Progress Report from the Cancer Immunology “Dream Team”

A “Dream Team” of scientists tasked with working collaboratively to harness the immune system’s power to conquer cancer has recently provided a report on progress the team has made in the two years since they received a $10 million grant jointly from the Cancer Research Institute (CRI) and Stand Up To Cancer (SU2C). The CRI-SU2C Cancer Immunology Dream Team, headed by James P. Allison, PhD, and Antoni Ribas, MD, PhD, is composed of a group of top-tier scientists, including Drew M. Pardoll, MD, PhD, Cassian Yee, MD, David Baltimore, PhD, Bert Vogelstein, MD, Suzanne Topalian, MD, Larry Norton, MD, and many others hailing from multiple leading research institutions. Their three-year grant has enabled the team to investigate cancer immunotherapies, with a focus on checkpoint blockade and adoptive cell transfer, two of the most promising approaches to cancer immunotherapy. Let’s look at some of their key accomplishments so far:

• A team at Memorial Sloan Kettering Cancer Center (MSKCC)—including Jedd Wolchok, MD, PhD, and Timothy Chan, MD, PhD—have found that melanoma tumors with a greater number of genetic mutations are more likely to respond to anti-CTLA-4 treatment. Anti-CTLA-4 is the first checkpoint inhibitor to receive FDA approval in 2011, after a phase III clinical trial demonstrated it provided the first ever survival benefit for roughly 20% of patients with metastatic melanoma. Since the approval, ongoing research has focused on uncovering clues as to why the drug works in some patients but not in others. The Dream Team collaborators found that tumors that do respond to treatment share a certain type of mutation that makes cancer cells express new antigens—substances that immune cells called T cells can detect and recognize as foreign to the body. These tumors, they discovered, were unequivocally associated with response to treatment. The study was published in the New England Journal of Medicine. The team’s evaluation of anti-PD-1 antibodies, the second checkpoint inhibitor to receive FDA approval in 2014, found a similar association in patients with non-small cell lung cancer (NSCLC).

• The team led by Michel Sadelain, MD, PhD, and colleagues at MSKCC are taking a new approach to chimeric antigen receptor (CAR) T cell therapy in the lungs. CAR T cells are genetically engineered immune cells with enhanced capability to recognize and destroy cancer cells. Unlike ongoing CAR T cell therapy trials, Sadelain constructed a CAR treatment where the primary route of administration is via the intrapleural membranes around the lungs, as opposed to the customary intraveinous infusion. They have shown in a preclinical study that intrapleurally administered mesothelin-targeted CAR T cells were able to effectively eradicate mesothelioma and lung cancer with 30-fold greater efficacy than intravenously administered CAR cells. A clinical trial testing the approach in humans will open in spring 2015. If proven to be successful, this approach can be extended to other mesothelin-expressing cancers, such as pancreatic, bile duct, gastric, colorectal, and ovarian.

• A University of California at Los Angeles (UCLA) study headed by Antoni Ribas, MD, PhD, is a first-in-human phase I clinical trial combining adoptive cell transfer of a T cell receptor engineered to recognize NY-ESO-1 along with Yervoy® (ipilimumab, anti-CTLA-4). NY-ESO-1 is a protein that is found in a number of cancers, but not normal tissue (with the exception of the testis). Yervoy is designed to “take the brakes off” the immune system, enabling a more powerful immune response against cancer. Investigators hope that putting them together will achieve a better response rate than the two of them alone. Two patients have been enrolled to date, one with melanoma and one with sarcoma. This is the first such study attempted anywhere.

A total of 13 Dream Team clinical trials are active right now, for patients with bladder cancer, kidney cancer, prostate cancer, triple-negative breast cancer, gastric cancer, pancreatic cancer, small cell and non-small cell lung cancer, sarcoma, and melanoma, and seven more trials are planned.

In the next year, members of the Dream Team will continue to study the tumor microenvironment before and after checkpoint blockade, to develop algorithms to identify and predict the best antigens on cancer cells that can be used for cancer immunotherapies, to analyze tumor tissues and blood for biomarkers that will help in selecting patients who will benefit, and identifying the best approaches to increase the strength of immune cells for adoptive cell therapy. These studies will open up new avenues for cancer immunotherapy and significantly advance the field, with the ultimate goal of benefitting patients. Stay tuned!

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