A first-in-human, phase I/IIa trial of the T cell immunotherapy personalised tumour trained lymphocytes in patients with advanced colorectal cancer: Study protocol

BACKGROUND: Adoptive T cell therapy is a promising alternative to conventional therapies for certain solid tumours. Personalized tumour-trained lymphocytes (pTTL) is an autologous T cell therapy derived from tumour-draining regional lymph nodes (RLNs), trained to target patient-specific neoantigens arising from tumour-specific mutations. The protocol for an ongoing phase I/IIa first-in-human trial of pTTL in Stage IV Colorectal Cancer (CRC), NEOGAP-CRC-01, is presented here. METHODS: pTTL is produced by in vitro expansion of T cells from RLNs using EpiTCer® technology. Tumour-specific neoantigen-forming mutations are identified through next-generation sequencing of tumour and blood samples and the most optimal neoantigens are selected using the bioinformatics software PIOR®. Selected neoantigen epitopes are included in recombinantly produced proteins and attached to paramagnetic EpiTCer® micro-particles, forming the tumour-selective T cell stimulus TC0301 used in pTTL manufacturing. The trial comprises three parts: Part I includes sequencing of tumour and blood samples, RLNs collection, TC0301 production and pTTL manufacturing. Part II includes preconditioning, pTTL administration and 26 weeks follow-up, and Part III consists of up to five years follow-up after pTTL administration. Up to 16 patients can be included. pTTL is administered as a single-dose infusion following preconditioning with cyclophosphamide and fludarabine. Between the limits of 20 x 106-1 x 109 cells, the entire pTTL yield will be administered. DISCUSSION: pTTL represents a novel approach within adoptive T-cell therapy, using autologous T cells trained to target selected neoantigens without genetic modification. The integration of PIOR® and EpiTCer® technology enables individualized neoantigen identification and delivery. Interpretation of treatment efficacy may be challenging due to the highly personalized nature of pTTL and the heterogeneity of CRC. The primary trial endpoint is safety. Secondary endpoints include objective treatment response, overall survival, and progression-free survival. Biomarkers of pTTL persistence, product characteristics, and treatment response will be assessed. TRIAL REGISTRATION: Authorized under the Clinical Trial Regulation (Regulation EU No 536/2014), EU CT #2024-512296-13-00. ClinicalTrials.gov ID NCT05908643.