The red-hot field of cancer immunotherapy is stealing the show

The annual American Society of Clinical Oncology (ASCO) meeting gets underway this weekend in Chicago, and to no one’s surprise immunotherapies will, once again, reign. The newer PD-1 antibodies are a prime example.

In advance of the meeting, several of Big Pharma’s biggest players released early findings on some of their most promising agents, notably AstraZeneca (AZ’s) immunotherapy agent,AZD9291Bristol-Myers Squibb’s monoclonal nivolumab for lung cancer and Merck’s MK-3475, which was developed for lung, and head and neck cancers. Roche also released data early on its most advanced PD-L1 inhibitor thus far, MPDL3280A, for the treatment of late-stage bladder cancer.

These agents work by preventing the tumor’s programmed cell-death 1 protein—hence the name PD-1—from binding to another protein that tricks the body’s T cells into being inactive. Companies have high hopes they will rise to blockbuster status.

With an attendance of around 25,000, the annual ASCO meeting, which runs from May 31-June 2, is a good place to take the pulse of the field. But further evidence of how much seems to be riding on this nascent wave is evident in the flurry of applications to the US Food and Drug Administration.  In recent months, the FDA granted coveted breakthrough status—a 2012 law that expedites the development of new therapies that offer substantial improvement for life-threatening conditions—to BMS’s nivolumab as well as Merck’s MK-3475for melanoma. And BMS’s melanoma drug Yervoy, an early leader in immunotherapy that works on a receptor with a similar function to PD-1, was approved through fast track in 2011.

Meanwhile, Merck started filing its candidate MK-3475 with U.S. regulators in January and expects to complete the process by July, opening up an unexpected lead on competitors. It already has a dedicated business unit set up to market the drug, the Wall Street Journal reported.

Yet interestingly enough, a quicker regulatory process hasn’t exactly made the development process faster. A 2011 study by Deloitte Recap of monoclonal antibodies (mAbs), discussed in this Fierce Biotech article, found the average time from investigational new drug filing (IND) to market was 6.7 years for 11 mABs approved between 1994 and 2003 compared to 8.7 years for 12 mAbs approved between 2004 and March 2011. The reason: Phase II and III trials for cancers are likely taking longer due to the “complexity of the targets and the kind of high unmet medical needs that developers are pursuing.”

Forging New Relationships

This lengthier process could be one reason the developers of some of these immunotherapies are linking up in ways practically unheard of in the biologics field until now. For instance, Cancer Research UK announced in April that AZ and Pfizer will be participating in a US$42 million initiative known as the National Lung Matrix trial that is expected to kick off in July or August. The study is using the genetics of each lung tumor to identify small groups of patients who, because of the specific genetic changes causing their cancer, are more likely to benefit from a certain drug. Researchers will have unprecedented access to libraries of drugs from AZ and Pfizer, allowing them to subject several drugs simultaneously to a “bake-off” of sorts, with the high scorers graduating to larger efficacy trials. Reportedly, the new trial will include two of AZ’s immunotherapies along with one of Pfizer’s top cancer prospects, palbociclib. Unlike the PD-1s, this drug is designed to block tumor regression.

US cancer researchers are taking a similar personalized approach with a five-drug clinical trial for advanced lung cancer patients known as the lung master protocol or simply Lung-MAP trial. The trial will be using the National Cancer Institute’s central Institutional Review Board, and will test drugs from Amgen, Genentech, Pfizer AZ and its global biologics R&D arm MedImmune.

These multi-drug studies aim to not only change how we study cancer—which as we all know is an incredibly complex web of dozens of diseases—but also to cut the time and cost it takes to bring a drug to market.

In the preclinical arena, one can also find examples of how drug companies and researchers are endeavoring to streamline the development of biologics, such as integrating safety pharmacology endpoints into toxicology studies. Though fundamentally different disciplines, incorporating safety pharmacology endpoints into a general toxicology study can actually be a robust predictor of risk in late-stage clinical trials—when exposure is repeated and occurs over a much longer duration. The discussion (and debate) seems particularly well-suited for the development of newer-generation biotherapuetics that are desperately needed to fight advanced cancers (see Jan. 26, 2104 Eureka blog).

Old and New Tools for Immunotherapy Programs

At the same time, syngeneic mouse models, which were the workhorse of preclinical cancer research before the rise of transgenic mouse models, have re-emerged as a hot avenue for the study of cancer immunotherapy. Because they retain intact immune systems, syngeneic mouse models created using a variety of hematological and solid tumors—leukemia, multiple myeloma, lung, colon and breast cancer to name a few—can be particularly relevant for studies of so-called targeted therapies, either used alone or in combination with other drugs that assist the immune system in seeking out and destroying cancer cells (see Oct. 30, 2013 Eureka blog). Advances in technology such as flow cytometry and a better understanding of the immune system have allowed the analysis of new immunological endpoints giving a new lease of life and utility to these models.

Increased mastery of genetic manipulation and surgical techniques has led to the development of another new exciting tool to aid with immunotherapy programs: mice with a humanized immune system. Such models are either transgenic or created using donor human cells in a super-immunodeficient mouse. Although current models still have many shortcomings, the field is progressing very rapidly and may soon become the gold standard for evaluating human immunotherapies in rodents.

So how hot is the field right now? Market data suggest  that the growth of antibody-drug conjugates and other engineered antibodies, which now comprise about 12% of the $70 billion mAb market, will occupy a quarter of the mAB market within 10 years, which by then is expected to top $100 billion.

Still, while drug manufacturers and investors like are clearly smitten with cancer immunotherapies, time will tell whether these agents become the dominant players in cancer. There is still a lot of science to be learned and the field is still very new.

So stay tuned.