5MO - CDK4/6 blockade is as effective as immune-checkpoint inhibition in tumor growth control of Mlh1-/- and Msh2loxP/loxP villin-Cre mice

Background

Mismatch-repair deficiency (dMMR) is a hallmark of Lynch syndrome-associated cancers, often resulting from inactivating mutations in MLH1 or MSH2. These tumors have a high likelihood of responding to immune checkpoint inhibitors (ICI). Still, intrinsic or acquired resistance mechanisms impair patients’ outcomes. Here, we compared the therapeutic potential of an anti-PD-L1 inhibitor with the CDK4/6 inhibitor abemaciclib in two preclinical mouse models of dMMR-driven carcinogenesis.

Methods

In this ongoing trial, Mlh1^-/- or Msh2^loxP/loxP Villin-Cre mice with gastrointestinal tumors were either treated with anti-PD-L1 monoclonal antibody (clone: 6E11, 2.5 mg/kg bw, i.p., q2wx3) or abemaciclib (75 mg/kg bw, p.o.,q1wx8). Control mice received the isotype (anti-IgG1 2.5 mg/kg bw, i.p., q2wx3) or were left untreated. Blood phenotyping was performed regularly. The tumor microenvironment was studied by immunofluorescence.

Results

Both therapies prolonged overall survival of mice significantly: Mlh1^-/-: 9.1 wks (6E11) vs. 11.1 wks (abemaciclib) vs. 3.5 wks (control); Msh2 ^loxP/loxP Villin-Cre: 6.0 wks (6E11, ongoing) and 8.2 wks (abemaciclib, ongoing) vs. 1.0 wk (control). One Mlh1^-/- mouse received complete remission upon abemaciclib, while anti-PD-L1 therapy primarily induced stable disease at best (PET/CT). Therapeutic effects of abemaciclib were accompanied by increased numbers of tumor-infiltrating CD4⁺/CD8⁺ T-cells and lower numbers of M2-macrophages. Blood phenotyping revealed PD-L1 upregulation under abemaciclib therapy.

Conclusions

While ICI-based therapies are effective and FDA approved for dMMR cancer, abemaciclib constitutes a promising alternative therapy option. The strong immune stimulation upon abemaciclib treatment renders this compound ideal for ICI-refractory or intrinsically resistant tumors.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

German Research Foundation.

Disclosure

All authors have declared no conflicts of interest.