune-modulating therapeutics and is undertaking an in-depth study of alterations in the immune system of patients under these treatments using state-of-the-art technologies. Hideho Okada, MD, PhD; Daud; Rosenblum; Krummel; and Fong are actively involved in translational studies investigating the immune system of patients undergoing novel immunotherapeutic treatments. In addition, Roybal and Lim are pioneering new technologies to improve the safety and efficacy of CAR T cell therapies by engineering systems to regulate expression and function of the introduced chimeric antigen receptors in pre-clinical studies. Pre-clinical studies are underway in the laboratories of many Program members to further knowledge about the interactions between immune cells and tumors to provide the foundation for planned future therapies.
Jeff Bluestone, PhD is the President and CEO of the Parker Institute for Cancer Immunotherapy (PICI). PICI is a consortium of six universities and cancer centers (UCSF, UC Los Angeles, Stanford, M.D. Anderson Cancer Center, Memorial Sloan Kettering Cancer Center, and University of Pennsylvania) with the goal of enhancing collaborations to accelerate basic discoveries in the field of cancer immunology and immunotherapy. Lewis Lanier, PhD serves as Center Director of the UCSF PICI, with Fong as co-Director.