CANCER IMMUNOTHERAPY-THE BREAKTHROUGH OF THE YEAR

Cancer immunology has been selected as the "Breakthrough of the Year" by the editors of Science, the flagship journal of the American Association for the Advancement of Science. A report on the subject was published in the December 20 issue.

"Immunotherapy marks an entirely different way of treating cancer — by targeting the immune system, not the tumor itself," according to the report. It beat out scientific advances in areas such as human stem cells from cloning and the understanding of sleep.

The choice was not without debate and worry about "hyping" an approach to cancer treatment that has only touched a "tiny fraction" of patients, according to the editors.

Nonetheless, in 2013, "clinical trials have cemented [cancer immunology's] potential in patients and swayed even the skeptics," reads the report. "A corner has been turned and we won't be going back."

In fact, this year, investigators of paradigm-making clinical trials presented results involving a number of agents and tumor types.

For example, the concurrent combination of the approved immunotherapy ipilimumab (Yervoy, Bristol-Myers Squibb) and the experimental agent nivolumab (Bristol-Myers Squibb) yielded an objective response rate of 53% in patients with metastatic melanoma. That is better than either drug alone, and higher than any rate seen before the advent of immunotherapy.

In addition, in patients with metastatic melanoma, the experimental anti-PD-1 antibody MK-3475 (Merck) had an objective response rate of 52% in one cohort of a phase 1 trial.

In another phase 1 trial, involving multiple tumor types that had metastasized or were incurable, the experimental anti-PD-L1 antibody MPDL3280A (Genentech) produced an overall response rate of 21%, with the best responses seen in patients with non-small cell lung cancer, kidney cancer, and melanoma. In the lung cancer group, responses were seen in patients who had a history of smoking. Those phase 1 results were comparable to results from an early trial of nivolumab in patients with a variety of cancer types.

Proven advances from clinical trials conducted this year have also involved a different experimental approach in the treatment of hematologic cancers. The personalized treatment involves extracting T-cells from the patient, subjecting them to chimeric-antigen receptor (CAR) cell engineering, and then infusing the engineered T-cells back into the patient.

In early December, results from the unprecedented research involving CAR therapy were presented at the annual meeting of the American Society of Hematology, as reported by Medscape Medical News.

A team from the University of Pennsylvania reported that 19 of 22 pediatric patients with acute lymphocytic leukemia (ALL) who were treated with CAR had a complete response, which was ongoing in 14 patients (5 have relapsed). Also, all 5 adults with ALL who were treated with CAR had a complete response, which was ongoing in 4.

The team also reported that 15 of 32 adults with chronic lymphocytic leukemia had partial responses and 7 had complete responses, all of which were ongoing.

In addition, a team of researchers from the National Cancer Institute reported that of the 13 adults with advanced B-cell lymphomas who were treated with CAR and evaluable for response, 12 responded; 7 had complete remissions and 5 had partial remissions.

Years of Research

The Science report chronicles some of the early research stories leading to the development of cancer immunotherapy, one of which begins in France and then jumps the pond to the United States.

In 1987, French researchers, who were not engaged in cancer research, identified a new protein receptor on the surface of T-cells, called cytotoxic T-lymphocyte antigen 4, or CTLA-4.

Cancer immunologist James Allison, PhD, then at the University of California, Berkeley, subsequently found that CTLA-4 "puts the brakes on T-cells, preventing them from launching full-out immune attacks. He wondered whether blocking the blocker — the CTLA-4 molecule — would set the immune system free to destroy cancer."

It would take 2 more decades for an anti-CTLA-4 antibody, eventually called ipilimumab, to demonstrate results in phase 3 trials. In 2010, at the American Society of Clinical Oncology annual meeting, researchers reported that, for the first time, a therapy (ipilimumab) had significantly improved survival in patients with metastatic melanoma, as reported by Medscape Medical News.

Some of these patients with metastatic melanoma are still alive 10 years later. Apparently, ipilimumab has "reset" patients' immune systems and turned a deadly cancer into a chronic disease.

The Science report emphasizes that immunotherapies do not work in all patients, and might not work in all cancer types.

Nevertheless, for "physicians accustomed to losing every patient with advanced disease," the results now being seen in clinical trials "bring a hope that they couldn't have fathomed a few years ago," according to the report.

Science. 2013:342:1432-1433. Abstract