A new type of immunotherapy that directs patients’ immune responses toward tumor cell killing, IMCgp100, was well-tolerated and showed efficacy in some patients with advanced melanoma. These phase I clinical trial results were presented at the American Association for Cancer Research 2014 Annual Meeting, in San Diego, California.
“The part of the immune system widely acknowledged for its cancer-killing abilities is a type of white blood cells called the T cell, and IMCgp100 is a novel type of cancer drug designed entirely on this cancer-killing component of the immune system,” said Mark Middleton, MD, PhD, of the University of Oxford in the United Kingdom. “When delivered to a cancer patient, IMCgp100 travels around the body in the patient’s blood stream, finds and binds tightly to the cancer cells, activates any adjacent T cell to kill the cancer cells, and recruits other parts of the immune system to help clear the disease.”
The drug is made up of two components: The first recognizes cancer cells and binds the drug tightly to the cancer cell; the second component works by binding to a specific molecule on any nearby T cell. This binding causes a cascade of immune activation that leads to destruction of the target cancer cell and also to the release of a range of immune-activating molecules, which serve to recruit other parts of the immune system.
“The drug is well-tolerated in advanced melanoma patients, and we have seen clinical responses in some of them,” said Middleton. “The one aspect that did surprise us is the extent of tumor inflammation that is possible to achieve from just a single dose of the drug, because we thought it might take several weeks to get going.
“The ability of IMCgp100 to target one of a largely unexplored class of molecular targets, HLA-peptides, opens the door to treatment of many forms of cancer for which no antibody-applicable target has yet been identified,” Middleton added.
This phase I trial determined toxicity and maximum tolerated dose of the drug. A total of 31 patients (18 men and 13 women) with late-stage and unresectable melanoma, including 60% of whom had received prior therapies, were recruited. Patients were enrolled in eight cohorts to receive 1 of 8 escalating doses of the drug. Those who tolerated the drug on day 1 went on to receive repeated cycles of six weekly doses.
The maximum tolerated dose was found to be 600 ng/kg. Adverse events included rash, fever, skin inflammation, and tumor flare, which Middleton explained were all expected from the drug’s mode of action.
Partial responses occurred in four patients, with two of them meeting RECIST criteria and two being smaller responses. The responses of two patients lasted for more than 9 months, and one of these patients continues to be asymptomatic.
Middleton concluded that an improved dosing regimen should increase the level of clinical activity. A phase IIa trial is testing a weekly dosing regimen.