Unleashing the immune system’s attack dogs

The first drug to improve the survival of people with end-stage melanoma works because of what it doesn’t do: attack tumors directly.

“Immune checkpoint blockade treats the immune system, not the tumor, so there’s a strong basis for expecting this approach to succeed across cancer types,” says James Allison, Ph.D., MD Anderson chair of Immunology, and recipient of The Economist’s 2013 Innovation Award for bioscience. “Clinical trials at MD Anderson explore that possibility right now, and there will be more to come.”
Yervoy (ipilimumab), a first-of-its-kind drug that extinguishes metastatic melanoma for years in 24% of patients, is built upon Allison’s basic science research on the biology of T cells, the attack dogs of the immune system.

“There are people on the early clinical trials who remain disease-free up to 12 years later,” Allison notes, an unprecedented response for patients whose melanoma has metastasized to other organs. Metastasis — the spread of cancer — causes 85% of all cancer deaths.

T cells are white blood cells that recognize and bind to antigens — distinctive abnormalities of invading infections or defective cells — and launch a customized attack to destroy and remember them. So why don’t they try to destroy foreign tissue such as cancer cells?

Through the discovery of how T cells do their job, Allison found a molecule that turns off the T cell, stopping the immune attack. This led to an antibody drug to block this molecule, or “checkpoint,” freeing T cells to attack. Federal regulators approved ipilimumab in 2011.

Based on his significant findings, the American Association for Cancer Research awarded Allison its first AACR-CRI Lloyd J. Old Award in Cancer Immunology in April 2013, and he recently won the Breakthrough Prize for Biosciences from the Breakthrough Foundation. In December, the journal Science named cancer immu¬notherapy, a field led by Allison’s pioneering treatments, its 2013 Breakthrough of the Year.

Allison arrived at MD Anderson in November 2012 to build and direct the Moon Shots Program’s immunotherapy platform, which blends expertise, technology and procedures to improve research and patient care.

“Our immunotherapy platform allows us to take the newest immune system-modifying drugs and test them in both preclinical and clinical settings, applying exceptionally strong and deep analyses of the mechanisms involved,” he says. “We expect to attract drug companies to test their most exciting immunotherapies across cancer types here at MD Anderson.”

Clinical trials are underway at the institution for melanoma, lung, breast, gastric and prostate cancers. A phase I trial tests a combination of these drugs for patients with advanced cancers. With patients’ permission to collect tumor and blood samples, investigators will learn more efficiently.

“We'll be able to compare immune responses to a particular immunotherapy drug across tumor types and from patient to patient, allowing us to generate better responses,” says Padmanee Sharma, M.D., Ph.D., associate professor in Genitourinary Clinical Oncology and scientific director of the platform.

Clinical Trials

Immune checkpoint blockade drugs (CTLA-4 blocker ipilimumab, PD-1 blockers, nivolumab and MK-3475) are being tested in 14 clinical trials against:

• Kidney cancer
• Non-small cell lung cancer
• Small cell lung cancer
• Melanoma
• Uveal melanoma (eye)
• Prostate cancer
• Gastric cancers
• Triple-negative breast cancer
• Advanced cancers (Phase I trial)