Photo Courtesy of Immunocore Limited
T cell (grey) killing a tumor cell (yellow)
A novel immunotherapeutic known as IMCgp100 induced clinical responses with manageable toxicity in patients with advanced melanoma, according to results from a phase I clinical trial presented at the 2014 AACR Annual Meeting.
“The drug is well tolerated in advanced melanoma patients, and we have seen clinical responses in some of them,” Mark Middleton, MD, PhD, lead author on the study and professor of experimental cancer medicine at the University of Oxford, said in a statement. “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 maximum tolerated dose (MTD) was determined to be 600ng/kg, with doses ranging from 5ng/kg to 900ng/kg explored in the study. Four patients received the highest dose, of which 50% developed grade 3 hypotension. In general, side effects included rash, fever, skin inflammation, and tumor flare. In 16 patients who received doses greater than 135ng/kg, 13% experienced a partial response (PR) by RECIST criteria that lasted longer than 9 months.
IMCgp100 is comprised of an enhanced T cell receptor fused to an anti-CD3 antibody fragment. The T cell receptor is engineered to be specific to gp100, which presents in the context of HLA-A2 on the surface of melanoma cells. Once joined to the antigen, the antibody fragment recruits and activates T cells to elicit an anti-tumor response.
In the trial, 31 patients with stage IV or stage III unresectable melanoma who tested positive for HLA-A2 were divided into 8 cohorts to receive IMCgp100. Following the initial dose, patients were followed for 30 days. Patients who tolerated the first dose received weekly doses of IMCgp100 for 6 cycles. Doses were escalated until criteria for MTD were reached.
The median age of patients was 61. In total, 60% of patients (n=19) received prior systemic treatment with DTIC (n=9), ipilimumab (n=2), vemurafenib (n=1), or one or more experimental therapies (n=7). Patients with symptomatic and unstable brain metastases requiring steroids and those eligible for vemurafenib were excluded from the trial.
Four patients achieve a PR by investigator assessment: 1 was observed following the first dose and 2 continued for more than 9 months of treatment. Additionally, 1 patient experienced stable disease for more than 10 months. Responses were seen in metastatic lesions in patients’ lungs, lymphatic systems, and various soft tissues.
The most common adverse events observed were transient grade 3 pruritic rash, initially seen at dose level 45ng/kg, and grade 2 pyrexia. Patients with cutaneous or subcutaneous disease experienced tumor flare. Adverse events were consistent with the mechanism of action of IMCgp100, the researchers noted.
“We’re still trying to understand how do we best deal with gp100 as a potential target, but certainly, additional research into new immune therapies is necessary,” Michael A. Postow, MD, an attending physician in the Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center, said in an interview. “Until we have a 100% cure for this disease, we’re going to continue to work.”
In October 2013, Immunocore Limited, the company developing IMCgp100, announced the initiation of a phase IIa trial to optimize the dosing regimen and maximize the efficacy of the agent. This study will administer weekly IMCgp100 at the MTD established in the phase I investigation.
“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,” Middleton said. “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.”
In the summer of 2013, Immunocore reached partnership agreements with Genentech and GlaxoSmithKline to discover, develop, and commercialize therapies against multiple targets using Immunocore’s proprietary T Cell Receptor technology platform known as ImmTAC. Each partnership could result in over $330 million in development and commercial milestones plus royalties.