Abstract
New research shows a novel immunotherapy method can shrink metastatic lesions in an epithelial cancer by targeting a mutated protein with a patient's own immune cells.
Researchers at the NCI have raised an army of immune cells that specifically target a mutation unique to a patient's tumor, leading to the regression of a metastatic epithelial cancer.
Until now, adoptive cell therapy using tumor-specific immune cells—so-called tumor-infiltrating lymphocytes (TIL)—has been successful in treating only metastatic melanoma. The new research also marks the first time scientists have used T cells to intentionally home in on a tumor mutation.
The findings, published in May, outline the treatment of a 43-year-old woman with metastatic cholangiocarcinoma (Science 2014;344:641–5). Scientists extracted TILs from tumor samples taken from her lungs and cultured them in the lab. Whole-exome sequencing identified 26 nonsynonymous mutations harbored by her cancer. Further tests showed that a mutant ERBB2-interacting protein (ERBB2IP) was recognized by some of her TILs.
After receiving lymphocyte-depleting chemotherapy, the patient was infused with 42.4 billion TILs, about 10 billion of which were reactive to the mutated ERBB2IP. She then received four doses of IL2 to enhance T-cell proliferation and function.
The metastatic lesions shrank and then stabilized for about 13 months before progressing. The patient received a second treatment, this time with 126 billion TILs, 95% of which were reactive to the mutated protein. Her tumors began shrinking within a month and continue to regress after 6 months, researchers report.
Steven Rosenberg, MD, PhD, the study's senior author and chief of the surgery branch at the NCI's Center for Cancer Research, calls it “the ultimate personalized treatment. This is a technique to develop a patient's own T cells against mutated proteins within their own cancer.” His team is now working to streamline the complex process.
Rosenberg says immunotherapy has been most successful in melanoma, in part because melanoma has up to 10 times as many mutations as common epithelial malignancies such as breast, colon, and lung cancers. The new research could serve as a “blueprint” for these common tumors, he says. Epithelial cancers comprise more than 80% of all cancers and are responsible for about 90% of cancer deaths each year in the United States.
CT scan of a patient's left lung before (left) and 6 months after (right) adoptive cell therapy with mutation-specific CD4+ T cells. Arrows point to metastatic cholangiocarcinoma lesions.
CT scan of a patient's left lung before (left) and 6 months after (right) adoptive cell therapy with mutation-specific CD4+ T cells. Arrows point to metastatic cholangiocarcinoma lesions.
However, Rosenberg and other cancer immunotherapy experts caution that the research is early and involved only one patient.
Cassian Yee, MD, a professor of melanoma medical oncology and immunology who directs the Solid Tumor Cell Therapy program at The University of Texas MD Anderson Cancer Center in Houston, says it is unknown how many patients with epithelial cancers will have targetable mutations.
“Almost every tumor has mutations but not all are recognized by the immune system,” says Yee, who was not involved in the research. “Whether you can attack the tumor in the next patient who has different mutations and a different T-cell repertoire remains to be seen.”
Rosenberg and his colleagues should soon find out. They have pinpointed unique tumor mutations recognized by the immune system in two patients with colon cancer. “We're now working to see if we can treat them,” he says.
For more news on cancer research, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
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