Mining the “Gold Rush” of Immunotherapy Clinical Trials

Immunotherapy has the potential to revolutionize cancer treatment, but as the number of immunotherapy clinical trials continues to grow, so do the challenges and obstacles – including the need to ensure meaningful results.

The highly specialized nature of immunotherapy, coupled with the seemingly infinite number of ongoing trials, can make it difficult to find patients to participate in the investigations. High costs, concerns about potential toxicity, and the difficulties of advancing immunotherapy agents quickly and safely through traditional trial designs also impede the march of scientific progress.

But even with these challenges, investigators are optimistic about the role of immunotherapy in treating myeloma, leukemia, and other hematologic malignancies.

ASH Clinical News spoke with several investigators to learn more about clinical trials for emerging immunotherapies, as well as the strategies to ensure the agents can be safely and effectively brought to market.

Finding Trial Participants

Immunotherapy harnesses the body’s own immune system to fight cancer and is being investigated in a variety of strategies, including checkpoint inhibitors, vaccines, and T-cell therapy. Initial studies show promising results in leukemia and myeloma, and the positive findings are propelling more academic centers and pharmaceutical companies to develop their own immunotherapy candidates.

One estimate suggests there are about 800 immunotherapy clinical trials under way in the United States,1 and another puts it closer to 1,000.2 With so many drugs being tested in various clinical trials, the patient population is stretched thin, some researchers argue.

“These therapies were once developed in academic centers in small phase I clinical trials often funded by the National Institutes of Health,” explained Cameron Turtle, MVVS, PhD, an associate member of the Clinical Research Division at the Fred Hutchinson Cancer Research Center in Seattle, Washington. “Now, there is much more involvement from pharmaceutical companies who are developing their own therapies.”

In many immunotherapy trials, it’s not just about finding patients to participate, but also about finding the right patients – those with the biomarker or targeted mutation most likely to respond to a given therapy.

According to Ivan Borrello, MD, associate professor of oncology at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, Maryland, this is one of the largest challenges facing immunotherapy. “We have to answer the questions, ‘Are there subsets of patients who have a high likelihood of not responding?’ And, conversely, ‘Are there subsets of patients who are going to be hyper-responsive to these therapies?’” he said.

Methods to help researchers differentiate patient groups are “in their infancy,” he noted, and they have yet to be fully incorporated into trial design and practice, making it difficult to determine who would be best suited for participation in a given trial.

In myeloma, according to Dr. Borrello, few specific biomarkers have been identified to guide treatment decisions in certain patient groups; however, other forms of cancer are further along in the use of biomarkers for patient stratification and enrollment.

Using biomarkers as enrollment criteria can sharpen a trial’s focus, but it also requires more screening and verification upfront, according to Lisa Butterfield, PhD, professor of medicine, surgery, and immunology at the University of Pittsburgh Medical Center’s Hillman Cancer Center. Trials designed to validate a predicated biomarker must be done in highly regulated, Clinical Laboratory Improvement Amendments–certified laboratories by trained professional technologists, which “can add to the complexity when this becomes part of a trial’s enrollment criteria.”

The success of earlier immunotherapeutic agents presents another challenge for new agents under investigation, Dr. Butterfield added: The U.S. Food and Drug Administration (FDA) has already approved several agents, such as CTLA-4, PD-1, and PD-L1 inhibitors. The agents are readily available and used in practice, making it more difficult for researchers to find an immunotherapy-naïve patient population.

“Everyone goes to the community first,” she explained. “They are unlikely to come as a newly diagnosed patient to the academic medical center that’s conducting the new combination trial.”

We have to answer the questions, ‘Are there subsets of patients who have a high likelihood of not responding?’ And, conversely, ‘Are there subsets of patients who are going to be hyper-responsive to these therapies?
—Ivan Borrello, MD

Weighing the Costs

As more immunotherapy treatments enter the market, the health-care industry will have to determine whether the clinical benefits outweigh the high price tags associated with these treatments.

