A treatment type that uses patients’ own immune cells to attack cancer looks ready for testing in human clinical trials of advanced colorectal cancer.
In a study paper published in the journal Cancer Immunology Research, researchers at Thomas Jefferson University in Philadelphia, PA, report how they tested the treatment, which is a type of immunotherapy known as chimeric antigen receptor (CAR) T-cell therapy, in mice that were implanted with human colorectal cancer tumors.
The treatment killed colorectal cancer tumors and prevented them spreading.
Successful completion of this last preclinical stage means that the next step would be a phase I clinical trial in human patients.
The progress is significant because there are few treatment options for colorectal cancer once it has advanced.
“The concept of moving [CAR T-cell] therapy to colorectal cancer is a major breakthrough,” states Dr. Karen Knudsen, who is director of the Sidney Kimmel Cancer Center at Thomas Jefferson University, “and could address a major unmet clinical need.”
Estimates suggest that there were 139,992 new cases of colorectal cancer and 51,651 deaths to the disease in the U.S. in 2014, the latest year for official figures.
As with most cancers, most deaths in colorectal cancer occur in patients with advanced disease, which begins when the primary tumor starts to spread.
The tumor can spread either locally into the neighboring tissue, or through metastasis, a process in which cells escape the primary tumor and migrate to other parts of the body where they can set up new, secondary tumors.
Not all cancer cells that escape a primary tumor succeed in forming secondary tumors. The process is complex and has many steps — from breaking away to migrating, evading the immune system, and setting up camp — and it can fail at any step.
The cells that eventually succeed may no longer resemble the cells of the primary tumor. This is one of the reasons that metastatic cancer is harder to treat.
CAR T-cell therapy is a type of immunotherapy in which clinicians reprogram genes in “patients’ own immune cells to attack cancer cells.”
To do this, immune system T cells are taken from the patient, genetically reprogrammed in the laboratory, multiplied to vastly increase their number, and then infused back into the patient.
The reprogramming of T cells restores their ability to find and attack cancer cells that had previously been very successful at suppressing the attacks.
However, in order for the T cells to find and kill only the target cancer cells, there has to be a way to identify them uniquely to the T cells. This is where the genetic reprogramming comes in — it makes the T cell seek out a unique marker, called a tumor antigen, on the cells.
In the case of the new study, the tumor antigen that they used was GUCY2C, whose potential had previously been identified by senior author Adam E. Snook, who is an assistant professor in the Department of Pharmacology and Experimental Therapeutics at Thomas Jefferson University.
Initially, the scientists tested the therapy on laboratory-cultured cancer cells. They showed that it targeted and killed only those cancer cells that expressed the GUCY2C marker; cancer cells without GUCY2C were spared.
Prof. Snook and colleagues then showed that the CAR T-cell therapy using the GUCY2C tumor antigen successfully treated mice implanted with human colorectal cancer tumors.
All the treated mice survived for the whole of the study’s observation time, which amounted to 75 days. Mice treated with a control therapy survived for an average of 30 days.
In another set of experiments, the researchers used mice that had developed their own “murine” colorectal cancer tumors but that had been genetically altered to “express human GUCY2C.”
When they treated those mice with T cells programmed to find GUCY2C-tagged cancer cells, the researchers found that they “provided long-term protection against lung metastases.”
The lung is a common site for secondary tumors in colorectal cancer in humans.
The mice that received CAR T-cell therapy lived for another 100 days with no secondary tumors, whereas the mice that received a control treatment only lived an average of 20 days after treatment.
Although this study did not test for any side effects that may have arisen from the engineered T cells going “off-target,” the researchers had previously shown, using a mouse version of the therapy, that there were “no off-target effects.”
Prof. Snook acknowledges the “major concern” about safety with using CAR T-cell therapy. “In other cancers,” he notes, “the field has observed lethal autoimmune responses.”
He says that there are ongoing efforts to create fast-acting antidotes to these off-target responses, but he and his colleagues believe that their study shows that GUCY2C CAR T-cell therapy “may be very effective and safe in cancer patients.”
They also see wider applications of the therapy in other hard-to-treat cancers that also express the GUCY2C tumor antigen.
“The antigen we target for colorectal cancer,” explains Prof. Snook, “is one that is shared across several high-mortality cancers including esophageal and pancreatic cancer.”
“Taken together, 25 percent of people who die from cancer could potentially be treated with this therapy.”
Prof. Adam E. Snook