“My bottom line is checkpoint inhibitors are exciting and fantastic, but not as successful as we originally hoped,” says Susanna Greer, PhD, the scientific director of clinical cancer research and immunology at the American Cancer Society in Atlanta, Georgia. But that reservation does little to diminish their impressive results in some patients with late-state cancers, especially melanoma and lung cancers, she said. “Given months to live, some of these patients are still alive today.”
Such notable exceptions provide the driving force behind renewed interest not only in peptide or whole-tumor cell vaccines, she said, but also dendritic cell vaccines, as investigators strive to ramp up the number of cytotoxic T cells to fight existing disease.
“We still don’t know everything about why T cells can be targeted to the tumor and not activated,” Dr Greer explained. Nor do researchers know the “order of events,” or whether patients should be vaccinated first, then treated afterwards with a checkpoint inhibitor blockade.
Dr Gulley noted that a study using a DNA-based vaccine with pembrolizumab found that giving the vaccine first and then administering the anti-PD-1 inhibitor showed little objective response in patients with advanced prostate cancer. When the two were given together at the same time, they worked far better, which may suggest an advantage to simultaneous administration. Unanswered, as of yet, however, is how long clinicians should continue to give the vaccine to keep a cancer from coming back.
As the complexity of the immune system continues to be studied, researchers seek answers to this and other questions and work towards making treatment vaccines more effective. Although tumor-specific neoantigen vaccines are generally considered more immunogenic than vaccines made from tumor-associated antigens, such as CEA, many investigators are testing less-precise vaccine formulations in hopes of broadening the number of patients with cancer who might benefit.
At Johns Hopkins Sidney Kimmel Cancer Center in Baltimore, Maryland, for example, investigators have long tested a cancer vaccine against pancreatic cancers, called GVAX,5 with some success, said Mark Yarchoan, MD, an assistant professor of oncology there. Because these cancers have among the lowest mutational burden of any cancer, he explained, the question is how to reprogram the immune system to see these cancers and reject them.