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

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 obtain...

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Published in:	Nature medicine Vol. 31; no. 1; p. 152
Main Authors:	Lopez, Juanita, Powles, Thomas, Braiteh, Fadi, Siu, Lillian L, LoRusso, Patricia, Friedman, Claire F, Balmanoukian, Ani S, Gordon, Michael, Yachnin, Jeffrey, Rottey, Sylvie, Karydis, Ioannis, Fisher, George A, Schmidt, Marcus, Schuler, Martin, Sullivan, Ryan J, Burris, Howard A, Galvao, Vladimir, Henick, Brian S, Dirix, Luc, Jaeger, Dirk, Ott, Patrick A, Wong, Kit Man, Jerusalem, Guy, Schiza, Aglaia, Fong, Lawrence, Steeghs, Neeltje, Leidner, Rom S, Rittmeyer, Achim, Laurie, Scott A, Gort, Eelke, Aljumaily, Raid, Melero, Ignacio, Sabado, Rachel L, Rhee, Ina, Mancuso, Michael R, Muller, Lars, Fine, Gregg D, Yadav, Mahesh, Kim, Leesun, Leveque, Vincent J P, Robert, Alberto, Darwish, Martine, Qi, Ting, Zhu, Jiawen, Zhang, Jingbin, Twomey, Patrick, Rao, Gautham K, Low, Donald W, Petry, Chris, Lo, Amy A, Schartner, Jill M, Delamarre, Lélia, Mellman, Ira, Löwer, Martin, Müller, Felicitas, Derhovanessian, Evelyna, Cortini, Andrea, Manning, Luisa, Maurus, Daniel, Brachtendorf, Sebastian, Lörks, Verena, Omokoko, Tana, Godehardt, Eva, Becker, Dirk, Hawner, Christine, Wallrapp, Christine, Albrecht, Christian, Kröner, Christoph, Tadmor, Arbel D, Diekmann, Jan, Vormehr, Mathias, Jork, Anette, Paruzynski, Anna, Lang, Maren, Blake, Jonathon, Hennig, Oliver, Kuhn, Andreas N, Sahin, Ugur, Türeci, Özlem, Camidge, D Ross
Format:	Journal Article
Language:	English
Published:	United States 01.01.2025
Subjects:	Adult Aged Aged, 80 and over Antibodies, Monoclonal, Humanized - administration & dosage Antibodies, Monoclonal, Humanized - adverse effects Antibodies, Monoclonal, Humanized - therapeutic use Antigens, Neoplasm - immunology Antineoplastic Combined Chemotherapy Protocols - therapeutic use CD8-Positive T-Lymphocytes - drug effects CD8-Positive T-Lymphocytes - immunology Female Humans Immunotherapy - methods Male Middle Aged Neoplasms - drug therapy Neoplasms - genetics Neoplasms - immunology Neoplasms - pathology Neoplasms - therapy
ISSN:	1546-170X, 1546-170X
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Summary:	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 .
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1546-170X 1546-170X
DOI:	10.1038/s41591-024-03334-7