Researchers Seek to Improve Responses With Checkpoint Inhibitors

Predictive genetic signatures and novel combination strategies may be the key to improving the often dramatic responses seen with immune checkpoint inhibitors.

Antoni Ribas, MD, PhD

Predictive genetic signatures and novel combination strategies may be the key to improving the often dramatic responses seen with immune checkpoint inhibitors, according to Antoni Ribas, MD, PhD, during a satellite symposium presented by the Society for Immunotherapy of Cancer (SITC) that took place before the opening of the 2015 Society for Melanoma Research Congress.

“It’s really remarkable that patients with late-stage melanoma, for instance, would get notable improvements in overall survival from treatments such as nivolumab. But these responders are still in the minority,” said Ribas, professor of Medicine, Surgery and Molecular and Medical Pharmacology at the Jonsson Comprehensive cancer Center at the University of California, Los Angeles. “Our job now is to select patients who are poised to respond to PD-1/PD-L1 blockade therapies.”

Ribas noted that recent studies have attempted to increase the efficacy of PD-1/PD-L1 blockade by combining treatments. Recent clinical trials have shown improved progression-free survival (PFS) in melanoma with combinations of CTLA-4 and PD-1 agents, but the price has been an increased incidence of serious adverse events, he noted.

In the CheckMate-067 trial, for example, patients with advanced melanoma treated with nivolumab plus ipilimumab had a median PFS of 11.5 months versus 6.9 months with nivolumab alone and 2.9 months with ipilimumab alone.

Yet, more patients who underwent the combination therapy suffered serious grade 3/4 adverse events. Grade 3/4 adverse events affected 55% of patients in the combination arm of CheckMate-067, as compared with just 16.3% of those who were administered nivolumab alone and 27.3% of patients who underwent ipilimumab therapy alone.2

In a trial published in The New England Journal of Medicine (NEJM) in 2011, patients with previously untreated metastatic melanoma also derived survival benefits from the combination treatment of ipilimumab plus the chemotherapy agent dacarbazine.3

More recent clinical trials have also highlighted reduced mortality in advanced melanoma with other checkpoint inhibitor therapies. In a clinical trial published in NEJM in January 2015, patients with previously untreated melanoma without BRAF mutations treated with nivolumab had less risk of mortality than those who underwent treatment with dacarbazine (HR, 0.42).4

“There are some patients in these clinical trials who are benefiting from targeting single checkpoints. And by using single checkpoint inhibitor therapies we can also reduce serious adverse events,” Ribas said. Yet increasing the number of patients who can benefit from single checkpoint inhibitor therapy requires understanding the biology of tumor response to these treatments, he added.

In patients who don’t respond to checkpoint inhibitor therapies, tumors may be able to protect themselves from T-cell infiltration through genetic mutations that trigger an adaptive PD-1/PD-L1 expression, according to recent research by Ribas and others. In other non-responder patients treated with checkpoint inhibitor therapies, T-cells may increase in the patient’s bloodstream, but they don’t make it into the tumor.

Biopsies of tumors taken before treatment with checkpoint inhibitors could identify genetic signatures that could set off an adaptive PD-1/PD-L1 response, said Ribas. Treatment could then be targeted to those likely to respond to single molecule checkpoint inhibitor therapy. Other methods of improving response to checkpoint inhibitor therapies could include increasing the T-cell infiltration of tumors through immune-activating antibodies, oncolytic viruses, macrophage inhibitors or targeted therapies, Ribas said.

“When we perform the initial decision-making in the use of checkpoint inhibitor therapies in patients, we should be taking biopsies to find out if there are T-cells in the tumor that could be turned off by PD-1/PD-L1 expression,” Ribas said. Biopsies after initial treatment can also reveal if there are no T-cells in the tumor, although they may be present elsewhere in the patient’s body.

“The idea is to use the right treatment for the right patient by understanding the biology of the tumor and its environment,” Ribas said.


  1. Ribas A. Checkpoint inhibitor therapy. Presented at: Tumor Immunology 101: A Navigation Guide for the Growing Field of Cancer Immunotherapy. The Society for Immunotherapy of Cancer (SITC) Satellite Symposium. November 18, 2015.
  2. Wolchok JD, Chiarion-Sileni V, Gonzales R, et al: Efficacy and safety results from a phase III trial of nivolumab alone or combined with ipilimumab versus ipilimumab alone in treatment-naive patients with advanced melanoma (CheckMate 067). 2015 ASCO Annual Meeting. Abstract LBA1. Presented May 31, 2015.
  3. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364(26):2517-2526.
  4. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320-330.


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