“Obviously, the more expensive the therapy is, the higher the therapeutic index is going to have to be,” Dr. Borrello said. “An expensive therapy is going to have to have a high response rate and duration of response.”

Treatment with an expensive new agent may not be justified, for instance, for a patient at the end of life who is unlikely to see significant improvement.

The editorial board of The Lancet Oncology recognized this limitation in a recent editorial, calling for a halt in the “immunotherapy gold rush” to make room for more thorough investigations of novel drugs.1

“While heralding an enticing treatment opportunity, it is essential to bear in mind that the current generation of immunotherapies merely extends life expectancy for a small proportion of patients,” the authors wrote. Before hastily developing their own entry in a new promising class of drugs, pharmaceutical companies and researchers should look closely at why a trial failed – or not – to ensure meaningful benefit for patients, the board wrote.

That many studies are not reproducible “must serve to temper the degree of off-label use fostering false hope and the amount of investment in this single line of investigation when other less-funded research avenues, also with potential to improve cancer outcomes, remain underexploited,” they concluded.

Though the costs of conducting trials and moving therapies through the review pipeline are significant – and manufacturers will likely set their prices to reflect those high investment costs – Dr. Turtle said that cost-benefit analyses of many of these therapies may work out in patients’ favor. Potentially curative chimeric antigen receptor (CAR) T-cell therapies, for instance, could help patients avoid transplants or years of maintenance therapy.

“The potential expense of these therapies is heavily criticized, but I think that until their role in overall care is well defined, it is extremely hard to answer questions about cost and benefit,” he said.

Exploring Alternate Routes

Immunotherapies are non-traditional, so evaluating their safety and efficacy through the usual three-phase clinical trial paradigm seems incongruous. To overcome some of the issues with recruitment and enrollment, clinical trial designs need to evolve to suit the types of drugs they are testing, according to Dr. Butterfield.

Two such strategies include creating more small studies (rather than a single large trial) that are sufficiently powered to produce high-quality results, or developing a consortium of medical centers that allow researchers to draw greater numbers of patients to one trial.

“We have a consortium of clinical academic medical centers, each with many myeloma specialty physicians,” she explained. “That enables us to work across three to six institutions within the same geographic area – eliminating the need for a larger, nationwide trial and allowing us to run trials in a shorter amount of time.”

In this era of precision medicine and effective immunotherapies, “the need for rapid and efficient cancer drug development has never been greater,” Dr. Butterfield and colleagues argued in a recent commentary published in the Journal for ImmunoTherapy of Cancer.3 “Given the array of available targets, drugs, and biomarkers of response and resistance to therapy, it is clear that traditional approaches to drug development are unable to support the speed and level of sophistication required for the development of effective cancer therapies today.”

The limitations, he noted, are related to the complexities of answering multiple questions within one clinical trial protocol. Deciding whether the information is statistically valid also requires complicated algorithms.

In 2015, the National Cancer Institute (NCI) launched the Molecular Analysis for Therapy Choice study, or NCI-MATCH, a basket trial that attempts to work around the obstacles of conventional trials by using DNA sequencing to screen patients’ tumor biopsies for many molecular abnormalities at once. Based on those results, patients are assigned to one of 19 treatment arms of FDA-approved or investigational agents that target genetic mutations.4

The study has the potential to make significant clinical advances, but, Dr. Butterfield cautioned, the frequency of some of the potentially targetable mutations was not as high as originally expected – limiting the applicability of this mass-screening approach. “Screening costs can go up three- to 10-fold over what was anticipated, because the mutation just isn’t as common as once thought,” she said.

Many patients consider immunotherapy to be a safe, “natural” way to treat cancer, but clinical experience has shown that training the immune system to target cancer cells can introduce significant toxicities.

Ensuring Safety

Many patients consider immunotherapy to be a safe, “natural” way to treat cancer, but clinical experience has shown that training the immune system to target cancer cells can introduce significant toxicities.

