Checkpoint Inhibitors: Where to Next?

In August 2015, former President Jimmy Carter announced that he had melanoma that had metastasized to his brain. Then 90 years old, he later told reporters that he thought he had weeks to live, at best. Nearly three years later, the indefatigable Carter has achieved one of his most cherished goals—stopping the spread of Guinea worm in South Sudan—and continues to build houses with Habitat for Humanity.

Carter’s remarkable turnaround, attributed to the then-novel immune checkpoint inhibitor pembrolizumab (Keytruda), put the spotlight on this class of immunotherapy drugs, which work by blocking certain proteins that help keep immune responses “in check” and prevent the body’s immune system from recognizing and killing cancer cells.

There are currently five PD1 or PDL-1 checkpoint inhibitors approved by the U.S. Food and Drug Administration:

PD1 inhibitors

Pembrolizumab (Keytruda): advanced melanoma, advanced non-small cell lung cancer, advanced head and neck squamous carcinoma, any unresectable or metastatic solid tumor with the biomarker microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

Nivolumab (Opdivo): advanced melanoma, advanced non-small cell lung cancer, advanced head and neck squamous carcinoma, advanced renal cell carcinoma, Hodgkin’s lymphoma, advanced hepatocellular carcinoma

PDL-1 inhibitors

Atezolizumab (Tecentriq): advanced non-small cell lung cancer, advanced urothelial cancer

Avelumab (Bavencio): advanced Merkel cell carcinoma, advanced urothelial cancer

Durvalumab (Imfinzi): advanced urothelial carcinoma, advanced non-small cell lung cancer cancer

The flurry of approvals for these new therapies within a span of just four years demonstrates that the immune system can indeed be harnessed to treat patients with both hematologic and non-hematologic cancers. These drugs have proven effective even in cancers that were once thought not to be immune-responsive, such as non-small cell lung cancer. But not everyone responds to checkpoint inhibitors as remarkably as Jimmy Carter.

These drugs have proven effective even in cancers that were once thought not to be immune-responsive…

“We have response rates for these drugs that are between 10% and 50%,” says Igor Puzanov, M.D., MSCI, FACP, Director of the Early Phase Clinical Trials Program at Roswell Park Cancer Institute. “Our challenge is to improve those percentages.” All the PD1 and PDL-1 agents seem to have similar efficacy, so it’s all about combinations after the first wave of these drugs. Everybody is trying to figure out what might be the best combinations of these drugs with other agents.”

PD1/PDL-1 inhibitors could be combined with a wide range of other therapies, as well as classic cancer treatments such as chemotherapy and radiotherapy, wrote Patrick Ott and colleagues in the Journal for ImmunoTherapy of Cancer in 2017. “The established anti-tumor activity of PD-1/PDL-1 inhibition as monotherapy in a wide spectrum of cancers coupled with its favorable toxicity profile provides a strong rationale for its use as a backbone for combinatorial strategies.”

Puzanov thinks that combination approaches involving these checkpoint inhibitors and vaccines, oncolytic viruses, cytokines, interleukin-2 molecules, and CAR T cell therapies all have promise. “It’s all about finding the right combination for each individual patient; and some may do better with combinations involving the old-fashioned agents.”

Some cancers have not proven as amenable to checkpoint inhibitors, he adds. “Tumors in the gastrointestinal system seems to be more protected against attacks by immunotherapy agents; pancreatic and prostate cancers also do not seem to be as responsive thus far.”

And while Jimmy Carter’s cancer, which had metastasized to his brain, responded to pembrolizumab, primary brain tumors have proven an elusive target indeed for checkpoint inhibitors and other immunotherapy approaches.

“A number of studies of checkpoint inhibitors are ongoing in brain tumors, but unfortunately, the only large Phase III study to date, involving nivolumab in recurrent glioblastoma, showed no improvement in overall survival,” says Howard Colman, MD, PhD, Director of Medical Neuro-Oncology at the Huntsman Cancer Institute of the University of Utah.

Although the results of the CheckMate 143 trial had not been fully released at press time, topline data released in early April showed that glioblastoma patients who recurred following radiation therapy and temozolomide (Temodar), did not survive longer when treated with nivolumab compared to standard-of-care treatment with bevacizumab (Avastin).

“Glioblastoma is a very difficult disease to treat, and many of the approaches that have had significant success in subsets of disease in other solid tumors have been less effective or not effective at all,” Dr. Colman says. “But we still hope that with modifications and a better understanding of how the immune system functions in the brain, immunotherapy might be effective.”

Combination therapy

Combination therapy might be one such modification; at the most recent meeting of the American Association for Cancer Research, held in Chicago last month, researchers from the University of Pennsylvania’s Abramson Cancer Center presented promising findings laboratory studies combining from CAR T cell therapy with immune checkpoint blockade inhibitors in glioblastoma. Using two different types of CAR T cells—one engineered to bind to epidermal growth factor receptor variant three (EGFRvIII), a gene commonly mutated in glioblastoma, and the other targeting the interleukin-13 receptor subunit alpha-2 (IL-13Rα2) protein—researchers found that CARs targeting EGFRvIII were five times more effective when paired with an anti-PD-1 treatment, while CARs targeting IL-13Rα2 were five times more effective when paired with CTLA4 inhibitors.

“So far, with CheckMate and other studies and anecdotal reports, no one appears to be seeing efficacy with checkpoint inhibitors alone in glioblastoma, and we did not see efficacy in our first CAR T study using single infusion cell therapy without checkpoint inhibitors,” says senior author Donald M. O'Rourke, MD, the John Templeton, Jr., M.D. Associate Professor in Neurosurgery at Penn. “Putting the two together is the next logical step. What is interesting is that the synergy is different depending on the CAR construct you’re using and the target. You can’t just pick any particular checkpoint. Certain checkpoints work better with certain CARs, and that differential response will tell us more about the pathways that are activated and how we more efficiently go about combination therapy. We need to back off from the hype and recognize that it seems as though only a fraction of patients respond well and durably to checkpoint inhibitors. The fundamental question is, what is the basis of sensitivity to these drugs? On that, much more basic and translational research needs to be done.”