Mar 22, 2018

What's next for cancer immunotherapies

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Cancer immunotherapies that trigger a person's own immune system to recognize and attack cancer cells have logged some success in certain patients and with certain types of cancers. "But overall that is a minority of cancer patients," says Antoni Ribas from the University of California, Los Angeles.

Now, researchers are looking to leverage their understanding of what's working and what's not in patients receiving this class of drugs. (Science published a special section about cancer immunotherapy Thursday.)

The challenge: These are new avenues for research but they also spur serious concerns that must be addressed: unwanted and sometimes deadly side effects, unexplained lack of response by some cancers, and questions arising from combining multiple therapies and finding the optimal timing — which can make or break treatment.

How it works: Cancer metastasizes when it successfully evades or tricks a person's immune system into allowing it to spread. Two of the main types of immunotherapies are "checkpoint inhibitors" that work by taking the brakes off the immune system so it can recognize and attack cancer cells, and CAR-T cell therapy that works by engineering a patient's immune cells to attack cancer.

1. Checkpoint inhibitors more frequently work in cancer cells that are genetically different from normal cells as the result of genetic mutations from carcinogens (think: smoking or sun exposure) or from a virus, explains Ribas. "That leaves all of the other cancers and what to do with them."

Washington University School of Medicine's Russell Pachynski says the concern with these is “on-target, off-tumor” toxicity — where the checkpoint inhibitors that are supposed to stimulate and activate T cells are doing this in the non-tumor cells, leading to "unwanted activation of the immune system, resulting in potentially life-threatening complications like immune-mediated colitis or auto-immune hepatitis."

  • One of the current challenges in evaluating these therapies is that there are currently more than 1100 trials testing combinations of the drugs, raising questions about whether the studies are motivated by business more so than science, Jocelyn Kaiser reports for Science.
  • But Ribas says, "The system is working. We're making progress...There are practicalities [behind these trials] but companies made [those drugs] because there is science that supports those drugs. It’s not trial and error."

2. CAR-T cell therapy is when a patient's T-cells are removed, manipulated and reinserted inside the body to fight the cancer. "That field will see the biggest growth in the future," predicts Ribas. “With checkpoint inhibitors, we'll get to the point where we’ve turned off everything we can and will have to engineer the immune system.”

Pachynski says that so far CAR-T therapy works best against cancers circulating through the blood such as leukemia and lymphoma. There's been limited research and success so far in "solid tumors" such as those in pancreatic and prostate cancers. He says that's because:

  • It can be more difficult to identify a common tumor target in solid tumors than liquid.
  • CAR-T cells have to be trafficked to the tumor. "In leukemia, the tumor is in the blood and thus intravenous administration of CAR-Ts gives immediate access to tumors, while solid tumors present additional barriers."
  • The activity of CAR-T cells has to be controlled so they only target tumor cells.
What's next in immunotherapy research
  • Researching personalized treatment vaccines have long been a pipedream but the idea has been slow in advancing via a multitude of small clinical trials. Research has recently focused on RNA-based vaccines that target a patient's tumor-specific mutations and alterations to trigger T-cell response. There are still the issues of expense, long lead-time to create the vaccines, and determining the best method of selecting the specific tumor to target.
"[V]accinating a patient with individual tumor mutations may become the first truly personalized treatment for cancer," study authors Ugur Sahin and Özlem Türec write in Science today.
  • Testing other checkpoint inhibitors: Currently available therapies focus on inhibiting the PD-1 receptor on T-cells that hampers the last step in the process of attacking cancer cells, or CTLA-4, which regulates the proliferation of T-cells earlier in the immune response. Researchers are looking at whether using other checkpoint inhibitors like LAG-3 in combination with an anti-PD-1 drug can increase their success.
  • Activating the immune system: Another approach being evaluated is whether the immune system can be readied to attack by injecting a virus, or virus-mimicking drug, that attacks cancer cells before giving someone a checkpoint inhibitor, Ribas says. Researchers are also attempting to spark the immune response by administering small proteins called cytokines that regulate the immune system.
  • Blocking adenosine: When cancer cells replicate fast, they can start dying because they outgrow their blood supply. In the process, a molecule called adenosine can be released which then inhibits the function of T-cells being called on to attack cancer cells. A new class of agents is being tested in the clinic to see whether that process, too, can be blocked.
  • Inhibiting monocytes and regulatory T-cells: Tumors attract monocytes — non-specific cells that are important for healing wounds — as well as a type of T-cell called regulatory T cells that actually turn off other T-cells. Research is aimed at trying to inhibit these immune suppressive cells.
  • Exploring the microbiome: Scientists are trying to understand the relationship between bacteria in the gut and how cancer therapies work. Pachynski says research is " yielding some exciting data. The microbiome no doubt impacts immune responses, but the key will be given the huge diversity of bacteria, which ones are key players in favorably modulating the responses for patients and how do we actualize that in patients."

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