A Reality Check for Checkpoint Inhibitors

They take the brakes off the immune system so it attacks cancer cells. But many people don’t respond to checkpoint inhibitors, so researchers are looking for ways to defeat the resistance.

Thomas Reinke
Contributing Editor

Immunotherapy is a major breakthrough, and manipulating the body’s immunological defenses so they go after malignancies is a brilliant strategy. The therapies that have been developed are ingenious and range from the oncolytic virus Imlygic (talimogene laherparepvec), which kills cancer cells by exploding inside a tumor, to Kymriah (tisagenlecleucel), which has been touted as the first-ever U.S. gene therapy.

But the fastest growing category is the checkpoint inhibitors, such as Keytruda (pembrolizumab) and Opdivo (nivolumab).The FDA has approved six checkpoint inhibitors (see the table below), and the list of cancers they battle continues to grow way beyond that number. At last count, Opdivo has nine indications.

The current crop of checkpoint inhibitors
Brand name Generic name Target Company
Bavencio avelumab PD-L1 EMD Serono and Pfizer
Imfinzi durvalumab PD-L1 AstraZeneca
Keytruda pembrolizumab PD-1 Merck
Opdivo nivolumab PD-1 Bristol-Myers Squibb
Tecentriq atezolizumab PD-L1 Roche
Yervoy ipilimumab CTLA-4 Bristol-Myers Squibb
Source: American Cancer Society, company press releases

Most do not respond

The checkpoint inhibitors work by preventing proteins on tumor cells, such as PD-L1, from binding to proteins on T cells, such as PD-1. When this binding occurs, it establishes a “checkpoint” that keeps T cells from killing tumor cells. Inhibiting that binding clears the way for T cells to stay on the attack—and in this case, the attack is directed at a tumor cell.

The first checkpoint inhibitors have been on the market for several years now, and clinicians are seeing cases with unprecedented durable responses: Disease progression halted and patients with metastatic melanoma who are alive years after treatment. For metastatic disease, that is nothing short of amazing.

But a plain, come-down-to-earth fact sometimes gets lost in the excitement about checkpoint inhibitors and the flurry of approvals: The majority of patients do not respond to these agents, and many of those who do respond eventually relapse.

Consider Keytruda. In the trial that was the basis for its approval in September 2014 as a treatment for metastatic melanoma, the overall response rate was 24%. For Opdivo, it’s a similar story: an overall response rate of 32% in the trials that led to its first approval, also as a treatment for metastatic melanoma.

In all fairness, these approvals were for patients with advanced disease who had failed an earlier treatment. Besides, the extended survival of some patients—people who would have died were not for these treatments—has oncologists truly excited. So researchers are now starting to explore how resistance to the checkpoint inhibitors might be overcome so they will be effective in more patients.

It’s more complicated than this, but one place to start is by grouping resistance into three categories: primary, acquired, and adaptive.

Primary resistance. Cancer tumors are fortresses. They are characterized by a dynamic microenvironment that adapts over time, putting up new defenses as the tumor progresses from a single cell to metastatic disease.

Primary resistance may be a pre-existing mechanism lying in wait that reacts right away to suppress the immune system’s attack. One example of primary resistance involves the interferon gamma pathway; cancer cells thwart the activating effects of interferon gamma (Ifn-γ) on T cells by cutting off or mutating molecules in Ifn-γ’s signaling mechanism.

Dmitriy Zamarin, MD, an oncologist at Memorial Sloan Kettering Cancer Center who specializes in gynecologic cancers, points out that the current group of checkpoint inhibitors tend to take the brakes off just one part of the immune system. Tumor cells have figured that out and activate other pathways that reapply the brakes, so the cancer can keep on growing.

Acquired resistance. Of course, it is not unusual for a cancer to respond initially to a treatment and then stop even as treatment continues. Researchers are trying to figure out how cancer cells can be smart enough to acquire a defense to treatment and escape from T cells that have been amped up to attack it.

“It involves the survival of the fittest,” says Zamarin.“Let’s say that the immunotherapy kills off the weak cancer cells. There may be another innate resistance mechanism or an adaptation by the tumor.”

Cancer cells may resist immunotherapy by switching off MHC genes, says Dmitriy Zamarin, MD, a researcher at Memorial Sloan Kettering Cancer Center.

Many acquired resistances are based on the core elements of immunotherapy. The surface of tumor cells express antigens that a T cell receptor recognizes as foreign, triggering T cell activation. T cells convert from tumor-naïve cells into tumor-fighting cells. They undergo clonal expansion, home in on the tumor microenvironment, and kill off cancer cells. Better yet, the T cells develop immunologic memory, so they keep on recognizing the cancer cells and fight them over the long haul.

Acquired resistance can interrupt this process. “As a defense, cancer cells can do one of two things,” says Zamarin. “They can eliminate or reduce the number of foreign antigens they present. Or, what we have seen is that they stop expressing the MHC on their surface. In essence the tumor hides from the immune system.” The major histocompatibility complex (MHC) is a group of genes that code for proteins on the surface of tumor cells that facilitate the presentation of antigens recognized by T cells.

Adaptive resistance. This term has been coined to describe the rise of immune suppressive pathways in the tumor following an attack by activated T cells. Adaptive resistance is a scalable process where the magnitude of immune suppression matches the magnitude of the durability of the therapy.

Viruses whip up a reaction

Tumors use devious methods to undermine the immune system, but drug companies and cancer researchers like Zamarin are developing their own sneaky ways to get through cancer’s fortress walls.

One of these approaches is to use oncolytic viruses that have a bait-and-switch effect upon the immune system. “Viruses infect cancer tumors and, when they do, they stimulate inflammation and a very strong immune system response. Once this happens the immune system response is not only against the virus but also against the cancer cells,” says Zamarin.

Amgen’s Imlygic is viral treatment that causes a type of cell death that ruptures tumors. When that happens, out spill tumor-derived antigens, that provoke an antitumor immune response.

Zamarin is investigating another virus called the Newcastle disease virus. His research team at Memorial Sloan Kettering has shown in preclinical models that this virus therapy in combination with checkpoint inhibitors is effective against both the injected and distant metastatic tumors.

Better together perhaps

The next step in immunotherapy is focused on the dual-therapy approach. Roche, Merck, and Bristol-Myers Squibb are racing to develop dual-therapy cancer regimens that will include their checkpoint inhibitors and other agents.

Bristol-Myers Squibb has, for example, reported positive results for regimens that include its two checkpoint inhibitors, Opdivo and Yervoy, although there has been concern that side effects increase along with the response rate and time to disease progressioon.

Last year, the FDA approved a Merck combination of Keytruda plus chemotherapy agents pemetrexed and carboplatin as a first-line therapy for metastatic non–small-cell lung cancer. Merck has announced that it is working on combining Keytruda with at least two other newer oncolytics. Roche is working to combine its checkpoint inhibitor, Tecentriq (atezolizumab), with Avastin (bevacizumab).

Immunotherapy is advancing at breakneck speed. But Zamarin advises against overconfidence against such a wily foe. “When we are designing these combination treatments,” he says, “we need to anticipate how cancer might stay one step ahead of us.”

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