1085P - Adoptive cell therapy with TCR gene-engineered T cells directed against MAGE-C2-positive melanoma: An ongoing phase I trial

Background

MAGE-C2 (MC2) is an immunogenic cancer germline antigen that is highly expressed in melanoma, but not in normal tissues. For adoptive T cell therapy, we selected a highly specific T cell receptor (TCR) and developed a method to generate young MC2 TCR T cells. The primary objective of this first-in-human phase I trial is to determine the recommended phase II dose and demonstrate the safety and feasibility of treatment with autologous MC2 TCR T cells. Secondary objectives include treatment efficacy and measurements of MC2 TCR T cells as well as immune parameters in blood and tumor tissue.

Methods

This is an investigator-initiated single center clinical trial with accelerated titration of five dose levels up to 5.0x10¹⁰ MC2 TCR T cells. Patients with advanced melanoma are eligible if they have progressive disease after standard treatment, an HLA-A2 genotype and MC2-positive tumors. Prior to infusion of T cells, obtained by leukapheresis and processed into advanced therapeutic medicinal products (ATMPs), patients are treated with the epigenetic drugs valproic acid and 5-azacitine. Infusion of MC2 TCR T cells is supported by administration of low dose IL-2. Adverse events (AEs) are documented according to CTCAE v5.0, and tumor response is evaluated according to RECIST v1.1.

Results

So far, six eligible patients with uveal (n=3) and mucosal (n=3) melanoma have been treated. T cell ATMPs were successfully produced for the first four doses (5x10⁷, 5x10⁸, 5x10⁹ and 1x10¹⁰ MC2 TCR T cells), and two T cell ATMPs were exceptionally released for a lower dose, enabling optimization of the production protocol. Up to the highest administered dose, no irreversible grade 3 or 4 AEs were observed. A mixed tumor response was observed at the second dose level. For higher dose levels, response evaluation is awaited. MC2 TCR T cells could be detected in blood up to six months post infusion.

Conclusions

Production of MC2 TCR T cell ATMPs is feasible. Treatment with MC2 TCR T cells, combined with epigenetic drugs and low dose IL-2, did not result in dose limiting AEs and is well tolerated. The recommended dose for phase II is expected to be at least 1x10¹⁰ TCR T cells, which is scheduled as an international, multicenter study with centralized production of T cell ATMPs.

Clinical trial identification

NCT04729543.

Editorial acknowledgement

Legal entity responsible for the study

Erasmus MC.

Funding

Dutch Cancer Society (EMCR 2015-7741).

Disclosure

A.A.M. Van der Veldt: Financial Interests, Institutional, Other, Consulting: BMS, MSD, Merck, Sanofi, Pierre Fabre, Roche, Novartis, Pfizer, Eisai, Ipsen. R. Debets: Financial Interests, Institutional, Funding, research support: MSD, Bayer; Financial Interests, Personal, Funding: Bluebird Bio, Genticel; Financial Interests, Institutional, Other: Pan Cancer T. All other authors have declared no conflicts of interest.