February 22, 2018

Her cancer wasn't treatable with immunotherapy. Somehow, the drugs still worked—and doctors want to know why.

Daily Briefing

    A group of women with a fatal form of ovarian cancer are in remission after undergoing immunotherapy, which physicians originally thought would be ineffective against their condition—a "befuddl[ing]" turn of events that "may open the door to new treatments for a wide variety of other cancers thought not to respond to immunotherapy," Gina Kolata writes for the New York Times' "Well."

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    How immunotherapy works

    According to Kolata, experts believe immunotherapy works by "dismantl[ing] a molecular shield that some tumors use to avoid an attack by the body's white blood cells." Kolata explains that while the body's immune system identifies such tumors as foreign bodies, white blood cells dispatched to attack the cancer cells end up rebuffed. Immunotherapy, however, enables those white blood cells to "pierce that protective shield … and demolish tumor cells," Kolata writes.

    But immunotherapy drugs aren't effective against several common forms of cancer, including prostate, pancreatic, breast, and ovarian cancers, Kolata reports. According to Kolata, experts believe immunotherapy is ineffective against those forms of cancer because they are generated by relatively few genetic mutations, meaning the body typically does not recognize the cancer cells as a foreign threat.

    Rather, immunotherapy seems to be most effective when used to treat cancers that have "huge numbers of mutations," Kolata writes, such as lung cancer or melanoma. As Drew Pardoll, the director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins Medicine, put it, "For the vast majority of cancers, there is an amazingly clean correlation between response to therapy and mean mutational load."

    That said, there are some exceptions, Kolata reports. Specifically, a type of skin cancer known as Merkel cell carcinoma responded to immunotherapy, despite resulting from few mutations—a reaction that scientists believe may occur  because the disease is caused by a virus. The infection, scientists hypothesize, may spur the immune system's attention. Mesothelioma also seems to be responsive, perhaps because asbestos—which causes the cancer—also inflames a body's immune system.

    A cure that shouldn't have worked

    According to Kolata,  hypercalcemic small cell ovarian cancer, "a rare, aggressive, and fatal form of ovarian cancer" that typically occurs in women in their teens or 20s, was not expected to respond to immunotherapy, as it's driven by a single genetic mutation.

    However, a group of four women suffering from such cancer all went into remission after taking immunotherapy drugs—perplexing scientists, "who are struggling to understand why the drugs worked when they should not have," Kolata reports.

    Jedd Wolchok, chief of the melanoma and immunotherapeutics service at Memorial Sloan Kettering Cancer Center, said, "What we are seeing here is that we have not yet learned the whole story of what it takes for tumors to be recognized by the immune system. … We need to study the people who have a biology that goes against the conventional generalizations."

    Looking for reasons why

    According to Kolata, researchers are now trying to determine why immunotherapy worked on these patients when it shouldn't have—and what that may mean for other cancers thought to be unresponsive to immunotherapy.

    Eliezer Van Allen, a cancer researcher at Dana-Farber Cancer Institute, offered one observation based on his studies of kidney cancer. He found that "a gene mutated in kidney cancer was sort of a master regulator of other genes," Kolata writes, "controlling which were turned on and when." Even though the regulated genes were normal, and did not produce proteins that might be classified as abnormal by the body's immune system, patients who had that "master gene mutation" responded to immunotherapy according to Kolata. "We saw this result and weren't sure what to make of it," Van Allen said.

    Douglas Levine, the director of gynecologic oncology at NYU Langone Medical Center, found the same mutation in patients with hypercalcemic ovarian cancer. He and Van Allen hypothesized that the immune system might recognize cells that are turning on and off randomly as dangerous, which would prompt a response. But "that is strictly hypothesis," Levine cautioned.

    Trials planned

    While researchers remain unsure about why immunotherapy worked among the ovarian cancer patients, they spotted clear evidence that white blood cells were in the tumors—demonstrating that the immune system had at least tried to attack. As a result, Pardoll and Padmanee Sharma from the M.D. Anderson Cancer Center have scheduled clinical trials aimed at identifying which patients stand to benefit from immunotherapy, regardless of their type of cancer.

    According to Kolata, Sharma's study will assess patients' tumors for the presence of white blood cells. If white blood cells are present, the patients will receive an immunotherapy drug to help white blood cells more effectively attack the tumor. On the other hand, if patients' tumors have only a few white blood cells, they will receive a mix of two immunotherapy drugs aimed at helping white blood cells enter the tumor and attack.

    "The trial is written for all comers," Sharma said. "If we have learned anything, it is that it is not the tumor type we are treating—it is the immune system."

    Meanwhile, Pardoll's study will give immunotherapy drugs to patients presenting with tumors that have a certain type of protein, PD-L1, that rebuffs an immune system attack. Pardoll admitted it was a stab in the dark, but he said, "Incredible things happen, and against all the odds" (Kolata, New York Times, "Well," 2/19).

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