Early studies of mRNA-based therapeutics for advanced cancer were presented at this year’s ASCO Annual Meeting.
Timothy Yap, MD, presented results of a BioNTech-sponsored study of BNT142 in advanced solid tumors positive for the oncofetal cell surface protein Claudin 6 (CLDN6) (Abstract 2501).
BNT142 is a lipid nanoparticle (LNP)-encapsulated mRNA encoding the anti-CLDN6/CD3 bispecific antibody RiboMab02.1. After intravenous administration, BNT142 RNA-LNPs are taken up by liver cells and translated into RiboMab02.1, which has two CLDN6-targeting fragments and a CD3-targeting fragment, and simultaneously engages CLDN6-postitive tumors and T cells to induce tumor cell killing.
BNT142-01 (NCT05262530) is a phase 1/2, open-label, multi-center trial to evaluate weekly BNT142 treatment in patients with CLDN6-positive advanced solid tumors (≥10% CLDN6 membrane positivity by immunohistochemistry). Objectives include safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity.
The completed phase 1 dose escalation enrolled 65 patients receiving weekly doses of 50 ng/kg to 100 µg/kg. Heavily pre-treated ovarian cancer (n=44) was the most frequent diagnosis.
Treatment-related adverse events (TRAE), primarily grade 1-2, were more frequent at higher doses. There were few TRAE-related treatment discontinuations, dose reductions, or dose-limiting toxicities (n=2 each). One patient died from cytokine release syndrome (CRS). The most common TRAE were CRS and transient liver enzyme elevation. TRAE were considered manageable.
Preliminary anti-tumor activity was observed, particularly at higher doses. The best responses were partial responses in 7 patients with ovarian cancer. There was no correlation between CLDN6 expression levels and the best response.
Discussant Guillem Argiles, MD, said this study demonstrates it is possible to use mRNA-encoded drugs for cancer therapy, and that CNDN6 is an excellent target for ovarian cancer treatment. He concluded that the best is yet to come.
Results of a phase 1 open-label, multicenter, dose escalation trial of STX-001, an LNP-encapsulated self-replicating mRNA expressing interleukin (IL)-12, in patients with advanced solid tumors was presented in a poster (Abstract 9556).
STX-001 is injected directly into tumors to drive local IL-12 production and limit high systemic IL-12 exposure and associated toxicities. STX-001 induces both local and distant anti-tumor immune effects. Eligibility criteria included treatment-refractory advanced solid tumors with ≥1 clinically injectable lesion(s). At data cutoff (April 3, 2025 for safety and May 1, 2025 for exploratory activity) of 22 patients enrolled, 73% had melanoma and 14% had breast cancer.
STX-001 was well-tolerated and TRAE were dose-dependent and manageable. Immune activation occurred in both injected and non-injected tumors. These was one complete response and two partial responses. Shrinkage of non-injected tumors suggest systemic immune activation via local STX-001 injection. A phase 1/2 study of intratumoral injection of STX-001 in advanced solid tumors as monotherapy or in combination with pembrolizumab (NCT06249048) is recruiting patients.
Two posters describe the construction of in vivo LNP-mRNA chimeric antigen receptor (CAR) therapies for advanced cancers that as off-the-shelf products avoid the logistic and technical challenges of traditional CAR therapies. MT-302 targets TROP2-expressing epithelial cancers (NCT05969041; Abstract 25910; MT-303 targets GPC3, highly expressed primarily on hepatocellular carcinoma (NCT06478693; Abstract TPS4218). These therapies could address unmet needs in these cancers.
Dr. Lederman has no conflicts of interest to report.
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