Immunotherapy Clinical Studies: The Way Forward
10-05-2016
by Dr. Brad Thompson, Oncolytics  |  Email the author

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Immunotherapy’s star continues to shine brightly. In the pages of medical journals as well as in the popular press, extraordinary stories of cancer treated effectively—or even put into remission—reflect the power of checkpoint inhibitors and, increasingly, CAR T cell therapy. Yet in the shadow of every reported success of these two major immunotherapies lurk the risks they are known to bring with them. However, even the known risks have not dissuaded doctors or patients from their enthusiasm for further clinical studies.
 
During these heady and still-early days in the age of clinical studies involving immunotherapy, it is useful to ponder some of the outstanding questions these studies raise. Do the benefits outweigh the risks for patients? What are the proper endpoints by which we can gauge the success of the studies? And is it possible that immunotherapy—perhaps in tandem with other cutting-edge therapies—could serve as the basis of more targeted therapy for patient subpopulations?
 
The rewards and the risks
 
The most significant observation regarding immunotherapy clinical studies is that for a small percentage of the population, they have been shown to produce dramatically better results than what is possible with previous therapies. As currently listed on ClinicalTrials.gov, there are more than 600 open clinical studies involving immunotherapy—either alone or combined with other treatments—underway for nearly every type of cancer.
 
The promising results continue to drive the field forward. In the case of checkpoint inhibitors, 15 percent to 40 percent of patients have good responses, according to the National Cancer Institute (NCI). These inhibitors are coming into widespread use and are being tried in advanced types of cancer for which standard chemotherapy offers little hope. Additionally, some metastatic patients have had success with checkpoint inhibitors. As for CAR T cell therapy, this method of turbocharging the immune system has shown extraordinary promise in patients with some B-cell lymphomas and leukemias. Indeed, reports The Hematologist, CAR T cell therapy has had great success in acute lymphoblastic leukemia, producing complete remissions in a significant percentage of patients.
 
With these successes come significant risks. For some, immunotherapy drugs do not work at all or they just help temporarily. In some cases, remissions can last for years; in others, relapses occur relatively quickly. As reported in Oncotarget, checkpoint inhibitors can cause problems ranging from diarrhea to liver toxicity. The immune system can also attack vital glands like the thyroid and pituitary. Meanwhile, CAR T cell therapy can also lead to severe and potentially fatal reactions resulting from the overstimulation of the immune system.
 
Despite these and associated risks, the outcomes derived to date have convinced many that refinements could improve the benefits for immunotherapy patients.
 
Endpoints in immunotherapy
 
This leads naturally to the question: How should the outcomes of future clinical studies in immunotherapy ideally be gauged? The debate on endpoints is a timely one given the fact that such cutting-edge therapies are holding out the promise for some patients of dramatically increasing their lifespan over what was previously possible. Patients who know that a treatment potentially stands to benefit them directly are much more likely to be psychologically invested in the outcome of a study and more motivated to stick with the treatment regimen—a benefit for them and for doctors alike.
 
Patients naturally tend define a useful therapy as one that improves quality, or increases the quantity, of survival. Those in the field should be able to design immunotherapy studies that accommodate what is best for the individual patient.
 
Currently, the three endpoints that the research community typically evaluates in clinical studies for cancer therapy are: response rate (i.e. tumor shrinkage), progression-free survival and overall survival. I believe that clinical studies in immunotherapy should focus on response rate as a primary endpoint and overall survival as a follow-on endpoint. The adoption of response rate as the sole primary endpoint would allow immunotherapy studies to run with smaller enrollments, since the number of patients needed to show tumor burden changes in a randomized study is much smaller than required in studies where progression-free survival and overall survival are the primary endpoints. This would ultimately result in the development of immunotherapies whose developers would not be making overall survival claims initially. Instead, they would claim the therapy kills more tumor than the standard of care when added to standard of care. The reduction of tumor burden in a safe manner should be a registration endpoint.
 
Response rates would allow developers to prove that immunotherapies mechanically do what they are supposed to do: kill tumors. Progression-free survival is not directly related to overall survival in any context involving the immune system, including the development of new immunotherapies. To use progression-free survival as an endpoint is neither scientifically nor technically warranted.
 
Combination therapy and targeted therapy
 
Even in the quest to boost response rate in immunotherapy, some hesitancy stems from concerns about tweaking the immune system in the wrong way. Some researchers are sensitive to the potential for damage if checkpoint inhibitor or CAR T cell therapies are combined with a separate immunotherapy or different type of cancer therapy. Although such concerns are to some degree justified, there are definite reasons why combination therapy offers a potentially promising pathway. For example, combination therapy could unlock the door to more targeted therapies offering potential benefit for patient subpopulations, such as female versus male patients.
 
Since the immune systems of men and women differ, it is therefore unsurprising to observe differential response rates in specific organ systems for a given form of immunotherapy. Earlier this year, for example, Oncolytics Biotech reported preliminary data from a Phase 2 clinical study of its lead product, REOLYSIN, a proprietary formulation of the human reovirus, in advanced or metastatic colorectal cancer, in combination with other cancer drugs. In the study, female patients had an objective response rate of 63.2 percent versus 23.8 percent in the control arm, a result with a level of significance higher than that observed among the men in the study. In a separate Phase 2 study of REOLYSIN and other cancer drugs in patients with non-small cell lung cancer, once again, female patients did better than in the standard treatment arms than male patients.
 
Based on these results, the company has filed for an additional Phase 2 study examining the treatment of female patients with metastatic colorectal cancer with REOLYSIN and other drugs including the checkpoint inhibitor pembrolizumab. The checkpoint inhibitor is being added to the treatment regimen based on an evolving understanding of how REOLYSIN upregulates immune responses and how the combination may make cancer cells more susceptible to attack by the immune system.
 
If future studies like these—combining immunotherapies such as checkpoint inhibitors and CAR T cell therapy with other cancer treatment approaches such as oncolytic virus therapy—prove effective, certain patient subpopulations such as women may be the beneficiaries of new targeted therapies.
 
The next few years will undoubtedly continue to bring new revelations from the frontiers of immunotherapy. We should not be surprised if the issues covered here—reward versus risk, choice of endpoints and targeted immunotherapy—continue to spur debate alongside analyses of the power of the therapies to benefit patients who need them.
 

Brad Thompson, PhD, is president and CEO of Oncolytics Biotech Inc., a Calgary-based biotechnology company focused on the development of oncolytic viruses as potential cancer therapeutics. Oncolytics' clinical program includes a variety of later-stage, randomized human trials in various indications using REOLYSIN, its proprietary formulation of the human reovirus.
Code: E10051600

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