The ability of the immune system to recognize and kill cancer depends on specialized immune cells, called T cells, being able to find tell-tale markers, or antigens, that it recognizes as altered or dangerous. Unfortunately, not all cancer cells display such antigens. As a result, these cells are more likely to escape destruction by the immune system. A Cancer Research Institute clinician-scientist has found a way to turn on antigen production in cancer cells, effectively coaxing them out of hiding and putting them in the immune system’s crosshairs.
In a new paper published in the journal Cancer Immunology Research, Kunle Odunsi, M.D., Ph.D., of the Roswell Park Cancer Institute in Buffalo, NY, and colleagues present results showing that a drug called decitabine increases the effectiveness of a vaccine designed to elicit an immune response against ovarian cancer—the leading cause of death from gynecologic cancer in the United States.
Like many cancers, ovarian cancer cells often produce an antigen called NY-ESO-1. Cancer cells producing this antigen raise immune system alarm bells and trigger an immune attack. Typically, however, only a certain percentage of cancer cells within an ovarian cancer tumor will produce this antigen, leaving the rest effectively “hidden.” Inside these sneaky cells, the DNA that codes for NY-ESO-1 is methylated—chemically shrouded in a way that makes it unavailable for protein synthesis. The researchers hypothesized that if they could remove this protective covering, then the NY-ESO-1 protein would be made and the immune system would detect it.
That’s where the drug decitabine comes in. Decitabine strips methylation from DNA, including the DNA encoding NY-ESO-1. Once NY-ESO-1 is made, T cells can more easily identify, target, and kill the cancer cells producing it. (Because changes in DNA sequence are not involved, this alteration in gene expression is referred to as ‘epigenetic.’)
Twelve patients with advanced epithelial ovarian cancer who had previously been treated with multiple rounds of chemotherapy were enrolled in the phase I trial. The treatment regimen consisted of decitabine on day 1, the chemotherapy drug doxorubicin on day 8, and the NY-ESO-1 cancer vaccine on day 15. The cancer vaccine (which includes an immune-stimulating adjuvant and another boosting chemical called GM-CSF) “primes” the immune system to form an aggressive response against all cells bearing this antigen.
The researchers found that the majority of patients receiving the experimental treatment showed measurable increases in T cells targeted specifically to the NY-ESO-1 antigen. Even more remarkable, the treatment seemed to nudge the immune system into recognizing and responding to other cancer-associated antigens besides NY-ESO-1, a process known as antigen spreading.
“Although we immunized against a single target [NY-ESO-1],” said Dr. Odunsi, “we analyzed and found that we were able to induce immune responses against three other antigens, against which we did not immunize.” Antigen spreading makes it more likely that the vaccine will produce a robust and durable clinical response.
While the phase I study was not designed to evaluate clinical effectiveness—only safety—the results were still remarkable: 6 of 10 evaluable patients who received the treatment showed either stable disease or had a partial regression of their tumors. Such a pronounced response in patients who had previously received multiple rounds of chemotherapy and whose tumors were considered chemo-resistant is highly encouraging, and suggests that this approach may overcome a principal mechanism by which ovarian and other cancers escape immune attack.
Odunsi and colleagues are currently planning a phase II trial at the Roswell Park Cancer Institute and the Fred and Pamela Buffett Cancer Center to test whether this treatment can extend survival in patients with advanced ovarian cancer.
Enrolling in a clinical trial to receive an experimental treatment is often the best course of action for patients with advanced disease. “We propose that patients should actively seek these kinds of combination therapies,” said Odunsi. “Even though the majority of these types of therapies are experimental at this point, there is enough scientific and clinical evidence to indicate that they are likely to be beneficial.”
Citation: Odunsi K, Matsuzaki J, James SR, et al. (2013) Epigenetic Potentiation of NY-ESO-1 Vaccine Therapy in Human Ovarian Cancer. Cancer Immunol Res; 2(1); 37–49.