DDNews Cancer Research Exclusive: Targeting epithelial cancers with TILs

NCI scientists reveal an immunotherapy approach that targets specific cancer mutations

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BETHESDA, Md.—Epithelial cells, which line the internal and external surfaces (such as skin) of the body, including the lung, bladder, pancreas and digestive tract, comprise more than 80 percent of all cancers. And while immunotherapies for cancer types such as melanoma and kidney cancer have seen some success, the same can’t be said for epithelial cancers.
Fortunately, Dr. Steven Rosenberg, chief of the Surgery Branch in the National Cancer Institute’s (NCI) Center for Cancer Research, and a team of NCI scientists have shown that the human immune system is capable of mounting a response to mutant proteins expressed by cancers that develop from epithelial cells. The study, “Cancer Immunotherapy Based on Mutation-Specific CD4+ T Cells in a Patient with Epithelial Cancer,” was published May 9 in Science.
All malignant tumors are mutated genetically to some degree, and in some cases that leads to the production of mutant proteins that can trigger an antitumor immune response. The team’s previous research led to the discovery that human melanoma tumors often contain mutation-reactive immune cells known as tumor-infiltrating lymphocytes (TILs), which might explain the success of adoptive cell therapy (ACT) and other forms of immunotherapy in the treatment of melanoma. ACT begins with the collection of a patient’s own TILs; those demonstrating the best antitumor activity are grown in the lab to produce large populations, which are then infused back into the patient.
In a previous paper, “Durable Complete Responses in Heavily Pretreated Patients with Metastatic Melanoma Using T-Cell Transfer Immunotherapy,” Rosenberg and colleagues studied ACT in melanoma patients. Ninety-three patients received TILs in conjunction with the anticancer drug interleukin-2 “following a lymphodepleting preparative regimen on three sequential clinical trials.” In that work, 20 patients (22 percent) saw complete tumor regression, with 19 demonstrating ongoing regression for more than three years. In melanoma, cell transfer therapy can result in “up to 40 percent complete durable regressions,” says Rosenberg.
Before this research, however, it was not known if the immune system could effectively mount a response against mutant proteins from epithelial cell cancers, nor if such a response could be used for personalized immunotherapies. One of the issues faced in translating this approach to epithelial cancers, Rosenberg notes, is that while it works in melanoma, melanoma cancers tend to have roughly 10 times the number of mutations as most epithelial cancers. The patient studied in the Science paper, whom Rosenberg says presents the “blueprint” for this approach in other cancers, presented with 26 mutations—and of those, only one was recognized by her immune system.
“The problem is that not all mutations are recognized by the immune system,” he explains. “They have to be processed inside the cell, they have to be brought to the cell’s surface, and most mutations are not recognized by the immune system.”
Rosenberg and his colleagues wanted to investigate whether TILs from patients with metastatic gastrointestinal cancers were capable of recognizing patient-specific mutations. They focused on a 43-year-old patient diagnosed with bile duct cancer that had metastasized to the lung and liver and had proven unresponsive to standard chemotherapy.
Whole-exome sequencing and additional testing revealed that some of the patient’s TILs recognized a mutation in the ERBB2-interacting protein (ERBB2IP). She then underwent adoptive cell transfer of 42.4 billion TILs, roughly a quarter of which were ERBB2IP mutation-reactive T lymphocytes—cells primarily responsible for activating other cells to help in cellular immunity—as well as four doses of interleukin-2 to enhance T-cell proliferation and function.
Following the ACT therapy, the patient’s metastatic lung and liver tumors stabilized. The disease progressed after roughly 13 months, at which point she received ACT again, this time with 95 percent of the transferred cells consisting of mutation-reactive T cells. After the second treatment, she saw tumor regression, which was ongoing as of the last follow-up (six months after the second infusion).
The team plans to continue investigating this approach in other cancers of the gastrointestinal tract, as well as bladder cancer. Rosenberg commented in a press release that “a major hurdle for the success of immunotherapies for gastrointestinal and other cancers is the apparent low frequency of tumor-reactive T cells.”
“The problem is that 90 percent of the almost 600,000 cancer deaths that occur in the United States each year are against epithelial cancers … It’s the common epithelial cancers that we have not had immunotherapies against,” says Rosenberg. “Epithelial cancers represent the real need now.”

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