Heralded as the “Breakthrough of 2013” by the leading scientific journal Science, cancer immunotherapy is finally getting the attention many in the field thought it long deserved.
This breakthrough is not the result of one or two “eureka” moments. Instead, it is the culmination of more than two decades of insights made into the basic biology of immune cell action, followed by remarkable success in pre-clinical studies, anecdotes of impressive responses in individual patients and, finally, robust clinical trials.
Immunotherapy, the use of the immune system to treat cancer, encompasses diverse approaches: from stimulating a patient’s immune system to attack tumor cells, to administering immune system components, such as antibodies, as a cancer treatment.
The identification of tumor antigens, which are the tumor-specific peptides or proteins that trigger an immune response, led to the development of specific therapeutic cancer vaccines against these antigens.
Our current understanding of the complex immunoregulatory processes active in the tumor microenvironment (i.e., the cellular environment in which tumor cells interact with blood vessels, immune cells, and other cell types) has further accelerated immunotherapy development.
In fact, anti-cytotoxic T-lymphocyte antigen (CTLA)-4 antibody (ipilimumab) treatment improved survival of melanoma patients by 20%.
It was approved by the U.S. Food and Drug Administration for the treatment of advanced melanoma in 2011. Recent studies of combination therapy with this antibody and nivolumab, an antibody against the programmed death 1 (PD-1) receptor, in melanoma patients looks even more promising.
These findings, and others, illuminate the potential of harnessing the immune system for cancer therapy and suggest that researchers are only scratching the surface of its promise.At the University of Chicago Medicine Comprehensive Cancer Center, investigators are pioneering new approaches to cancer immunotherapy and discovering the basic mechanisms by which cancer cells and immune cells in the tumor microenvironment communicate.
The laboratory of Yang-Xin Fu, MD, PhD, professor of pathology, is developing ways to mobilize the immune system for more robust anti-tumor therapy. In a recent report published in the journal Cancer Cell, they uncovered how tumors develop resistance to therapeutic antibodies that target oncoproteins, such as HER2 and the epidermal growth factor receptor (EGFR).
These antibodies, such as cetuximab and trastuzumab, are used to treat specific types of breast, head and neck, and colorectal cancer. Fu and his team demonstrated that immune modulation with the powerful cytokine interferon beta (IFNβ) controls antibody resistance in preclinical tumor models. This design of a next generation of antibody-based cancer therapy, which Fu compared to the combination of a missile and a bomb, allows for stimulation of immune cells in the tumor microenvironment for sustained tumor destruction.As Fu explained, “Tumors are heterogeneous, and traditional treatments will result in the outgrowth of a particular population that has become resistant to that treatment. To prevent tumor relapse, we now appreciate that you have to understand and mobilize the immune system.”
In a long-time collaboration with Ralph Weichselbaum, MD, D.K. Ludwig Professor and Chair of Radiation and Cellular Oncology, Fu also is identifying ways to use the immune system to enhance the anti-tumor effects of radiation therapy.
Their recent work showed that blockade of the T-cell modulator programmed death-ligand 1 (PD-L1) made radiation much more effective at shrinking tumors in preclinical models. These findings suggest that radiation, T cells, and the PD-L1 signaling networks function together and could be exploited for designing potent combination therapies with immune modulators and radiotherapy.Other promising advances in the field of immunotherapy have come from Comprehensive Cancer Center members Thomas Gajewski, MD, PhD, professor of pathology and medicine and leader of the Immunology and Cancer Program of the Comprehensive Cancer Center, and Hans Schreiber, MD, PhD, professor of pathology.
Gajewski’s group focuses on the regulation of anti-tumor immunity and recently showed that CD8+ T cells drive PD-L1 production and regulatory T cell accumulation in the melanoma tumor microenvironment, which are now being targeted therapeutically. Characterizing how tumors escape from host immunity is a major effort in Schreiber’s laboratory.
They showed, in a 2013 study published in Cancer Cell, that tumor relapse is determined by how strongly tumor antigens are bound to the cell surface molecules that ultimately elicit an immune response, such that only high-affinity interactions lead to cancer eradication. Additionally, all three laboratories collaborate extensively to tackle the biggest challenges in immunotherapy field.
This article is part of a special series on personalized medicine by the University of Chicago Medicine Comprehensive Cancer Center.