Benoit Rousseau and Luis Diaz Shared New Findings on MMR Deficient Cancers Published in Cancer Cell by Cell Press
Benoit Rousseau, Assistant Attending Physician and Assistant Lab Member at Memorial Sloan Kettering Cancer Center, shared a post on LinkedIn:
“Mismatch repair deficient cancers are exquisetely sensitive to immunotherapy. What if we were able to induce a mismatch repair deficient genotype in proficient cancer cells using tailored chemical mutagenesis? Will this result in improved immunosensitivity?
Today, I am thrilled to share our two simultaneously published articles in Cancer Cell by Cell Press exploring this fundamental question.
In vivo, we identified that the combination of temozolomide and cisplatin was able to induce a high TMB and microsatellite instability in MMRp cells. This MMRd genotype was acquired thanks to the epigenetic loss of Msh2. This resulted in high immunogenicity in multiple preclinical models, characterized by the reprogramming of the tumor immune microenvironment toward strong adaptative immunity.
In a pilot phase I/II study, we investigated the combination of temozolomide, cisplatin and nivolumab in patients with advanced chemorefractory MMRp colorectal cancers. While we didnt observe responses and clinical activity was limited, we did observe the emergence of MMRd signatures and rapid immunoediting using serial ctDNA profiling. Translational analyses suggest an association between an increase in plasma TMB and MSI scores and prolonged survival in this trial. Translational analyses identified possible mechanisms precluding the acquisition of a MMRd genotype such as MMR gene amplification.
Treatment regimen seems key as pulse treatment and continuous treatment leads to different genotypes and modulate MSH2 with different intensity, which may have had impacted clinical outcomes in our trial.
Next steps includes selection based on genomic profile and improving the regimen to increase the probability of reaching a MMRd genotype and immunosensitivity.
These works have been realized thanks to an international collaboration of Dr Luis Diaz’ team, Memorial Sloan Kettering Cancer Center and Dr Alberto Bardelli’s team, IFOM.
I would like to thank our patients, families, and teams involved in these study.
And the continous and amazing support of Swim Across America!”
Luis Diaz, Head of the Division of Solid Tumor Oncology within the Department of Medicine at Memorial Sloan Kettering Cancer Center, shared this post on LinkedIn, adding:
“Hopefully the next phase of cancer therapeutics, by rewiring cancers to become sensitive to the immune system.
Special acknowledgement to the talented Drs. Benoit Rousseau, Pietro Paolo Vitiello and Alberto Bardelli.”
Janjigian, shared Luis Diaz’s post, adding:
Title: Cisplatin and temozolomide combinatorial treatment triggers hypermutability and immune surveillance in experimental cancer models
Authors: Pietro Paolo Vitiello, Benoit Rousseau, Rosaria Chilà, Paolo Battuello, Vito Amodio, Vittorio Battaglieri, Gaia Grasso, Sharon Scardellato, Achille Anselmo, Francesca Clemente, Giuseppe Rospo, Simona Lamba, Alice Bartolini, Federica Pisati, Claudio Tripodo, Noemi Congiusta, Mariangela Russo, Giovanni Crisafulli, Federica Di Nicolantonio, Giovanni Germano, Luis A. Diaz Jr., Alberto Bardelli
Title: Induction of a mismatch repair deficient genotype by tailored chemical mutagenesis in experimental models of cancer
Authors: Benoit Rousseau, Mitesh Patel, Oliver Artz, Georgios Vlachos, Shrey Patel, Omar Hayatt, Guillem Argilés, Michael B. Foote, Lingqi Luo, Rachna Shah, Shub Mehta, Karthik Rangavajhula, Caitlin-M. Stewart, Drew Gerber, Rohini Bhattacharya, Dennis Stephens, David Mieles, Violaine Randrian, Somer Abdelfattah, Lin Zhang, Nathalie Membreno-Berganza, Michelle F. Lamendola-Essel, Florence Piastra-Facon, Joana Vidal, Paul Johannet, Steve Lu, James R. White, Steven B. Maron, Afsar Barlas, Caroline M. Weipert, Eric Rosiek, Taotao Zhang, Bing He, Sebastien Monette, Rui Qu, Deborah Fidele, Sydney Bowker, Alec Kahn, Pietro Paolo Vitiello, Giovanni Germano, Alberto Bardelli, Rajarsi Mandal, Xiaoxiao Ma, Tim A. Chan, Sydney Lu, Andrea Cercek, Omar Abdel-Wahab, Elisa de Stanchina, Neil H. Segal, Luis A. Diaz Jr.
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