May 14, 2014
BALTIMORE, Md -- May 14, 2014 -- A new method for using immunotherapy to specifically attack tumour cells that have mutations unique to a patient’s cancer has been developed by scientists at the National Cancer Institute (NCI), part of the National Institutes of Health (NIH).
The researchers demonstrated that the human immune system can mount a response against mutant proteins expressed by cancers that arise in epithelial cells which can line the internal and external surfaces (such as the skin) of the body. These cells give rise to many types of common cancers, such as those that develop in the digestive tract, lung, pancreas, bladder, and other areas of the body.
The research, published in the journal Science, provides evidence that this immune response can be harnessed for therapeutic benefit in patients.
“Our study deals with the central problem in human cancer immunotherapy, which is how to effectively attack common epithelial cancers,” said Steven A. Rosenberg, MD, NCI’s Center for Cancer Research, Rockville, Maryland. “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.”
All malignant tumours harbour genetic alterations, some of which may lead to the production of mutant proteins that are capable of triggering an antitumor immune response. Research led by Dr. Rosenberg had shown that human melanoma tumours often contain mutation-reactive immune cells called tumour-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. These cells comprise more than 80% of all cancers. It was also not known whether such a response could be used to develop personalised immunotherapies for these cancers.
In the current study, Dr. Rosenberg and his team set out to determine whether TILs from patients with metastatic gastrointestinal cancers could recognise patient-specific mutations. They analysed TILs from a patient with bile duct cancer that had metastasised to the lung and liver and had not been responsive to standard chemotherapy. The patient, a 43-year-old woman, was enrolled in an NIH trial of ACT for patients with gastrointestinal cancers (Clinical trial number NCT01174121).
The researchers first did whole-exome sequencing, in which the protein-coding regions of DNA are analysed to identify mutations that the patient’s immune cells might recognise. Further testing showed that some of the patient’s TILs recognised a mutation in a protein called ERBB2-interacting protein (ERBB2IP). The patient then underwent adoptive cell transfer of 42.4 billion TILs, approximately 25% of which were ERBB2IP mutation-reactive T lymphocytes, which are primarily responsible for activating other cells to aid cellular immunity, followed by treatment with 4 doses of interleukin-2 to enhance T-cell proliferation and function.
Following transfer of the TILs, the patient’s metastatic lung and liver tumours stabilised. When the patient’s disease eventually progressed, after about 13 months, she was re-treated with ACT in which 95% of the transferred cells were mutation-reactive T cells, and she experienced tumour regression that was ongoing as of the last follow up (6 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.
“Given that a major hurdle for the success of immunotherapies for gastrointestinal and other cancers is the apparent low frequency of tumour-reactive T cells, the strategies reported here could be used to generate a T-cell adoptive cell therapy for patients with common cancers,” said Dr. Rosenberg.
SOURCE: National Institutes of Health
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