This summer, the FDA placed clinical holds on three trials evaluating the PD-1 inhibitor pembrolizumab (in combination with immunomodulatory treatments) in patients with myeloma, following reports of patient deaths. After data monitoring committee review, the FDA determined that available data indicated that the risks of pembrolizumab plus immunomodulatory treatment outweighed any potential benefits. Then, after issuing a statement reiterating the safety concerns associated with this class of drugs, the FDA placed all trials of PD-1 and PD-L1 inhibitors on clinical hold on September 7, 2017.

Ensuring patient safety is of chief concern; however, some researchers argue that the highly specialized nature of immunotherapy has created such small study populations that it is difficult to know whether the safety findings apply to broader populations or whether adverse events were missed.

“Personally, I don’t think there is a magic bullet that will allow us to treat 10 patients and definitively say the treatment is safe in every single person who would require it,” Dr. Turtle said. “What [these trials] do help us with is identifying a suitable dose and getting a better idea of the therapy’s risk-benefit ratio.”

As more academic centers and pharmaceutical companies create their own immunotherapy products, Dr. Turtle noted another challenge: “We’re starting to realize that different immunotherapy products that are made by different centers or companies can have very different effects.” Though products may have similar mechanisms of action, it’s unclear whether the findings from one product can be applied to other similar products.

The excitement over immunotherapies – and the rush to move investigational drugs through trials – could have its own unintended, adverse events affecting patients and research.

“Many of the oldest trials, now with at least five years of follow-up, are uncovering a range of unusual side effects that require different supportive interventions,” stated the authors of The Lancet Oncology editorial. “These findings emphasize the importance of accruing sufficient data before launching another trial, especially if the new study combines multiple immune-targeting drugs each with unknown safety profiles.”

Without sufficient time to analyze results from trials before conducting the next one, trial sponsors may also be “suffocating research,” the authors continued, through “an inefficient use of funds spent on research and development.”

To ensure patient safety, Dr. Borrello commented, early-stage immunotherapy trials should be conducted in centers that have significant experience with immunotherapy and by knowledgeable investigators. The safety concerns surrounding CAR T-cell products and cytokine release syndrome (CRS) highlight such concerns.

The same day the FDA approved the CAR T-cell therapy tisagenlecleucel for the treatment of relapsed or refractory B-cell precursor acute lymphocytic leukemia, it also approved the interleukin (IL)-6 inhibitor tocilizumab for the treatment of patients with CRS that occurs with CAR T-cell therapy.

“There has been a lot of work done to show that giving an anti–IL-6 antibody very early on can significantly reduce a lot of these serious complications from the CRS, but the problem is you have to be able to recognize what the CRS is in order to start a patient on this therapy,” Dr. Borrello said.

Because of the risks for CRS and neurologic events, the CAR T-cell product was approved with a Risk Evaluation and Mitigation Strategy; the FDA is requiring that hospitals and their associated clinics that dispense tisagenlecleucel be specially certified and that, as part of that certification, staff involved in the prescribing, dispensing, or administering of tisagenlecleucel be trained to recognize and manage CRS and neurologic events. Additionally, the certified centers must have protocols in place to ensure that tisagenlecleucel is given only to patients after staff have verified that tocilizumab is available for immediate administration.

Regardless of the challenges facing the industry, investigators still see immunotherapy as a promising treatment strategy that could significantly improve patient outcomes and transform cancer treatment in the years ahead.

“Immunotherapy is here to stay,” Dr. Borrello said. “The question of how much penetrance these therapies will have is going to be driven by results, accessibility, and cost.”
—By Jill Sederstrom ●


  1. The Lancet Oncology Editorial Board. Calling time on the immunotherapy gold rush. Lancet Oncol. 2017;18:981.
  2. Kolata G. A cancer conundrum: too many drug trials, too few patients. The New York Times. Accessed September 5, 2017, from
  3. Emens L, Butterfield L, Hodi FS Jr., et al. Cancer immunotherapy trials: leading a paradigm shift in drug development. J Immunother Cancer. 2016;4:42.
  4. National Cancer Institute. NCI-MATCH trial (Molecular Analysis for Therapy Choice). Accessed September 5, 2017, from