A phase I multicenter study to assess the safety, tolerability, and immunogenicity of mRNA-4157 alone in patients with resected solid tumors and in combination with pembrolizumab in patients with unresectable solid tumors.

Abstract

2523 Background: T-cell targeting of mutation-derived epitopes (neoantigens) has been demonstrated to drive anti-tumor responses. Immunizing patients against such neoantigens in combination with a checkpoint inhibitor (CPI) may elicit greater anti-tumor responses than CPI alone. Mutations are rarely shared between patients, thus requiring a personalized approach to vaccine design. Methods: A phase I dose escalation study of mRNA-4157 as adjuvant monotherapy in patients with resected solid tumors (melanoma, bladder carcinoma, HPV negative HNSCC, NSCLC, SCLC, MSI-High, or TMB High cancers) and in combination with pembrolizumab in patients with advanced or metastatic cancer is being conducted to evaluate safety. mRNA-4157 is a lipid encapsulated personalized vaccine encoding multiple neoantigens selected using a proprietary algorithm designed to induce neoantigen specific T cells and associated anti-tumor responses. Patients may receive up to 9 cycles (Q3W) of mRNA-4157 by intramuscular injection (0.04 – 1 mg). In the combination arm, pembrolizumab (200 mg) is administered for two cycles prior to combination with mRNA-4157; patients may continue pembrolizumab after completion of 9 cycles of combination therapy. Primary end points include safety, tolerability, and recommended phase 2 dose. Results: 33 patients received mRNA-4157; 13 as monotherapy and 20 in combination with pembrolizumab. No DLTs were reported, and treatment related AEs have generally been of low grade and reversible, and no drug related SAEs or AEs ≥ grade 3 have been observed. Of the 13 patients on adjuvant monotherapy (3 melanoma, 8 NSCLC, 2 MSI-High), 12 patients remain disease free on study, median follow-up of 8 months. 20 patients have been treated in combination (1 TMB-high, 4 bladder, 2 HNSCC, 1 melanoma, 7 NSCLC, 2 SCLC, 3 MSI-high), 12 had progressed on prior CPI, 16 have been restaged and there are 1 CR (on pembrolizumab prior to vaccination), 2 PR, 5 SD for at least 5 combination cycles, 5 PD, 2 iuPD, and 1 patient is non-evaluable for response but remains on study. Neoantigen specific T cell responses have been detected by IFN-γ ELISpot from PBMCs. Conclusions: mRNA-4157 is safe and well tolerated at all dose levels tested. Clinical responses have been observed in combination with pembrolizumab and neoantigen-specific T cells have been induced, supporting the advancement of mRNA-4157 to phase 2. Clinical trial information: NCT03313778.

Gene Therapy in Cancer Treatment: Why Go Nano?

“…The KEYNOTE-603 phase I clinical trial (NCT03313778), intends to analyze the safety, tolerability and immunogenicity of mRNA-4157 alone or combined with pembrolizumab for treatment of unresectable solid tumors. The mRNA-4157 is a personalized mRNA-based vaccine, designed after identification of twenty patient specific epitopes that are transcribed and loaded on a single mRNA molecule in a solid-lipid vesicle [254]. The mRNA translation by APCs allowed the induction of T-cells that target the patient's tumor-specific epitopes [254].…”

“…The mRNA-4157 is a personalized mRNA-based vaccine, designed after identification of twenty patient specific epitopes that are transcribed and loaded on a single mRNA molecule in a solid-lipid vesicle [254]. The mRNA translation by APCs allowed the induction of T-cells that target the patient's tumor-specific epitopes [254]. The favorable clinical responses, consisting in mRNA-4157 tolerability at all dose levels tested, suggested the possibility of further clinical trials [254].…”

“…The mRNA translation by APCs allowed the induction of T-cells that target the patient's tumor-specific epitopes [254]. The favorable clinical responses, consisting in mRNA-4157 tolerability at all dose levels tested, suggested the possibility of further clinical trials [254].…”

798 Safety, tolerability, and immunogenicity of mRNA-4157 in combination with pembrolizumab in subjects with unresectable solid tumors (KEYNOTE-603): an update

“…Justin Gainor. 1 University of Arizona, Tuscon, AZ, USA; 2 SCRI, Nashville, TN, USA; 3 Duke, Durham, NC, USA; 4 Florida Cancer Specialists, Sarasota, FL, USA; 5 NYU, New York, NY, USA; 6 Hackensack, Hackensack, NJ, USA; 7 Moderna, Tenafly, NJ, USA; 8 Mass General Hospital, Boston, MA, USA…”

“…The initial data was presented at ASCO2019. 1 Methods This study evaluates the safety and efficacy of mRNA-4157 as monotherapy in patients with resected solid tumors (Part A) and in combination with pembrolizumab in patients with advanced/metastatic solid tumors (Parts B). The selected solid tumors in Part A-B includes melanoma, bladder carcinoma, HPV-negative (HPV-neg) HNSCC, NSCLC, SCLC, MSI-High (MSI-h), or TMB-High cancers.…”