Keeping up with progress in the field of cancer immunotherapy requires paying close attention. The number of approved drugs that help the body’s immune system fight cancer continues to grow, as does the list of different cancers in which immunotherapy is proving effective – in some cases yielding dramatically longer-lasting benefits than standard chemotherapy.
A surge of advances began in 2011, when ipilimumab, the first “checkpoint inhibitor” drug was approved by the Food and Drug Administration (FDA) to treat advanced melanoma. By mid-2016 the FDA had approved four checkpoint inhibitors as therapy for six forms of cancer. And these drugs, alone and in combination with a wide variety of other agents, are in clinical trials in more than 20 cancer types.
“The future is combination therapy,” says Dana-Farber immunologist Gordon Freeman, PhD. Such therapies could hit cancer with two or more checkpoint blocking drugs along with drugs that stimulate the immune system, or teamed with agents that directly attack cancer cells. “We’re enthusiastic about checkpoint blockade plus targeted kinase inhibitors.”
Checkpoints are molecular switches that act as brakes to shut down immune responses when they are no longer needed. Cancer cells can activate these checkpoints, which include molecules such as CTLA-4, PD-1, and PD-L1, to effectively shut down the T cell response. Freeman made a landmark discovery that the PD-L1 protein, carried on the surface of many cancer cells, interacts with the PD-1 protein on T cells to turn off the immune response. Blocking this process with checkpoint inhibitor drugs releases the brakes and frees the immune system to go on the offensive against tumors.
Of the four approved checkpoint inhibitors, ipilimumab (Yervoy) targets the CTLA-4 pathway, while pembrolizumab (Keytruda) and nivolumab (Opdivo) disable the PD-1 checkpoint, and atezolizumab (Tecentriq) targets PD-L1. Atezolizumab was approved in June 2016 to treat bladder cancer. In addition to melanoma and bladder cancer, these drugs are approved to treat patients with lung, head and neck, and kidney cancers, and Hodgkin lymphoma.
Investigators are testing checkpoint blockers, as well as cancer vaccines and other immunotherapy strategies, in a wide array of cancer types. Among them: ovarian, colon, pancreatic, breast, and esophageal cancers; blood cancers such as leukemia and lymphoma; sarcomas, neuroblastomas, and glioblastomas.
In advanced melanoma particularly, immunotherapy has been game-changing for some patients, enabling them to live 10 years or more when previously their outlook would have been dire. Scientists are tweaking immunotherapy drugs and combinations in melanoma to improve on their successes. For example, combining ipilimumab and nivolumab as initial treatment for metastatic melanoma appears to lengthen the two-year survival rate, according to a recent report by F. Stephen Hodi, Jr., MD, director of Dana-Farber’s Melanoma Treatment Center and its Center for Immuno-oncology. The report was an interim analysis of data from the CheckMate 069 Phase II trial, which is still in progress.
Dana-Farber scientists pioneered the use of nivolumab immunotherapy in treatment-resistant Hodgkin lymphoma, demonstrating in a pilot study that 87 percent of patients went into full or partial remission. In 2016, the FDA approved the drug in this setting following a larger trial that achieved responses in about two-thirds of patients.
In a small study in one form of advanced colon cancer, pembrolizumab shrank tumors in 62 percent of patients, prompting a larger trial that is ongoing. Checkpoint blockers have shrunk tumors in as many as 30 percent of selected patients with non-small cell lung cancer. In advanced Merkel-cell carcinoma, pembrolizumab attained a response rate of 56 percent.
Overall, the drugs currently work in about 20 to 30 percent of patients – a number scientists are determined to improve.
The blue-ribbon panel advising Vice President Joe Biden’s Cancer Moonshot project has recommended setting up a national clinical trials network to register patients involved in or interested in immunotherapy trials. The aim is to focus and accelerate finding answers to question such as: Why does immunotherapy work so well in some patients but not most? What tests or biomarkers can be used to predict which patients will benefit? How can the power of immunotherapy be broadened to encompass more patients and more cancer types?
In some of the cancers treated with the checkpoint blockers, it appears that tumors carrying a lot of PD-L1 molecules on their surface respond best. This is not always the case, but testing for the presence of PD-L1 is currently the best biomarker for identifying the best candidates for immunotherapy.
But it’s clear that many more factors are involved in immunotherapy response. For example, tumors containing large amounts of activated T cells – indicating that the body has previously mounted a response against the cancer – may be more responsive to immunotherapy treatment, studies show. And responses to immunotherapy may vary depending on interactions between the tumor and its surrounding tissues – the microenvironment. Research is ongoing at a rapid pace into these and other variables with the aim of bringing precision and predictability to immunotherapy for as many cancer patients as possible.