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March 15, 2018

Immunotherapy Raises the Stakes and Ovarian Cancer Blinks

  • “I’ll see your neoepitope and raise you a tumor-infiltrating lymphocyte.” Such bets could be placed more confidently if cancer immunotherapy would deal itself a stronger hand, one that would include the “juiciest” T cells—the T cells that are best at recognizing and killing cancer cells.

    Unfortunately, the juiciest T cells often get lost in the shuffle. Either they don’t reach the bloodstream, where many T cells intended for cell-based immunotherapy are drawn, or they end up at the bottom of the tumor-infiltrating lymphocyte (TIL) deck. Not content to play the hand they were dealt, scientists at the Ludwig Institute for Cancer Research decided that a little bottom dealing might be in order.

    “We developed a new methodology to identify highly reactive TILs and expand them in a manner that, rather than diluting the juiciest TILs, enriches them instead," said Alexandre Harari, Ph.D., a Ludwig Lausanne investigator and a co-leader of a new study that aims to improve personalized cancer immunotherapy. "This allowed us to compare the activity of TILs that target neoepitopes with their counterparts in the peripheral bloodstream."

    The new study was detailed in a study that appeared March 15 in Nature Communications, in an article entitled “Sensitive and Frequent Identification of High Avidity Neo-Epitope Specific CD8+ T Cells in Immunotherapy-Naive Ovarian Cancer.” This article explains that ovarian tumors, which have tended to resist cell-based immunotherapies, harbor highly reactive killer T cells that can be identified and selectively grown.

    "Tumors whose cells tend to be highly mutated, like those of melanoma and lung cancer, are the ones that respond best to immunotherapies," noted Harari. "It has long been a question whether we'd even be able to detect sufficiently mutation-reactive T cells in patients with tumors that have low mutational loads."

    Ovarian tumors have a low mutational load. In a sense, they keep their cards close to their vest. Nonetheless, they are infiltrated with mutation-sensitive T cells.

    Cancer cells that have a relatively large number of mutations in their DNA express aberrant proteins—or neoantigens—that reveal the cancer to the immune system. Killer T cells recognize tiny, mutated bits of these antigens, known as neoepitopes. But neoepitopes vary wildly from patient to patient, even within the same type of cancer. This has long stymied efforts to develop generally effective therapies that target cancer antigens.

    “Comprehensive and deep analysis of circulating and tumor-infiltrating lymphocytes (TILs) for neoepitope specific CD8+ T cells has allowed prompt identification of oligoclonal and polyfunctional such cells from most immunotherapy-naive patients with advanced epithelial ovarian cancer studied,” the article’s authors wrote. “Neoepitope recognition is discordant between circulating T cells and TILs, and is more likely to be found among TILs, which display higher functional avidity and unique TCRs [T-cell receptors] with higher predicted affinity than their blood counterparts.”

    Essentially, the researchers developed a new way to select and expand T cells from patients that best target a patient's cancer and then reinfuse them into the patient. The researchers also showed that killer T cells isolated from ovarian tumors using their method are much better at both recognizing neoepitopes than are those isolated from blood.

    “Our results,” the authors asserted, "imply that identification of neoepitope specific CD8+ T cells is achievable even in tumors with relatively low number of somatic mutations, and neoepitope validation in TILs extends opportunities for mutanome-based personalized immunotherapies to such tumors.”

    "We could even compare T cells from the two compartments targeting the exact same mutation and show that the TILs were more functional than the T cells we collected from the peripheral bloodstream," noted Harari.

    Notably, the researchers found that, using their methods, highly reactive TILs could be obtained from some 90% of the ovarian cancer patients whose tumor samples they examined.

    "The big message," added George Coukos, M.D., Ph.D., study co-leader and director of the Ludwig Institute for Cancer Research, Lausanne, "is that future cell-based therapies can be envisioned for low-mutational-load tumors and should prioritize the use of TILs over T cells collected from peripheral blood. This novel strategy to obtain enriched TILs also offers great therapeutic opportunities."

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