Ascites and resistance to immune checkpoint inhibition in dMMR/MSI-H metastatic colorectal and gastric cancers

Fucà, Giovanni; Cohen, Romain; Lonardi, Sara; Shitara, Kohei; Elez, Maria Elena; Fakih, Marwan; Chao, Joseph; Klempner, Samuel J.; Emmett, Matthew J.; Jayachandran, Priya; Bergamo, Francesca; García, M. Díez; Mazzoli, Giacomo; Provenzano, Leonardo; Colle, Raphaël; Svrcek, Magali; Ambrosini, Margherita; Randon, Giovanni; Shah, Aakash Tushar; Salati, Massimiliano; Fenocchio, Elisabetta; Salvatore, Lisa; Chida, Keigo; Kawazoe, Akihito; Conca, Veronica; Curigliano, Giuseppe; Corti, Francesca; Cremolini, Chiara; Overman, Michael J.; André, Thierry; Pietrantonio, Filippo

doi:10.1136/jitc-2021-004001

Cited by 62 publications

(38 citation statements)

References 33 publications

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“… 396 , 397 In May 2017, pembrolizumab was approved for solid tumor patients with MSI-H or dMMR who have progressed after previous treatment and have no satisfactory alternative treatment. 386 , 396 , 398 In 2017 and 2018, the FDA successively approved the treatment of metastatic colorectal cancer patients with MSI-H or dMMR after treatment with fluorouracil, oxaliplatin and nivolumab alone or in combination with ipilimumab. Therefore, MSI-H and dMMR can be used as primary screening methods.…”

Section: Biomarkers For Immunotherapy—lessons From Icb and Car-t Cellsmentioning

confidence: 99%

Therapeutic targets and biomarkers of tumor immunotherapy: response versus non-response

Wang

Sun

2022

Sig Transduct Target Ther

226

114

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Cancers are highly complex diseases that are characterized by not only the overgrowth of malignant cells but also an altered immune response. The inhibition and reprogramming of the immune system play critical roles in tumor initiation and progression. Immunotherapy aims to reactivate antitumor immune cells and overcome the immune escape mechanisms of tumors. Represented by immune checkpoint blockade and adoptive cell transfer, tumor immunotherapy has seen tremendous success in the clinic, with the capability to induce long-term regression of some tumors that are refractory to all other treatments. Among them, immune checkpoint blocking therapy, represented by PD-1/PD-L1 inhibitors (nivolumab) and CTLA-4 inhibitors (ipilimumab), has shown encouraging therapeutic effects in the treatment of various malignant tumors, such as non-small cell lung cancer (NSCLC) and melanoma. In addition, with the advent of CAR-T, CAR-M and other novel immunotherapy methods, immunotherapy has entered a new era. At present, evidence indicates that the combination of multiple immunotherapy methods may be one way to improve the therapeutic effect. However, the overall clinical response rate of tumor immunotherapy still needs improvement, which warrants the development of novel therapeutic designs as well as the discovery of biomarkers that can guide the prescription of these agents. Learning from the past success and failure of both clinical and basic research is critical for the rational design of studies in the future. In this article, we describe the efforts to manipulate the immune system against cancer and discuss different targets and cell types that can be exploited to promote the antitumor immune response.

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Section: Biomarkers For Immunotherapy—lessons From Icb and Car-t Cellsmentioning

confidence: 99%

Therapeutic targets and biomarkers of tumor immunotherapy: response versus non-response

Wang

Sun

2022

Sig Transduct Target Ther

226

114

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“…We tended to ascribe the results to the small sample size-driven instability of the analysis model. Actually, it was reported that patients with peritoneal metastases and ascites had worse PFS and OS than those without peritoneal metastases and those with peritoneal metastases and no ascites when receiving ICI-based therapy [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

The Optimal Therapy after Progression on Immune Checkpoint Inhibitors in MSI Metastatic Gastrointestinal Cancer Patients: A Multicenter Retrospective Cohort Study

