A team of NCI researchers has reported that several types of gastrointestinal cancers have tumor-specific mutations that can be recognized by the immune system, offering a potential therapeutic opportunity for patients with these tumors.
In the study, published Oct. 29 in Science, researchers showed that T cells (white blood cells that destroy cells) by targeting tumor-specific genetic mutations can be identified in metastatic gastrointestinal tumors, according to lead study author Dr. Steve Rosenberg, head of the Surgery Unit at the NCI Cancer Research Center.
The discovery is important, Dr. Rosenberg said, because the most common form of immunotherapy, point-of-control inhibition, has shown no efficacy against most gastrointestinal cancers.
But this new study, he continues, “opens the door” to the conception of a different type of immunotherapy, called cellular foster transfer, for these and possibly for many other cancers.
Some cancers, such as melanoma and lung cancer induced by smoking, have many genetic mutations, which makes them especially immunogenic, that is, they tend to generate very strong immune responses.
Control point inhibitors such as nivolumab (Opdivo®) and pembrolizumab (Keytruda®) have shown the greatest efficacy against these types of cancer.
But, said Dr. Rosenberg, has not been clear whether cancers epithelial common, including gastrointestinal cancers, which tend to have fewer mutations than melanoma and lung cancer, induce an immune response specific to the tumor.
Last year, her research team reported that T cells directed against a single mutation in the tumor of a woman with advanced cholangiocarcinoma ( bile duct cancer ) were identified in lung metastases. The patient then underwent cellular adoptive transfer, using an extended set of her own mutation-specific T cells, and experienced regression of her metastatic lung and liver tumors that lasted for more than 2 years.
The new study, which is based on that finding, included nine additional patients who were being treated at NCI as participants in an ongoing clinical trial. All patients had metastatic cancer, including colorectal cancer, pancreatic cancer, bile duct cancer and esophageal cancer. The analysis also included data from the patient with cholangiocarcinoma.
More patients and more possibilities
In general, patient tumors had a modest number of genetic mutations. Still, the researchers were able to identify T cells that recognized at least one tumor-specific mutation in metastatic tumors in 9 of the 10 patients evaluated. The NCI team has extended this program since then, and has identified mutation-specific immune cells in 15 of the 16 patients studied, Dr. Rosenberg said.
In several patients, the research team isolated immune cells that recognized a mutation in the KRAS gene that is commonly seen in patients with pancreatic and colorectal cancers and many other cancers. The KRAS mutation was the only mutation recognized by the immune system seen in more than one metastasis of patients.
Given the overall frequency of the KRAS mutation in some cancers, the finding lays the foundation for a possible immunotherapy treatment with pre-prepared T cells manipulated to express a receptor that recognizes tumors with this mutation, Dr. Rosenberg said.
Two patients in the original group of 10 were further treated with their own mutation-specific T cells but did not respond to treatment. In these patients, the researchers found few infused T cells, if any, that had been left in patients’ circulation for an extended period. However, in the patient with cholangiocarcinoma, one month after treatment, almost a quarter of their circulating T cells were adoptively transferred to the mutation-specific cells.
A blue copy for many cancers
Much remains to be done, Dr. Rosenberg said, including how to improve the persistence of transferred T cells. But he is optimistic of what this discovery could represent.
“The whole idea of identifying mutations in a patient’s cancer and identifying and manipulating T cells that specifically recognize those mutations is a blue copy to treat many different types of cancer, he said.
The NCI team is already moving ahead with plans for an early-stage clinical study as a sequel to these findings, Dr. Rosenberg said.