A phase 1, open-label, multicenter study to assess the safety, tolerability, and immunogenicity of mRNA-4157 alone in subjects with resected solid tumors and in combination with pembrolizumab in subjects with unresectable solid tumors (Keynote-603).

Abstract

93 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: This is an interim report of a phase I dose escalation study of mRNA-4157 given as monotherapy in patients with resected solid tumors and in combination with pembrolizumab in patients with unresectable solid tumors. 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 received up to 9 cycles (Q3W) of mRNA-4157 by IM injection (0.04 – 1 mg). In combination arm, pembrolizumab (200 mg) was administered for two cycles prior to combination with mRNA-4157 for up to 9 cycles and may continue on pembrolizumab monotherapy for up to 2 years. Results: As of 10-May-2019, 33 patients received mRNA-4157 alone or in combination. No DLTs or related SAEs or AEs ≥ grade 3 were reported. Of the 13 patients treated with monotherapy (3 melanoma, 8 NSCLC, 2 MSI-high CRC), 11 patients remain disease free on study, median follow-up of 10 months. Of the 20 patients treated in combination (1 TMB-high metastatic cutaneous squamous cell, 4 bladder, 2 HNSCC, 1 melanoma, 7 NSCLC, 2 SCLC, 3 MSI-high (CRC, prostate, endometrial), 13 had received prior CPI, 5 PRs (2 in patients previously treated with PD-1/L1 inhibitors), 6 SD, and 8 PD were reported. Neoantigen specific CD8+ T-cell responses have been detected. 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: NCT 03739931.

Therapeutic Liposomal Vaccines for Dendritic Cell Activation or Tolerance

“…So far, pre-clinical data has shown promising results in favor of using DC-targeting nanoparticle formulations for the induction of potent anti-tumor responses. While nanotechnology for directly targeting DCs for anti-cancer immunotherapy is mainly applied in in vivo and ex-vivo models, some clinical trials are conducted with this platform ( 106 , 191 ). Unfortunately, liposomes targeting the DC-SIGN receptor in patients with metastatic melanoma did not yield desired clinical results ( 106 ).…”

Advances in COVID-19 mRNA vaccine development

“…Finally, the overall response rate (ORR) for the treatment of 10 cases of HPV-negative head and neck squamous cell carcinoma (HPV - HNSCC) with the mRNA-4157 vaccine was 50%, of which 2 cases achieved complete remission (CR). 355 – 358 …”

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“…Another Phase I trial involved administration of a lipid-coated mRNA-4157 that encodes for a wide range of tumour antigens to elicit tumour responses independently, as well as in combination with the anti-PD1 humanized antibody pembrolizumab. The initial study showed good dose tolerance paving way for Phase II trials for this combination [ 171 ]. Another Phase I trial had investigated the anticancer potential of a RNA-lipoplex for triggering dendritic cell maturation and T-cell response in a small cohort of patients with advanced melanoma.…”