Drugs that direct a cancer patient's immune system to eradicate her or his disease, known as cancer immunotherapies, promise to be a new tool in the fight against cancer. Since the Koch Institute's inception, exploring the close relationship between the immune system and cancer has been one of the Institute's priority research areas. The recent release of very encouraging early-stage clinical data from various cancer immunotherapies in development has generated considerable optimism in the cancer research and clinical communities, and in the pharmaceutical industry.
Following this excitement, on June 14, 2013, the KI dedicated its annual Summer Symposium to the topic, hosting "Cancer Immunology and Immunotherapy." Approximately 1,000 cancer researchers, tumor immunologists, engineers, and clinical oncologists gathered at MIT's Kresge Auditorium to discuss the latest breakthroughs in developing cancer immunotherapies, as well as challenges in unraveling the complexities of the immune system's interactions with growing tumors. Among the symposium speakers was Robert Schreiber from Washington University School of Medicine. Twelve years ago, Schreiber's work led to the concept of cancer immunoediting, which has gained widespread acceptance in the last few years. According to this principle, the immune system can suppress tumor growth by destroying cancer cells or inhibiting their growth, but it also promotes tumor progression by selecting for tumor cells that are more fit to survive or by establishing conditions within the tumor microenvironment that facilitate tumor growth.
To date, the FDA has approved only two cancer immunotherapies. One, ipilimumab, is for advanced melanoma; the other, sipuleucel-T, is for prostate cancer. "These are just the leading edge of a number of new immunotherapies that are showing tremendous promise in the clinic," said KI faculty member and symposium co-organizer Darrell Irvine during his opening remarks. In his comments, KI Director Tyler Jacks noted that the significant advances made in cancer immunology over the last three decades are finally coming to fruition and are being translated into the clinic very quickly - more so than in any other area of cancer research. Ongoing trials may soon bring immunotherapies for lung, kidney, and stomach cancers to the market. It is estimated that in ten years, cancer immunotherapy drugs will be used to treat 60% of cancers.
In line with the KI's commitment to revolutionizing cancer research by integrating advanced biological investigation with engineering technology, the symposium highlighted not only basic research and clinical breakthroughs but also novel engineering solutions that help us better understand the immune response against cancer and create new therapies that improve that response.
Reprogramming T-cells
One of the major themes discussed at the symposium was how to boost the function of T-cells, the workhorse of the immune system, so that they become more efficient cancer killers. PROVENGE® (sipuleucel-T), for example, the first approved cancer vaccine and one of only two FDA-approved immunotherapies on the market, is an infusion made from activated dendritic cells from the patient. Inside the body, these cells prime a specific T-cell response to attack the patient's advanced prostate cancer. The reprogramming of these cells, however, is done ex vivo. The patient's own dendritic cells are collected three days before each scheduled infusion, manipulated in the lab, and infused back into the patient. Speaker David Mooney, from the Wyss Institute for Biologically Inspired Engineering at Harvard, described his groundbreaking work designing biomaterials that eliminate the need for this external manipulation. Small pieces of plastic (implantable polymer vaccines) are engineered to recruit the dendritic cells and do all the reprogramming and activation in situ, or inside the body. Mooney has demonstrated the therapeutic effect of these dendritic cell vaccines in pre-clinical models, and a clinical trial for a therapeutic melanoma vaccine that uses the same technology is about to start enrolling patients.
Developing a therapeutic cancer vaccine can nevertheless be a daunting task. For example, symposium speaker Cornelia L. Trimble, from Johns Hopkins University School of Medicine, described the challenges involved in the development of therapeutic cancer vaccines to treat preinvasive HPV disease, which causes certain types of cervical cancer. Most of these efforts, including a DNA vaccine she has developed, have failed because they trigger peripheral blood T-cell responses but lack responses in the tissue where the disease establishes itself. "It's not only about triggering a bigger immune response but also about telling it where to go," she said.
In contrast, symposium co-organizer Darrell Irvine explained how his team has enhanced the success of immune cell therapy by applying drug-delivery modifications to T-cells. Irvine's team boosts T-cell function in vivo by linking drug carriers directly to the surface of the cells. These engineered surface-decorating nanoparticles selectively augment the T-cells' ability to infiltrate the tumor. With Irvine's technology, T-cells can be programmed in vitro to home to specific tissues without relying on antigen recognition. Presenting another example of reprogramming T-cells to attack cancer, Carl June, from the University of Pennsylvania's Perelman School of Medicine, described his work using a form of HIV to reengineer patients' T-cells. Thanks to the treatment his clinical trial patients, whose leukemia did not respond to standard therapies, are in full or partial remission with a very high response rate.
