The striking success of checkpoint inhibition in the treatment of certain cancers has reinvigorated cancer research into therapeutic vaccines. Although, historically, lone vaccine treatments for cancer hold a modest track record, combining them with checkpoint inhibitors, which override a tumor’s ability to escape detection, may turn “hot cancers even hotter,” said James Gulley, MD, PhD, chief of the genitourinary malignancies branch at the National Cancer Institute in Bethesda, Maryland. Also, he said, combining these therapies may turn “cold” tumors hot, enabling the immune system to better recognize cancer cells as foreign and unleash a vigorous attack.
By definition, hot tumors contain abundant cancer-fighting T cells, many of which (but not all) respond to immunotherapy. Melanoma is widely considered a prototype hot tumor, because as these cancers progress, they develop numerous DNA mutations that produce distinctive tumor-specific molecules called neoantigens. Many of these tumor-exclusive antigens now form the backbone of personalized vaccines for individual patients.1
In comparison, cold tumors, which researchers say make up a majority of human solid tumors, lack an underlying immune response. T cells either fail to see these malignancies as nonself or they evoke too weak an immune response to recruit tumor-infiltrating lymphocytes into tumors to kill them.1
So far, the U.S. Food and Drug Administration has approved only 2 therapeutic cancer vaccines, one for advanced prostate cancer2 and another for metastatic melanoma.3 However, many early vaccine trials are now under way with 1 or both known checkpoint inhibitors and approved indications for checkpoint inhibitors have soared with over 33 indications to treat multiple cancers, Dr Gulley said.
In theory, the idea behind combining these highly tailored antibodies with vaccines seems fairly straightforward: prime the immune system against a specific cancer target with a vaccine, then administer checkpoint inhibitors to take the brake off proteins that cancers use to pervert the normal immune response.
Checkpoint inhibitors by themselves, and in combination with other immunotherapies, already have brought rapid, deep, and durable responses, although the benefits are seen in only a small subset of patients. In advanced melanoma, for example, patients’ clinical responses range widely from 10% to 60%, while in solid tumors, such as lung, breast, and colon cancers, response rates in patients are much smaller — just 10% to 20%.1
And, in rare cases, these drugs can overstimulate the immune system, leading to potentially life-threatening toxicities.4 When this happens, severe autoimmune reactions may occur not only in the intestines and lungs, but in joints and muscles and even the heart and brain. Most of these side effects, however, can be resolved quickly with immunosuppressive treatments given within the first few weeks of onset, according to researchers.