Journal Article

Autogene cevumeran with or without atezolizumab in advanced solid tumors: a phase 1 trial

Sullivan, Ryan J., Rhee, Ina, Dirix, Luc, Kröner, Christoph, Karydis, Ioannis, Robert, Alberto, Paruzynski, Anna, Sabado, Rachel L., Jork, Anette, Wong, Kit Man, Leveque, Vincent J. P., Friedman, Claire F., Muller, Lars, Qi, Ting, Mancuso, Michael R., Kuhn, Andreas N., Zhu, Jiawen, Maurus, Daniel, Manning, Luisa, Schuler, Martin, Omokoko, Tana, Lopez, Juanita, Twomey, Patrick, Blake, Jonathon, Kim, Leesun, Diekmann, Jan, Hawner, Christine, Darwish, Martine, Fine, Gregg D., Mellman, Ira, Türeci, Özlem, Albrecht, Christian, Lörks, Verena, Balmanoukian, Ani S., Cortini, Andrea, Wallrapp, Christine, Rittmeyer, Achim, Löwer, Martin, Low, Donald W., Fong, Lawrence, Petry, Chris, Hennig, Oliver, Henick, Brian S., Melero, Ignacio, Derhovanessian, Evelyna, Camidge, D. Ross, Schartner, Jill M., Yadav, Mahesh, Becker, Dirk, Rao, Gautham K., Braiteh, Fadi, Fisher, George A., Brachtendorf, Sebastian, Zhang, Jingbin, Powles, Thomas, Galvao, Vladimir, Steeghs, Neeltje, Lo, Amy A., Burris, Howard A., Jaeger, Dirk, Schiza, Aglaia, Vormehr, Mathias, Jerusalem, Guy, Godehardt, Eva, Delamarre, Lélia, Aljumaily, Raid, LoRusso, Patricia

2025

Overview

Effective targeting of somatic cancer mutations to enhance the efficacy of cancer immunotherapy requires an individualized approach. Autogene cevumeran is a uridine messenger RNA lipoplex-based individualized neoantigen-specific immunotherapy designed from tumor-specific somatic mutation data obtained from tumor tissue of each individual patient to stimulate T cell responses against up to 20 neoantigens. This ongoing phase 1 study evaluated autogene cevumeran as monotherapy ( n  = 30) and in combination with atezolizumab ( n  = 183) in pretreated patients with advanced solid tumors. The primary objective was safety and tolerability; exploratory objectives included evaluation of pharmacokinetics, pharmacodynamics, preliminary antitumor activity and immunogenicity. Non-prespecified interim analysis showed that autogene cevumeran was well tolerated and elicited poly-epitopic neoantigen-specific responses, encompassing CD4 + and/or CD8 + T cells, in 71% of patients, most of them undetectable at baseline. Responses were detectable up to 23 months after treatment initiation. CD8 + T cells specific for several neoantigens constituted a median of 7.3% of circulating CD8 + T cells, reaching up to 23% in some patients. Autogene cevumeran-induced T cells were found within tumor lesions constituting up to 7.2% of tumor-infiltrating T cells. Clinical activity was observed, including one objective response in monotherapy dose escalation and in two patients with disease characteristics unfavorable for response to immunotherapy treated in combination with atezolizumab. These findings support the continued development of autogene cevumeran in earlier treatment lines. ClinicalTrials.gov registration: NCT03289962 . In this phase 1 trial, patients with locally advanced or metastatic solid tumors were treated with the individualized mRNA neoantigen-specific immunotherapy (iNeST) autogene cevumeran alone or in combination with the anti-PD-L1 agent atezolizumab, showing long-lasting neoantigen-specific immune responses and preliminary clinical activity, supporting further development of this therapeutic approach.

• Publisher: Nature Publishing Group US,Nature Publishing Group,Nature Research
• Subject: 631/67/1059/153 / 631/67/1059/2325 / Adult / Aged / Aged, 80 and over / Antibodies, Monoclonal, Humanized / Antibodies, Monoclonal, Humanized - administration & dosage / Antibodies, Monoclonal, Humanized - adverse effects / Antibodies, Monoclonal, Humanized - therapeutic use / Antigens, Neoplasm / Antigens, Neoplasm - immunology / Antineoplastic Combined Chemotherapy Protocols / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Antitumor activity / atezolizumab / Biochemistry, Genetics and Molecular Biology (all) / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer immunotherapy / Cancer Research / CD4 antigen / CD8 antigen / CD8-Positive T-Lymphocytes / CD8-Positive T-Lymphocytes - drug effects / CD8-Positive T-Lymphocytes - immunology / Effectiveness / Exploratory behavior / Female / Health services / Human health sciences / Humans / Immunogenicity / Immunotherapy / Immunotherapy - methods / Infectious Diseases / Lymphocytes / Lymphocytes T / Male / Metabolic Diseases / Metastases / Middle Aged / Molecular Medicine / Monoclonal antibodies / mRNA / Mutation / Neoantigens / Neoplasms / Neoplasms - drug therapy / Neoplasms - genetics / Neoplasms - immunology / Neoplasms - pathology / Neoplasms - therapy / Neurosciences / Oncologie / Oncology / Patients / PD-L1 protein / Pharmacodynamics / Pharmacokinetics / Sciences de la santé humaine / Solid tumors / Targeted cancer therapy / Tumors / Uridine