K. Dane Wittrup, Associate Director of the KI, provided a different example of how to use T-cell therapy. To exploit the full power of the immune system in tumor-targeting antibody therapies, Wittrup combines standard antibody therapy with T-cell cancer immunotherapy. "In mouse models, taking an engineered long-lived form of IL-2 that enhances T-cell signaling properties and combining it with an anti-tumor antibody gives a qualitatively bigger effect than any of the two agents alone," Wittrup explained. "CD8 T-cells and neutrophils are required for this therapeutic effect."
Removing the immune system's brakes
The approval of Yervoy (ipilimumab) in 2011 generated a lot of excitement, as it was the first drug to significantly extend survival in patients with advanced melanoma. This monoclonal antibody boosts the immune system by blocking a protein named cytotoxic T-lymphocyte antigen or CTLA-4, which plays a role in slowing down or turning off the body's immune system and affects its ability to fight off cancer cells. Symposium speaker F. Stephen Hodi, Jr., Director of the Melanoma Center at the Dana-Farber Cancer Institute, is the principal investigator of the first phase II clinical trial to look at the combination of ipilimumab with a medication that stimulates the production of white blood cells (the granulocyte macrophage colony-stimulating factor sargramostim). Hodi reported that in patients with metastatic melanoma, this combination noticeably extended survival rates and improved tolerability when compared with ipilimumab alone. These data open the door to considering the potential use of GM-CSF in combination with other immune therapies in development to improve efficacy and minimize side effects.
Building on the concept behind successful anti-CTLA-4 therapy, there have been several clinical trials of antibodies that interfere with negative signaling pathways through the PD-1, PDL-1, and PDL-2 receptors, which suppress immune responses against tumors. Cancer triggers an immune response that sends T-cells to attack the tumor, and the tumor, in response to signaling molecules from the T-cells, expresses PD-L1. This protein then suppresses the T-cells by engaging their PD-1 receptors. Symposium speaker Lieping Chen, Director of the Cancer Immunology Program at Yale Cancer Center, provided an overview of his seminal work on the discovery of the PD-1 immune inhibitory pathway (initially known as B7-H1), its role in tumor evasion of immune response, and the therapeutic benefit of blocking the pathway in primary and metastatic cancers. In fact, the early-stage clinical success of anti-PD-1 or anti-PD-L1 antibodies, currently in development by pharma giants Merck, Bristol-Myers Squibb and Genentech, has generated great optimism among cancer specialists.
New tools to continue exploring cancer immunology
Despite the great strides made in cancer immunology, the complex regulation of the immune system, the tumors' immunosuppressive mechanisms, and the potential systemic side effects associated with systemic drug therapies that modify immune reactions represent major hurdles in the development of cancer immunotherapies. The availability of new technologies is crucial to the continued exploration of the immune response to cancer, and to learning more about how to manipulate it for therapeutic applications. In this regard, the symposium offered several examples of relevant technological innovations. KI faculty member J. Christopher Love, for instance, described his engineering of single-cell bioanalytical technologies that allow for greater breadth and resolution in the analysis and measurement of immune responses. A nanowell-based modular platform he has developed enables multiple measurements to be taken from a single immune cell (integrative single-cell analysis). The device can also be used to analyze time-resolved functional responses of T-cells (cytokine trajectories), or to look at interactions of immune cells with tumor cells by loading them together in the nanowells (pairs or multiple cells). KI researcher Jianzhu Chen, also a symposium co-organizer, explained his work on developing improved mouse models of the human immune system. These mice can be used to more realistically model human cancer, test new treatments, study immune responses, and assess immunotoxicity in ways that more closely reflect clinical reality, thus accelerating the development of cancer immunotherapeutics. Robert Schreiber showed that cancer exome analysis can be used to identify tumor mutations that give rise to mutant proteins that the immune system sees as foreign and reacts against. The technology could be used to design individualized cancer vaccines and immunotherapies.
Symposium proceedings
To expand the audience and impact of the KI's symposium, many of the speakers' presentations have been made available on the KI website. In addition, the proceedings of the symposium will be published as a meeting report in Cancer Immunology Research, a new journal of the American Association for Cancer Research (AACR).
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