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CDK4/6 blockade provides an alternative approach for treatment of mismatch-repair deficient tumors.

ABSTRACT: Mismatch repair-deficient (dMMR) tumors show a good response toward immune checkpoint inhibitors (ICI), but developing resistance impairs patients' outcomes. Here, we compared the therapeutic potential of an α-PD-L1 antibody with the CDK4/6 inhibitor abemaciclib in two preclinical mouse models of dMMR cancer, focusing on immune-modulatory effects of either treatment. Abemaciclib monotherapy significantly prolonged overall survival of Mlh1^-/- and Msh2^{loxP/loxP;TgTg(Vil1-} ^cre) mice (Mlh1^-/-: 14.5 wks vs. 9.0 wks (α-PD-L1), and 3.5 wks (control); Msh2^{loxP/loxP;TgTg(Vil1-} ^cre): 11.7 wks vs. 9.6 wks (α-PD-L1), and 2.0 wks (control)). The combination was not superior to either monotherapy. PET/CT imaging revealed individual response profiles, with best clinical responses seen with abemaciclib mono- and combination therapy. Therapeutic effects were accompanied by increasing numbers of tumor-infiltrating CD4⁺/CD8⁺ T-cells and lower numbers of M2-macrophages. Levels of T cell exhaustion markers and regulatory T cell counts declined. Expression analysis identified higher numbers of dendritic cells and neutrophils within tumors together with high expression of DNA damage repair genes as part of the global stress response. In Mlh1^-/- tumors, abemaciclib suppressed the PI3K/Akt pathway and led to induction of Mxd4/Myc. The immune-modulatory potential of abemaciclib renders this compound ideal for dMMR patients not eligible for ICI treatment.

SUBMITTER: Salewski I

PROVIDER: S-EPMC9278458 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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CDK4/6 blockade provides an alternative approach for treatment of mismatch-repair deficient tumors.

Salewski Inken I Henne Julia J Engster Leonie L Krone Paula P Schneider Bjoern B Redwanz Caterina C Lemcke Heiko H Henze Larissa L Junghanss Christian C Maletzki Claudia C

Oncoimmunology 20220711 1

Mismatch repair-deficient (dMMR) tumors show a good response toward immune checkpoint inhibitors (ICI), but developing resistance impairs patients' outcomes. Here, we compared the therapeutic potential of an α-PD-L1 antibody with the CDK4/6 inhibitor abemaciclib in two preclinical mouse models of dMMR cancer, focusing on immune-modulatory effects of either treatment. Abemaciclib monotherapy significantly prolonged overall survival of Mlh1<sup>-/-</sup> and Msh2<sup>loxP/loxP;TgTg(Vil1-</sup> <su ...[more]

PMID: 35845723

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Project description:BackgroundSomatic mutations have the potential to encode "non-self" immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade.MethodsWe conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti-programmed death 1 immune checkpoint inhibitor, in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency. Pembrolizumab was administered intravenously at a dose of 10 mg per kilogram of body weight every 14 days in patients with mismatch repair-deficient colorectal cancers, patients with mismatch repair-proficient colorectal cancers, and patients with mismatch repair-deficient cancers that were not colorectal. The coprimary end points were the immune-related objective response rate and the 20-week immune-related progression-free survival rate.ResultsThe immune-related objective response rate and immune-related progression-free survival rate were 40% (4 of 10 patients) and 78% (7 of 9 patients), respectively, for mismatch repair-deficient colorectal cancers and 0% (0 of 18 patients) and 11% (2 of 18 patients) for mismatch repair-proficient colorectal cancers. The median progression-free survival and overall survival were not reached in the cohort with mismatch repair-deficient colorectal cancer but were 2.2 and 5.0 months, respectively, in the cohort with mismatch repair-proficient colorectal cancer (hazard ratio for disease progression or death, 0.10 [P<0.001], and hazard ratio for death, 0.22 [P=0.05]). Patients with mismatch repair-deficient noncolorectal cancer had responses similar to those of patients with mismatch repair-deficient colorectal cancer (immune-related objective response rate, 71% [5 of 7 patients]; immune-related progression-free survival rate, 67% [4 of 6 patients]). Whole-exome sequencing revealed a mean of 1782 somatic mutations per tumor in mismatch repair-deficient tumors, as compared with 73 in mismatch repair-proficient tumors (P=0.007), and high somatic mutation loads were associated with prolonged progression-free survival (P=0.02).ConclusionsThis study showed that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab. (Funded by Johns Hopkins University and others; ClinicalTrials.gov number, NCT01876511.).

Project description:BackgroundNeoadjuvant chemotherapy and radiation followed by surgical resection of the rectum is a standard treatment for locally advanced rectal cancer. A subset of rectal cancer is caused by a deficiency in mismatch repair. Because mismatch repair-deficient colorectal cancer is responsive to programmed death 1 (PD-1) blockade in the context of metastatic disease, it was hypothesized that checkpoint blockade could be effective in patients with mismatch repair-deficient, locally advanced rectal cancer.MethodsWe initiated a prospective phase 2 study in which single-agent dostarlimab, an anti-PD-1 monoclonal antibody, was administered every 3 weeks for 6 months in patients with mismatch repair-deficient stage II or III rectal adenocarcinoma. This treatment was to be followed by standard chemoradiotherapy and surgery. Patients who had a clinical complete response after completion of dostarlimab therapy would proceed without chemoradiotherapy and surgery. The primary end points are sustained clinical complete response 12 months after completion of dostarlimab therapy or pathological complete response after completion of dostarlimab therapy with or without chemoradiotherapy and overall response to neoadjuvant dostarlimab therapy with or without chemoradiotherapy.ResultsA total of 12 patients have completed treatment with dostarlimab and have undergone at least 6 months of follow-up. All 12 patients (100%; 95% confidence interval, 74 to 100) had a clinical complete response, with no evidence of tumor on magnetic resonance imaging, 18F-fluorodeoxyglucose-positron-emission tomography, endoscopic evaluation, digital rectal examination, or biopsy. At the time of this report, no patients had received chemoradiotherapy or undergone surgery, and no cases of progression or recurrence had been reported during follow-up (range, 6 to 25 months). No adverse events of grade 3 or higher have been reported.ConclusionsMismatch repair-deficient, locally advanced rectal cancer was highly sensitive to single-agent PD-1 blockade. Longer follow-up is needed to assess the duration of response. (Funded by the Simon and Eve Colin Foundation and others; ClinicalTrials.gov number, NCT04165772.).

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CDK4/6 blockade provides an alternative approach for treatment of mismatch-repair deficient tumors.

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CDK4/6 blockade provides an alternative approach for treatment of mismatch-repair deficient tumors.

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