Combined vaccine-immune-checkpoint inhibition constitutes a promising strategy for treatment of dMMR tumors

Abstract

Background Mlh1-knock-out-driven mismatch-repair-deficient (dMMR) tumors can be targeted immunologically. By applying therapeutic tumor vaccination, tumor growth is delayed but escape mechanisms evolve, including upregulation of immune-checkpoint molecules (LAG-3, PD-L1). To counteract immune escape, we investigated the therapeutic activity of a combined tumor vaccine-immune-checkpoint inhibitor therapy using α-PD-L1. Design In this trial, Mlh1-knock-out mice with established gastrointestinal tumors received single or thrice injections of α-PD-L1 monoclonal antibody clone 6E11 (2.5 mg/kg bw, q2w, i.v.) either alone or in combination with the vaccine. Longitudinal flow cytometry and PET/CT imaging studies were followed by ex vivo functional immunological and gene expression assays. Results 6E11 monotherapy slightly increased median overall survival (mOS: 6.0 weeks vs. control 4.0 weeks). Increasing the number of injections (n = 3) improved therapy outcome (mOS: 9.2 weeks) and was significantly boosted by combining 6E11 with the vaccine (mOS: 19.4 weeks vs. 10.2 weeks vaccine monotherapy). Accompanying PET/CT imaging confirmed treatment-induced tumor growth control, with the strongest inhibition in the combination group. Three mice (30%) achieved a complete remission and showed long-term survival. Decreased levels of circulating splenic and intratumoral myeloid-derived suppressor cells (MDSC) and decreased numbers of immune-checkpoint-expressing splenic T cells (LAG-3, CTLA-4) accompanied therapeutic effects. Gene expression and protein analysis of residual tumors revealed downregulation of PI3K/Akt/Wnt-and TGF-signaling, leading to T cell infiltration, reduced numbers of macrophages, neutrophils and MDSC. Conclusions By successful uncoupling of the PD-1/PD-L1 axis, we provide further evidence for the safe and successful application of immunotherapies to combat dMMR-driven malignancies that warrants further investigation.

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

“…Treatment with abemaciclib was given weekly at a dose of 75 mg/kg bw because of its therapeutic activity in vitro even after drug removal and its capacity to stimulate the immune system. 14 , 16 , 18 , 29 The treatment schedule of the α-PD-L1 antibody was adopted to our previous study 8 with a biweekly application route at a dose of 2.5 mg/kg bw. Tumor growth was monitored in both mouse models before and after treatment using 18 F-FDG PET/CT (please see Figure 2a for experimental protocol).…”

“…Evaluation of the images was performed as described before. 8 Treatment outcome determined according to clinical staging as follows: (I) progressive disease (PD) = tumor volume >25% vs . baseline (= day 0); (II) stable disease (SD): tumor volume similar to initial staging (≤25% vs .…”

“…Our preclinical data additionally support the use of α-PD-L1 antibodies either alone or in conjunction with cytostatic drugs and immunotherapy. 7 , 8 Still, in most cases, resistance mechanisms evolve finally contributing to relapse. 9 …”

Prophylaxis with abemaciclib delays tumorigenesis in dMMR mice by altering immune responses and reducing immunosuppressive extracellular vesicle secretion

“…The RNA concentration was measured by Nanodrop and was adjusted to a specific concentration. The analysis of RNA was performed by Nanostring analysis as described before [ 28 ].…”

The effects of dendritic cell-based vaccines in the tumor microenvironment: Impact on myeloid-derived suppressor cells

“…The use of blockade agents has also improved the efficacy of different types of vaccines ( 85 , 86 ). Specifically, immune checkpoint inhibitors have successfully targeted MDSCs in melanoma-bearing mice treated with the tyrosinase related protein (TRP)1/tyrosine DC vaccine ( 70 ).…”