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Old 03-31-2015, 01:31 AM
gdpawel gdpawel is offline
Join Date: Feb 2007
Location: Pennsylvania
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Default Cancer Immunotherapy 'Has Entered Mainstream'

Cancer immunotherapy takes centre stage in a series of articles about harnessing the immune system for therapy published March 25 as a special issue of Science Translational Medicine.

While the articles trace the progress being made across all fields of medicine, it is in cancer that immunotherapy has made the greatest strides.

"Recent treatment successes with antibodies that regulate immune activation have essentially ended the debate about whether the immune system sees and regulates cancer growth. Tumor immunotherapy has entered the mainstream and is a strategy to be considered within the clinician's toolbox of standard therapies for cancer," write Alexander M. Lesokhin, MD, from Memorial Sloan Kettering Cancer Center in New York City, and colleagues in a perspective.

"The recent approvals of two drugs that block the function of the immune checkpoint programmed cell death 1 (PD-1) have firmly planted tumor immunotherapy in the mainstream of clinical oncology," they write.

The two PD-1 inhibitor drugs that have reached the market — nivolumab (Opdivo, Bristol-Myers Squibb) and pembrolizumab (Keytruda, Merck & Co) — have been both approved for use in melanoma, and nivolumab was recently approved also for use in non-small cell lung cancer. But there are numerous clinical trials in progress in many other cancer types and with other compounds, and these PD inhibitor drugs "are expected to be approved in multiple malignancies," the authors write.

Dr Lesokhin and colleagues also trace the development of the first immune checkpoint inhibitor, ipilimumab (Yervoy, Bristol-Myers Squibb), now approved as a first-line treatment for melanoma. This drug acts at a different point in the immune cascade, as a CTLA-4 blocker, and another agent with this mechanism of action, tremelimumab (Pfizer) is in ongoing clinical trials.

"Perhaps the most clinically exciting observation has been the remarkable durability of responses with CTLA-4 blockade. Although responses are restricted to a minority of treated patients, those who respond are likely to enjoy a durable response, often measured in years," they comment.

Both the PD-1 inhibitors and the CTLA-4 blockers were discovered as a result of basic research directed at a better understanding of the immune system, notes a related editorial authored by Jeffrey Bluestone, PhD, and Qizhi Tang, PhD, both from the University of California, San Francisco.

Cancer immunotherapy has shown signs of a "decisive victory over certain cancers," they write, but "the path to this remarkable victory began in a seemingly unrelated quest to understand the molecular basis of immune activation, which revealed myriad T-cell receptor (TCR) subunits and TCR costimulatory and coinhibitory molecules."

"This intricate system of checks and balances is hijacked by cancer cells to evade immune rejection and, in reverse, is defective in autoinflammatory diseases that lead to the disruption of normal tissue functions. This deeper mechanistic understanding of the human immune system drove the discovery of a plethora of new drugs," they write.

Dr Lesokhin and colleagues predict that further therapeutic advances will result from this work. "The multiple molecules involved in T-cell costimulation raise hopes that more patients will ultimately derive benefit from continued basic research and clinical study of this family of therapeutic targets," they write.

"All of this is enough to make one wonder if perhaps there is a limit to the reign of the 'Emperor of All Maladies'," they conclude, in a reference to the sobriquet for cancer in the title of the Pulitzer Prize–winning book by Siddhartha Mukherjee.

Adoptive Cellular Therapy

Another success story in harnessing the immune system to treat cancer — the adoptive cellular therapy approach — is discussed in a perspective article authored by Carl June, MD, from the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, and colleagues.

This group were pioneers in the development of chimeric antigen receptor (CAR) engineered T-cells for the treatment of leukemia, and they have now teamed up with Novartis to commercialize this therapy, which is developed individually for each patient. Other groups are also developing this CAR T-cell approach, including a team at the National Cancer Institute that is collaborating with Kite Pharmaceuticals. Results from early clinical trials show durable responses and suggest that this CAR T-cell approach can "eradicate disease" and have generated great excitement among the hematological malignancy community.

In their article, Dr June and colleagues say that the "remarkable success in patients treated on trials at academic centers has enticed unprecedented interest from the biotechnology and pharmaceutical industry."

"The recent entry of the pharmaceutical industry to this area has dramatically changed the prospects for the widespread availability of engineered T-cells," they write, adding that this approach is now rapidly advancing toward approval by the US Food and Drug Administration.

"The field faces numerous scientific, regulatory, and economic obstacles and challenges in educating clinicians in the use of ACT," they write. "Surmounting these obstacles will require collaboration between academia and biotechnology in order to ensure that therapy with engineered T-cells is established as a viable approach for common human malignancies."

Sci Transl Med. 2015;7:280ed3, 280sr1, 280ps7.

Citation: Cancer Immunotherapy 'Has Entered Mainstream'. Medscape. Mar 25, 2015.
Gregory D. Pawelski
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