A phase I/II escalation trial design T-RAD: Treatment of metastatic lung cancer with mRNA-engineered T cells expressing a T cell receptor targeting human telomerase reverse transcriptase (hTERT)

Sólrún Melkorka Maggadóttir; Gunnar Kvalheim; Patrik Wernhoff; Stein Sæbøe-Larssen; Mona-Elisabeth Revheim; Dag Josefsen; Sébastien Wälchli; Åslaug Helland; Else Marit Inderberg

doi:10.3389/fonc.2022.1031232

A phase I/II escalation trial design T-RAD: Treatment of metastatic lung cancer with mRNA-engineered T cells expressing a T cell receptor targeting human telomerase reverse transcriptase (hTERT)

Front Oncol. 2022 Nov 10:12:1031232. doi: 10.3389/fonc.2022.1031232. eCollection 2022.

Affiliations

¹ Translational Research Unit, Department of Oncology, Section for Cellular Therapy, Oslo University Hospital, Oslo, Norway.
² Department of Medical Genetics, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway.
³ Division of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway.
⁴ Department of Clinical Medicine, University of Oslo, Oslo, Norway.
⁵ Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
⁶ Department of Oncology, Oslo University Hospital, Oslo, Norway.

Abstract

Background: Adoptive cellular therapy (ACT) with genetically modified T cells aims to redirect T cells against resistant cancers through introduction of a T cell receptor (TCR). The Radium-4 TCR was isolated from a responding patient in a cancer vaccination study and recognizes the enzymatic component of human Telomerase Reverse Transcriptase (hTERT) presented on MHC class II (HLA-DP04). hTERT is a constitutively overexpressed tumor-associated antigen present in most human cancers, including non-small-cell lung cancer (NSCLC), which is the second most common type of cancer worldwide. Treatment alternatives for relapsing NSCLC are limited and survival is poor. To improve patient outcome we designed a TCR-based ACT study targeting hTERT.

Methods: T-RAD is a phase I/II study to evaluate the safety and efficacy of Radium-4 mRNA electroporated autologous T cells in the treatment of metastatic NSCLC with no other treatment option. Transient TCR expression is applied for safety considerations. Participants receive two intravenous injections with escalating doses of redirected T cells weekly for 6 consecutive weeks. Primary objectives are safety and tolerability. Secondary objectives include progression-free survival, time to progression, overall survival, patient reported outcomes and overall radiological response.

Discussion: Treatment for metastatic NSCLC is scarce and new personalized treatment options are in high demand. hTERT is a tumor target applicable to numerous cancer types. This proof-of-concept study will explore for the first time the safety and efficacy of TCR mRNA electroporated autologous T cells targeting hTERT. The T-RAD study will thus evaluate an attractive candidate for future immunotherapy of solid tumors.

Keywords: ACT; NSCLC; TCR immunotherapy; hTERT; mRNA electroporation; solid tumor immunotherapy.