Immunologic Rejection of Pancreatic Cancer without Autoimmune Side Effects

Principal Investigator: CURRAN, MICHAEL
Program: PRCRP
Proposal Number: CA140792
Award Number: W81XWH-15-1-0142
Funding Mechanism: Career Development Award
Partnering Awards:
Award Amount: $575,997.00


Unfortunately, as they form, cancers evolve means to hide from and locally dampen the immune system, allowing them to thrive when they would otherwise be eliminated. In melanoma, we and others have shown that by blocking key molecules that cancers engage to shut off the immune system, even bulky metastatic tumors can be immunologically rejected. Unlike most therapies for solid tumors, immunotherapy has the potential to effectively cure a patient of all cancer and ward against its return. The percentage of patients achieving these complete, durable responses remains low for melanoma and extremely low for aggressive solid tumors such as castration-resistant prostate cancer; therefore, research in immunotherapy is focused on finding combination therapies that will allow more people to experience this type of prolonged benefit.

Tumors surround themselves with a barrier of suppressive cells called the stroma that insulates them from the immune system. Any killer cells that enter this stroma are rapidly inactivated before they can harm, or often even reach, the tumor itself. We have extensively studied how the tumor and its surrounding stroma inactivates the immune system and have identified three antibodies that together can expand and protect killer cells restoring their capacity to eradicate tumors just as they would a foreign organism like a bacteria. Pancreatic cancer surrounds itself with one of the most immunosuppressive barriers of any cancer; thus, this proposal also includes a novel approach to break down immune resistance from within the tumor itself by hijacking the stroma and not just inactivating it, but turning it against the tumor. We have already seen this combination of protecting and empowering the immune system while sabotaging the tumor's immune resistance demonstrate the ability to cure mice of established pancreatic tumors. The agents we are studying or equivalent ones are already in clinical trials; therefore, little time would be required before any effective combinations we find could enter the clinic and begin benefitting pancreatic cancer patients, for whom there are virtually no effective therapies.

Pancreatic cancer is more common in military members due to exposure to carcinogens in the field including certain chemicals and ionizing radiation. This type of exposure causes mutations in DNA, which increases the rate of cancer development; however, the greater the number of these mutations, the more foreign the tumor appears to the immune system. The immune system works by killing anything that appears not to be "self." The proposed immune therapy, then, is likely to be most effective in military members with pancreatic cancer as their tumors are likely to have a higher rate of mutations for the immune system to target than most.

Dr. Curran has been an independent faculty at University of Texas MD Anderson Cancer Center for 2 years. Dr. Curran was the first to describe a combination of immunotherapies that was recently fast tracked by the Food and Drug Administration for advanced study for patients with metastatic melanoma. Prior to 2011, the 2-year survival rate for metastatic melanoma was under 20%; in contrast, nearly 90% of patients treated with this immune therapy are alive at 2 years and some are completely cured. With the help of this award, Dr. Curran can continue to establish his own independent lab dedicated to bringing the same type of clinically transformative immune therapy to pancreatic cancer patients for whom the 2-year survival rate is currently under 10%.