New Paradigms Emerge for Translating Immunotherapy Into Broad Clinical Use
Published Online: Friday, March 14, 2014
Axel Hoos, MD, PhD
In interviews with OncologyLive, leading immunologists identified four broad areas that researchers, regulators, and drug developers are tackling in order to fully realize the promise of the emerging therapies: (1) product development and clinical trial design; (2) immune-based prognostic and predictive biomarkers; (3) response criteria and clinical endpoints; and (4) treatment guidelines.
In recent months, significant strides have been made in elucidating those challenges (Table) and optimism about the potential for immunotherapy remains unbridled. Immunotherapy was named the “Top Scientific Breakthrough for 2013” by Science magazine and the American Association for the Advancement of Science. The Economist’s 2013 innovation award went to James P. Allison, PhD, of the University of Texas, MD Anderson Cancer Center, a leading developer of the “checkpoint blockade” immunotherapy approach.
Broadly defined, cancer immunotherapies are agents aimed at promoting an antitumor immune response and are generally classified either as “active,” in which the patient’s immune system is actively induced to recognize tumor cells (eg, vaccines) or “passive,” in which the need for an immune response is bypassed by directly administering components of the immune system to the patient (eg, monoclonal antibodies and adoptive T-cell therapies).
The current enthusiasm for such strategies has been building since April 2010, when the FDA approved sipuleucel-T (Provenge) for advanced prostate cancer as the first therapeutic cancer vaccine. Less than a year later, the agency approved ipilimumab (Yervoy), a first-in-class checkpoint inhibitor of CTLA-4, for the treatment of metastatic melanoma.
Now, excitement is swirling around an emerging class of checkpoint inhibitors aimed at the programmed death–1 pathway and its ligand (PD-1/ PD-L1). The implications are significant, according to Howard L. Kaufman, MD, vice president of the Society for Immunotherapy of Cancer (SITC). “In the past, immunotherapy was something that seemed to be very effective in only a small number of patients, often with rare tumors like melanoma and renal cell cancer,” said Kaufman, chief surgical officer and associate director for Clinical Science at the Rutgers Cancer Institute of New Jersey. “I think one of the real paradigm shifts that’s occurring now is what’s going on with the PD-1/PD-L1 pathway, because this seems to be a very important therapeutic target across a wide range of different types of cancer.”
The immunotherapy field has made great strides in less than a decade, noted Axel Hoos, MD, PhD, whose work has focused on developing and translating novel approaches for clinical use. He helped lead the development of ipilimumab (Yervoy) at Bristol-Myers Squibb and is now vice president of Oncology R&D at GlaxoSmithKline Pharmaceuticals. “We have spent at least 30 or 40 years trying to make the immune system work against cancer and haven’t been successful, and just recently—I would say the past five to eight years—we have been able to understand both pieces that you need for success,” he said. “The first is the science, obviously, (we’ve understood mechanisms better and know what to target) and then we also improved the methodology (such as clinical endpoints for trials).”
“I think the outlook for this is huge, probably more successful than any other kind of cancer therapy that we have used in the past,” said Hoos. “We have a positive outlook in all ways—in a scientific way, a clinical benefit way for the patient, and also in a financial way. The sector is growing.”
Changing Drug DevelopmentWhile practicing oncologists are increasingly willing to embrace immunotherapies, the pathway to regulatory approval for those promising medicines has highlighted distinct development challenges. In the past, regulators applied methods used to assess conventional cytotoxic cancer therapies to immunotherapeutic agents, but now they are recognizing the unique biologic activity of these emerging drugs.
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