New Immunotherapy IMCgp100 Shows Early Promise in Advanced Melanoma Patients
SAN DIEGO — 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 in a phase I clinical trial, according to results presented here at the AACR Annual Meeting 2014, April 5-9.
“The part of the immune system widely acknowledged for its cancer-killing abilities is a type of white blood cell 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, M.D., Ph.D., professor of experimental cancer medicine at 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, Middleton explained. 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, and this binding causes a cascade of immune activation, leading to destruction of the target cancer cell, but 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 the treatment of many forms of cancer for which no antibody-applicable target has yet been identified,” Middleton added.
Middleton and colleagues conducted a phase I trial to determine the toxicity and maximum tolerated dose of the drug. They recruited 31 patients—18 male and 13 female—with late-stage and unresectable melanoma, 60 percent of whom had received prior therapies. Patients were enrolled in eight cohorts to receive one of the eight escalating doses of the drug. Those who tolerated the drug on day one went on to receive repeated cycles of six weekly doses.
The investigators determined the maximum tolerated dose of the drug to be 600 nanograms for every kilogram of the patient’s body weight. Side effects included rash, fever, inflammation on the skin, and tumor flare, all of which were reactions expected from the drug’s mode of action, explained Middleton.
Of the 16 patients who received more than 135 nanograms of IMCgp100 per kilogram and were evaluable, four had partial responses. Two of them met the RECIST criteria and the other two had smaller responses. The first two patients’ responses lasted for more than nine months, and one of them had further disease shrinkage months into treatment; this patient continues to be asymptomatic, according to Middleton.
“Although we are encouraged by the clinical activity observed, all of the available scientific and clinical data suggest that it should be possible to increase the level of clinical activity with an improved dosing regimen,” said Middleton. “We have initiated a phase IIa trial, in which we are testing a weekly dosing arm, building on the clinical data generated to date, and a second arm exploring a more intensive regimen that should maximize the activity of the drug.”
This study is funded by Immunocore. Middleton declares no conflicts of interest.