Despite significant advances in the treatment of metastatic melanoma long-term remission for the majority of patients remains elusive. Kinase inhibitors provide potent but short-term responses for a significant proportion of patients and immunotherapy elicits long-term responses but only in a minority.
IMCgp100 is a novel bi-specific immunotherapy comprising a soluble, affinity-enhanced, T cell receptor (TCR) specific for the melanoma-associated antigen gp100, fused to an anti-CD3 specific antibody fragment (scFv). The engineered TCR portion of the drug targets the gp100 peptide 280-288 antigen, which is over-expressed and presented by HLA-A2 on the surface of melanoma cells, thereby effectively coating these cells with CD3-specific antibody fragments. The anti-CD3 scFv portion captures and redirects T cells in physical contact with the melanoma cell to kill it. In vitro IMCgp100 potently redirects T cells from the blood of late stage cancer patients to target melanoma cells exhibiting substantial HLA-down regulation, even in the presence of high numbers of regulatory T cells. Target cell killing is observed within hours, and is associated with the release of pro-inflammatory cytokines and dendritic cell cross-presentation of gp100 and other melanoma-specific antigens. Thus, IMCgp100 demonstrates the potential to elicit potent short-term responses and trigger longer-term anti melanoma activity.
As part of a Phase 1 dose-finding study in HLA-A2 positive patients with advanced melanoma, 18 patients have received single IV infusions of 5, 15, 45, 135, 270 or 405ng/Kg of IMCgp100. Seven patients have subsequently received weekly IMCgp100 infusions for 6 weeks, with a brief clinical response in 1 patient at 270ng/Kg.
To date, the most frequent drug related toxicities observed are rash (12 patients), pruritus (7), hypotension (5) and oedema (7), starting at the 45ng/Kg dose level. The frequency, severity and duration of adverse events demonstrate a clear dose response relationship. Pharmacodynamic data show a transient reduction in peripheral lymphocyte count 24h after dosing, consistent with the proposed mechanism of action of IMCgp100. Pharmacokinetic analysis indicates a linear dose relationship, with Cmax at 4h and T1/2 of approximately 9h. IMCgp100 is well-tolerated, with evidence of T-cell trafficking after dosing. Toxicity to date has been consistent with on target effects.
Citation Format: Mark Middleton, Jeff Evans, Neil Steven, Pippa G. Corrie, Clive Mulatero, Debbie Baker, Giovanna Bossi, Katherine Adams, Jane Harper, Andy Johnson, William Shingler, Dominic Smethurst, Namir Hassan, Yvonne McGrath, Bent Jakobsen. IMCgp100: a novel bispecific biologic for the treatment of malignant melanoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1238. doi:10.1158/1538-7445.AM2013-1238