Chen

Wang

Liu

et al. 2022

Cancers

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Background: In microsatellite instability (MSI)/mismatch repair-deficient (dMMR) gastrointestinal cancers, the optimum therapy after the progression of immune checkpoint inhibitors (ICIs) is yet unknown. Here, we compared the efficacy of programmed death 1 (PD1)/programmed death ligand-1 (PD-L1) inhibitors plus other therapy and chemotherapy with or without targeted therapy in MSI/dMMR gastrointestinal cancer patients after progression on anti-PD1/PD-L1 monotherapy. Methods: We retrospectively recruited MSI/dMMR gastrointestinal cancer patients who had progressed on anti-PD1/PD-L1 monotherapy. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and PFS ratio (PFSr) were compared between patients who received anti-PD1/PD-L1 plus other therapy (ICI-plus group) and patients who received chemotherapy with or without targeted therapy (chemo-targeted group). Results: In total, 26 and 25 patients were recruited in the ICI-plus group and chemo-targeted group, respectively. Significantly better DCR (80.8% vs. 44.0%, p = 0.007), PFS (median PFS 6.9 months vs. 3.0 months, p = 0.001), OS (median OS NR vs. 14.1 months, p = 0.043), and PFSr (2.4 vs. 0.9, p = 0.021), along with a numerically higher ORR (23.1% vs. 12.0%, p = 0.503) were observed in the ICI-plus group compared with the chemo-targeted group. Multivariate analyses identified the therapy regimen as an important prognostic factor in gastrointestinal cancers. Conclusions: Compared to conventional chemotherapy with or without targeted therapy, continuing anti-PD1/PD-L1 in combination with other treatments showed better clinical outcomes in MSI/dMMR gastrointestinal cancer patients who progressed on PD1/PD-L1 blockade, which should be validated prospectively in clinical trials.

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“…Moreover, Fucà et al showed that the presence of peritoneal metastases and ascites was associated to a poor outcome in a cohort of 502 patients with dMMR/MSI-H mCRC treated with ICI [ 44 ]. This has been hypothesized to be a consequence of an immune-suppressive environment in serous cavities.…”

Section: Resistance To Icis In Dmmr/msi-h Mcrc Patientsmentioning

confidence: 99%

Immune-Checkpoint Inhibitors (ICIs) in Metastatic Colorectal Cancer (mCRC) Patients beyond Microsatellite Instability

Borelli

Antoniotti

Carullo

et al. 2022

Cancers

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Immune-checkpoint inhibitors (ICIs) showed impressive results in terms of activity and efficacy in metastatic colorectal cancer (mCRC) patients bearing tumors with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H). Despite that microsatellite status is the major predictive biomarker for the efficacy of ICIs, a proportion of dMMR/MSI-H mCRC tumors do not achieve benefit from immunotherapy due to the primary resistance. Deeper knowledge of biological mechanisms regulating dMMR/MSI-H CRC tumors and immune response may be useful to find new predictive biomarkers of ICIs benefit and tailor the use of immunotherapy even in dMMR/MSI-H mCRC patients. Moreover, several issues are still open, such as the secondary resection of metastases and the optimal duration of ICIs therapy in dMMR/MSI-H mCRC patients. Looking beyond microsatellite status, in a future perspective, several tools (i.e., Tumor Mutational Burden and PD-L1 expression) have been investigated to clarify their possible role as predictive biomarkers. Furthermore, a small subgroup of pMMR/MSS CRC tumors with a POLE mutation of the proofreading domain is characterized by hypermutated phenotype and might derive benefit from immune checkpoint inhibition. In the present work, we aim to review the most recent literature regarding treatment with ICIs in mCRC, focusing on dMMR/MSI-H and special subgroups of CRC patients. Hence, we summarize possible future targets and the most promising predictive biomarkers.

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Ascites and resistance to immune checkpoint inhibition in dMMR/MSI-H metastatic colorectal and gastric cancers

Cited by 62 publications

References 33 publications

Therapeutic targets and biomarkers of tumor immunotherapy: response versus non-response

Therapeutic targets and biomarkers of tumor immunotherapy: response versus non-response

The Optimal Therapy after Progression on Immune Checkpoint Inhibitors in MSI Metastatic Gastrointestinal Cancer Patients: A Multicenter Retrospective Cohort Study

Immune-Checkpoint Inhibitors (ICIs) in Metastatic Colorectal Cancer (mCRC) Patients beyond Microsatellite Instability

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