A new method of immunotherapy developed by researchers at the National Cancer Institute has proven successful in the reduction of a metastasized tumor size by specifically attacking tumor cells that have mutations unique to a patient's cancer. The researchers demonstrated that the human immune system can mount a response against mutant proteins expressed by many common cancers that arise in epithelial cells which can line the internal and external surfaces of the body.
Steven A. Rosenberg, M.D., PhD., chief of the surgery branch at the NCI's Cancer Research Center, and his colleagues have shown that human melanoma tumors often contain mutation-reactive immune cells called tumor-infiltrating lymphocytes (TILs). The presence of these cells may help explain the effectiveness of adoptive cell therapy (ACT) and other forms of immunotherapy in the treatment of melanoma. In ACT, a patient’s own TILs are collected, and those with the best antitumor activity are grown in the laboratory to produce large populations that are infused into the patient. However, prior to this work it had not been clear whether the human immune system could mount an effective response against mutant proteins produced by epithelial cell cancers.
They analyzed TILs from a patient with bile duct cancer that had metastasized to the lung and liver and had not been responsive to standard chemotherapy. The patient, a 43-year-old woman, was enrolled in a trial of ACT for patients with GI cancers. The researchers first did whole-exome sequencing, in which the protein-coding regions of DNA are analyzed to identify mutations that the patients' immune cells might recognize. Further testing showed that some of the patients' TILs recognized a mutation in a protein called ERBB2-interacting protein (ERBB2IP). The patient then underwent adoptive cell transfer of 42.4 billion TILs, approximately 25 percent of which were ERBB2IP mutation-reactive T lymphocytes, which are primarily responsible for activating other cells to aid cellular immunity, followed by treatment with four doses of the anticancer drug interleukin-2 in order to enhance T-cell proliferation and function. Following transfer of the TILs, the patient’s metastatic lung and liver tumors stabilized (2).
When the patient’s disease eventually progressed, after about 13 months, she was re-treated with ACT in which 95 percent of the transferred cells were mutation-reactive T cells, and she experienced tumor regression that was ongoing as of the last follow up (six months after the second T-cell infusion). These results provide evidence that a T-cell response against a mutant protein can be harnessed to mediate regression of a metastatic epithelial cell cancer.
Figure 1. Left lung scan of patient before (left) and six months after ACT with mutation-specific Tcells (right). Arrows point to tumors that metastasized to the liung which have shrunk after treatment (right). (2)
Rosenburg said of the study, “Given 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 strategies reported here could be used to generate a T-cell adoptive cell therapy for patients with common cancers” (1). The struggle with this type of immunotherapy is finding the DNA sequences that the immune cells can recognize. It will be interesting to see where this development takes future immunotherapy treatments and if this method will work on other tissue with various forms of cancer.
Sources:
1. "New Immunotherapy Could Be Effective against a Wide Range of Cancers."National Cancer Institute. N.p., 8 May 2014. Web. 25 May 2014.
2. "Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer." Science. May 9, 2014.2
