May 19, 2014

Personalized Immunotherapy Treats Epithelial Cancer

Shrunken tumor. Six months after treatment, tumors that metastasized to the lung have shrunk.Rosenberg lab

A new treatment uses a patient’s own immune system to attack tumor cells. The approach might be used to treat many common cancers.

All malignant tumors harbor genetic alterations. Some of these mutations lead to the production of modified proteins that can trigger an immune response. Research led by Dr. Steven A. Rosenberg of NIH’s National Cancer Institute (NCI) has shown that human melanoma tumors are often infiltrated by immune cells called T lymphocytes that can recognize antigens expressed by the cancer.

The presence of tumor-infiltrating lymphocytes, or TILs, might explain the effectiveness of adoptive cell therapy and other forms of immunotherapy in treating melanoma. In adoptive cell therapy, a patient’s own TILs are collected, and those found to have the best antitumor activity are grown in the laboratory to produce large populations that are then infused into the patient.

More than 80% of all cancers arise in epithelial cells—the cells that line the internal and external surfaces of the body. Such cancers can develop in the skin, digestive tract, lung, pancreas, bladder, and other areas of the body. These cancers often contain fewer mutations than melanoma, which tends to be highly mutated. It had been unclear whether the human immune system could mount an effective response against epithelial cancers.

Rosenberg’s team set out to test personalized immunotherapies for metastatic digestive tract cancers—epithelial cell cancers that are difficult to treat and have poor survival rates. The study was published on May 9, 2014, in Science.

A 43-year-old woman with cholangiocarcinoma, a cancer that develops in the bile duct, was enrolled in an NIH clinical trial for patients with gastrointestinal cancers. Her cancer had spread to her lung and liver and hadn’t responded to standard chemotherapy.

The researchers first did whole-exome sequencing of the patient’s lung metastases. The exome (protein-coding regions of DNA) was analyzed to identify mutations that might trigger a reaction from her immune cells. Further testing showed that some of the woman’s TILs recognized a mutation in a protein called ERBB2IP.

The TILs were grown in the lab and then used for adoptive cell transfer. The patient received 42.4 billion TILs, about 25% of which were ERBB2IP mutation-reactive. The woman then received 4 doses of the drug interleukin-2 to enhance T-cell proliferation and function.

Following transfer of the TILs, the woman’s metastatic lung and liver tumors stabilized. When her disease eventually progressed, after about 13 months, she was re-treated with a 95% pure population of mutation-reactive T cells. After this treatment, she experienced tumor regression that was ongoing as of the last follow-up 6 months later.

These results show that the immune system’s response against a mutant protein can be harnessed to treat an epithelial cell cancer. “Our study deals with the central problem in human cancer immunotherapy, which is how to effectively attack common epithelial cancers,” Rosenberg says. “The method we have developed provides a blueprint for using immunotherapy to specifically attack sporadic or driver mutations, unique to a patient’s individual cancer.”

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References: Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Tran E, Turcotte S, Gros A, Robbins PF, Lu YC, Dudley ME, Wunderlich JR, Somerville RP, Hogan K, Hinrichs CS, Parkhurst MR, Yang JC, Rosenberg SA. Science. 2014 May 9;344(6184):641-5. doi: 10.1126/science.1251102. PMID: 24812403.

Funding: NIH’s National Cancer Institute (NCI) and the Milstein Family Foundation.