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. 2025 Jul 14;43(7):1296-1312.e7.
doi: 10.1016/j.ccell.2025.05.014. Epub 2025 Jun 12.

Cisplatin and temozolomide combinatorial treatment triggers hypermutability and immune surveillance in experimental cancer models

Pietro Paolo Vitiello  1 , Benoit Rousseau  2 , Rosaria Chilà  3 , Paolo Battuello  1 , Vito Amodio  3 , Vittorio Battaglieri  1 , Gaia Grasso  4 , Sharon Scardellato  3 , Achille Anselmo  5 , Francesca Clemente  6 , Giuseppe Rospo  4 , Simona Lamba  4 , Alice Bartolini  7 , Federica Pisati  8 , Claudio Tripodo  9 , Noemi Congiusta  7 , Mariangela Russo  4 , Giovanni Crisafulli  3 , Federica Di Nicolantonio  10 , Giovanni Germano  11 , Luis A Diaz Jr  12 , Alberto Bardelli  13
Affiliations
Free article

Cisplatin and temozolomide combinatorial treatment triggers hypermutability and immune surveillance in experimental cancer models

Pietro Paolo Vitiello et al. Cancer Cell. .
Free article

Abstract

Hypermutation induced by mismatch repair (MMR) inactivation leads to immune surveillance in colorectal cancer (CRC) and in several other malignancies. We investigated the impact of a rationally designed chemotherapy combination on the generation of hypermutation and immunogenicity in otherwise immune-refractory CRC and breast cancer mouse models. Combinatorial treatment with cisplatin (CDDP) and temozolomide (TMZ) induces an adaptive downregulation of MMR, resulting in chemotherapy-dependent hypermutability and increase in predicted neoantigens. This combination specifically alters the immune fitness of the tumors, ultimately leading to CD8+ T cell-mediated immune surveillance, immunoediting of chemotherapy-induced neoantigens, and durable immunological memory. Treatment with CDDP and TMZ also remodels the innate immune microenvironment and induces long-lasting responses and complete rejections when combined with anti-PD-1 therapy in mice. The same effects are not observed using the clinically approved combination of 5-fluorouracil, oxaliplatin, and irinotecan (FOLFOXIRI). Treatment-induced hypermutation can enhance anti-tumor immune responses, offering additional avenues for cancer treatment.

Keywords: chemotherapy; cisplatin; colorectal cancer; cytotoxic chemotherapy; immune checkpoint blockade; immune rewiring; immune surveillance; mismatch repair modulation; neoantigens; temozolomide.

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Conflict of interest statement

Declaration of interests P.P.V. served in a consulting role for Biocartis and has received speaking fees from Biocartis and Merck outside of the current manuscript. A. Bardelli served in a consulting/advisory role for Guardant Health. A. Bardelli received research support by Neophore, AstraZeneca, and Boehringer Ingelheim outside of the current manuscript. A. Bardelli and G. Germano are cofounders and shareholders of NeoPhore limited. A. Bardelli is a shareholder of Kither Biotech. A. Bardelli is a member of the scientific advisory board of NeoPhore. B.R. served in a consulting/advisory role for Neophore. B.R. has received travel, accommodations, and expenses from Bayer, Servier, and Astellas outside of the current manuscript. L.A.D. and B.R. are inventors of a patent related to this work including the use of temozolomide and cisplatin in combination with immunotherapy (US20230056846A1). L.A.D is a member of the board of directors of Quest Diagnostics and Epitope. He is a compensated cosultant to Innovatus CP, Se'er, Delfi, Blackstone, and Absci. L.A.D. is an inventor of multiple licensed patents related to technology for circulating tumor DNA analyses and MMR deficiency for diagnosis and therapy. Some of these licenses and relationships are associated with equity or royalty payments to the inventors. He holds equity in Quest Diagnostics, Epitope, Se'er, Delfi, and Absci. He divested his equity in Personal Genome Diagnostics to LabCorp in February 2022 and divested his equity in Thrive Earlier Detection to Exact Biosciences in January 2021. His spouse holds equity in Amgen. The terms of all these arrangements are being managed by Memorial Sloan Kettering in accordance with their conflict-of-interest policies.

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