Review Highlights Potential of Cancer Immunotherapy Plus Targeted Therapy

Jo-Carolyn Goode | 4/9/2015, 5:53 p.m.
The prospect of combining genomically targeted therapies with drugs that free the immune system to attack cancer suggests “we are ...
Padmanee Sharma, M.D., Ph.D.

Jim Allison, Ph.D.

Jim Allison, Ph.D.

HOUSTON -- The prospect of combining genomically targeted therapies with drugs that free the immune system to attack cancer suggests “we are finally poised to deliver curative therapies to cancer patients,” researchers at The University of Texas MD Anderson Cancer Center note in a review in the April 9 edition of Cell.

“To support this goal and accelerate these efforts, changes in directions of research support and funding may be required,” co-authors Padmanee Sharma, M.D., Ph.D., professor of Genitourinary Medical Oncology and Immunology, and Jim Allison, Ph.D., chair of Immunology, said in the review.

The review, titled “Immune Checkpoint Targeting in Cancer Therapy: Toward Combination Strategies with Curative Potential,” covers the strengths and weaknesses of the two forms of therapy and notes how their combination could be particularly potent.

While individual researchers and pharmaceutical companies are studying and developing both types of drugs, a major initiative is needed to understand how both drug types might best work together, Sharma and Allison note.

“Without a major initiative, it will be harder to make progress because the groups focused on genomically targeted therapy and the checkpoint blockade researchers will largely stay in their own camps,” Sharma said.

Targeted therapy: Frequent but short-lived responses

The molecular mechanisms involved in the development of cancer have been uncovered by extensive research over the past 30 years, culminating in The Cancer Genome Atlas, a National Institutes of Health project that identified and characterized many genetic mutations that fuel cancer.

Drugs that hit a specific genomic defect that drives a patient’s cancer provoke good initial responses in most patients, the review notes. For example, drugs that target a specific BRAF gene mutation commonly found in melanoma shrink tumors in about half of patients with the mutation.

However, resistance almost always develops because tumors harbor multiple genomic defects capable of driving the disease after a targeted drug knocks down one driver. BRAF inhibitors prolonged median survival in clinical trials by about seven months.

Checkpoint blockade: Fewer but stronger results

Allison pioneered immune checkpoint blockade, an approach that treats the immune system, rather than the tumor directly, by blocking molecules on T cells that shut those attack cells down, protecting tumors from immune response.

The first such drug, called ipilimumab (Yervoy), developed out of Allison’s basic science research, showed much lower response rates against advanced melanoma than those obtained with targeted drugs, but long-term follow-up found that 22 percent of those treated with Yervoy survived at least four years, unprecedented results for the disease. Importantly, those who survived three years have gone on to live up to 10 years and beyond.

Drugs that hit other immune checkpoints have been developed after Yervoy and show similar response rates in a variety of cancers.

Immunity is key to long-term responses

Knowing that the immune system is capable of recognizing distinctive features of cancer cells and launching a T cell attack against those tumor antigens, and that checkpoint blockade removes a roadblock to that attack, it’s logical that these drugs should work against many tumor types. But the impact varies across cancers.