PREDICTIVE FACTORS OF RESPONSE OF MELANOMA TO IMMUNOTHERAPY

Expression of major histocompatibility complex (MHC) class I and class II proteins may help predict a patient's response to melanoma immunotherapy, researchers have found.

In patients with advanced melanoma, treatment with an anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) agent plus an anti-programmed cell death protein 1 (PD-1) agent provides a benefit over either therapy alone, but "the shared and unique biological effects derived from inhibiting the two immune checkpoint proteins are still poorly understood," Dr. Scott Rodig of Brigham and Women's Hospital in Boston and colleagues write in Science Translational Medicine, online July 18.

To investigate, the researchers examined the expression of MHC class I and class II proteins in pretreatment biopsy samples from clinical trial patients treated with one of four regimens: ipilimumab (an anti-CTLA-4 agent) followed by nivolumab (an anti-PD-1 agent); nivolumab followed by ipilimumab; ipilimumab alone; or nivolumab and ipilimumab given concurrently.

Partial or complete loss of melanoma MHC class I proteins, seen in 43% of untreated patients, was associated with progressive disease and with primary resistance to single-agent ipilimumab and ipilimumab given before nivolumab, but not to the two agents given concurrently.

By contrast, a deficiency of MHC class I proteins was not associated with nivolumab resistance. According to the authors, that's because PD-1 inhibition is associated with pre-existing interferon-gamma-mediated immune activation, which includes tumor-specific MHC class II proteins and components of innate immunity that come into play when MHC class I is compromised.

Specifically, patients whose tumors had higher pre-treatment levels of interferon-gamma had better outcomes when treated with nivolumab or concurrent therapy, but not with single-agent ipilimumab. Further, MHC class II expression (>1%) was associated with a higher likelihood of complete or partial responses or stable disease after single-agent nivolumab, rather than progressive disease.

"The real-world implications are that we may be able to identify which patients with melanoma are likely to benefit or not benefit clinically from anti-CTLA-4 or anti-PD-1 therapy based upon an examination of their tumor tissue and their endogenous immune response to the tumor," Dr. Rodig told Reuters Health.

"This is especially important for patients receiving anti-CTLA-4 since the therapy is associated with significant toxicity and if we can spare some patients a therapy that will not be useful and is associated with toxicity, this would be good," he said by email.

"Testing these biomarkers prospectively in a clinical trial will be needed to show whether the tests can be used routinely in the clinic to tailor the choice of immune therapy to individual patients," he added.

"The discovery that Hodgkin lymphoma and melanoma, two very different tumors, have similar means of escaping immune recognition may mean that other common tumors use the same mechanisms," Dr. Rodig said. "We are currently testing this hypothesis in lung cancer and head-and-neck cancers."

Dr. Rohit Sharma, assistant professor of surgery in the division of oncology at UT Southwestern Medical Center in Dallas, said the findings "seem reasonable."

"Systemic therapy for melanoma has been previously limited by few and ineffective options," he said in an email to Reuters Health. "In the past few years there has been a tremendous evolution in the management of melanoma through the discovery of checkpoint and immunotherapy agents. One of the challenges stemming from the rapid influx of (these agents) has been understanding their optimal use in the management of the disease."

The study "begins to identify potential biomarkers that could predict response to specific checkpoint/immunotherapies and also sheds light on potential ways of approaching sequencing of drug therapy," he said. "The potential benefit could be a more enhanced immune response that may translate to improved outcomes for patients."

The study was funded in part by Bristol Myers Squibb. Dr. Rodig and other coauthors have received funds from the company.

SOURCE: http://bit.ly/2OjHIrL

Sci Transl Med 2018.