June 2014 Edition Vol.11, Issue 6

Immunotherapies at ASCO 2014: Checkpoint Inhibitors

Immunotherapies at ASCO 2014: Checkpoint Inhibitors (continued)

A Tale Nearly Untold

Though the adjectives abound (ie, “most benign, unprecedented, remarkable”) checkpoint inhibitors were nearly passed on. “Pfizer had one of these in development,” recalled Gary Schwartz, MD, Chief of Memorial Sloan-Kettering’s Melanoma and Sarcoma Service, and Associate Editor of the Journal of Clinical Oncology. “But they abandoned it because patients were progressing in the first eight weeks of treatment. And what happened then was Jedd had a patient in the BMS trial [for Yervoy] who progressed at eight weeks…”

Jedd, being Dr. Jedd Wolchok, also of Memorial Sloan-Kettering, told the patient ‘come back in two months and we’ll see how you’re doing,’ not actually expecting to see the patient return because the guy’s liver was 80 percent replaced by tumor.”

Yet, eight weeks later the patient did return and he was seemingly healthy. “They did a CAT scan,” said Dr. Schwartz. “All those liver lesions? They were just the infiltration of T-cells fighting the cancer cells. Every one of those lesions was gone and the guy was in complete remission, and that’s been durable. That one single clinical observation probably saved the whole field of immunological therapies for Bristol-Myers Squibb.”

And for everyone else in the space – the Yervoy experience established that immunotherapies require different clinical trial endpoints, to whit: There may be early progression with these drugs, but a robust response then follows – indicative of the kinetics of a working immune system.

The wonder and timeframe of this activity aside, it’s also been established that checkpoint inhibitors, on their own, are not magic bullets.

“Tumors are more sophisticated than that,” observed Nabil Ahmed, MD, of the Center for Cell and Gene Therapy, Baylor College of Medicine. “Tumors look like a genetic mess, but this is a very organized mess. It’s almost like looking at a slum and thinking that this is a slum, yet, slums have systems. They are deranged; the same way as signaling is in tumors, and molecules are in tumors. Deranged, but they continue to function. There has to be a multi-mechanism to be able to collapse the tumor system.”

Critical to the mechanism is the presence of T-cells that can be activated, and this dynamic varies greatly between patients, and between tumor types. “If I look in my crystal ball, I see a future combination of a checkpoint inhibitor antibody with an infusion of T-cells (so-called TILs, or CARs).  I think this is what will make it work. We are not there yet, of course, because we’re still kind of testing each approach alone.”

Dr. Tim Bullock of the Human Immune Therapy Center, University of Virginia, concurs. “The weakness of checkpoint blockade at the moment is patients who don’t have preexisting responses in their tumors are very unlikely to respond to them.” No T-cells, no T-cell response. “Are we going to need vaccination strategies to amplify the immune response against tumor antigens, and then use the checkpoint inhibitors once these T-cells get into the tumor microenvironment?”

Indeed, such questions abound in the cancer immunotherapy space: Are there other ways to train the immune system to “see” the cancer cells? Is it simply doing damage to the tumor with chemo- or are radiotherapies going to elicit this immune response against those tumors? What about priming the tumor, as has been suggested, with agents known to increase PD-1 expression, which would, in a way, drive a tumor towards therapeutic vulnerability?  

“In the short term, I think combinatorial checkpoint blockade or the combination of checkpoint blockade with T-cell activation strategies are going to be very effective, but potentially very dangerous. So we have to be very careful moving forward.”

Bench to Bedside

The shiniest new therapeutic tool, even one as sophisticated as immunotherapy is useless if you’re afraid to use it. “I would say the majority of the community oncologists do have their finger on the pulse of what’s going on,” suggested Julie Brahmer, MD, Johns Hopkins University, “But they may or may not feel comfortable using some of these new therapies. Some of the community docs I’ve talked with who are using ipilimumab in their clinic say it’s not that easy, and that they don’t feel comfortable using it.” Even so, Dr. Brahmer sees the PD-1 antagonists as less toxic than the CTLA-4 targeting drugs. “They may be a little bit easier to handle in the clinic, and hopefully continuing education will increase physician comfort level.”

Dr. Michael Gordon, of the Arizona Center for Cancer Care, also sees the agents targeting PD-1, and PD-L1 (the PD-1 ligand) as more user friendly than the first-in-class approved drug, Yervoy. “The good news is that the PD-1, PD-L1 agents have a different safety profile than the other immune checkpoint inhibitors like ipilimumab, so the concern about the high rate of toxicity for colitis, skin rash, and endocrine system dysfunction, we’re not seeing that as quickly with these drugs. So I expect that we’ll see a much greater uptake.”

And to facilitate that uptake doctors may need to have a talk with their nurses. “We’ve known for a long time that patients are much more open with nurses than they are with physicians,” Dr. Gordon readily admitted. “I think patients fear that sharing their infirmities with their doctors will lead to dose modification, or dose reductions and a potential compromise of their therapy, and so the nurses become a crucial component of our patient care profile, and they [nurses] need to be educated on these immunotherapies so that they can bring to the physician’s attention, or on their own, execute processes for managing adverse events.”

At the end of the day, inclusion is what immunotherapy is all about. As Jedd Wolchok put it, “With these drugs we treat the patient, but it’s the patient that treats the tumor.”

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