643 A first in human phase I/IIa trial of personalized tumor-trained lymphocytes, pTTL, derived from regional lymph nodes for treatment of colorectal cancer

Background

The new generation of adoptive T cell therapy utilizing high-precision neoantigen targeting is gaining increasing interest, especially in solid tumors, where the unmet medical need is high. Personalized tumor trained lymphocytes (pTTL) is a novel autologous adoptive T cell therapy targeting patient-specific neoantigens. A phase I/IIa First in Human (FIH) clinical trial of pTTL in Stage IV colorectal cancer (CRC) patients has started 2023.

Methods

pTTL is produced through in vitro expansion of T cells derived from tumor-adjacent regional lymph nodes (RLN). The T cells are stimulated with a patient-specific array of neoantigens utilizing the proprietary EpiTCer® technology. Tumor-specific mutations are identified from next generation sequencing data obtained from tumor and normal tissue samples, and personal neoantigen epitopes are selected and ranked using the in-house bioinformatic software PIOR®. Polypeptides containing the selected neoantigens are designed, produced and linked to paramagnetic micro-particles to form EpiTCer® beads, a tumor-selective T cell expansion stimulus used for pTTL manufacturing.

Results

pTTL can be manufactured with a high rate of success despite the product’s personalized nature. pTTL consists mainly of T cells, with small proportions of NK and B cells. The CD4/CD8 T cell ratio varies between products. pTTL contains a significant proportion of memory T cells expressing markers indicating functionality, with limited levels of late-stage T cells. TCR sequencing has demonstrated increased T cell clonality in pTTL compared to in the RLN starting material, indicating antigen-specific expansion.

Conclusions

The ongoing FIH Phase I/II trial will include up to 16 patients with Stage IV CRC. pTTL is administered as a single-dose monotherapy after chemotherapy-based preconditioning with cyclophosphamide and fludarabine. A dose-escalation design is applied. The trial is divided into three parts. Part I: Collection of materials for sequencing and pTTL production (tumour biopsy, surgical collection of RLNs), and manufacturing of EpiTCer® beads and pTTL. Part II: pre-conditioning, administration of pTTL and follow-up for 6 months. Part III: Long-term follow-up to 5 years after pTTL administration. The primary endpoint is safety. Secondary outcomes include response, overall survival, and progression-free survival. Biomarkers for pTTL persistence, pTTL characteristics, and response will be evaluated.

Trial Registration

Trial Registration EUDRA CT #2022–000394-96. Clinicaltrials.gov Identifier #NCT05908643

Ethics Approval

The trial is approved by the Swedish MPA (5.1–2022-89272) and the Swedish Ethical Review Authority (2022–01842-01). All patients must give their informed consent to participation before inclusion in the trial.