8MO - Effective tumour growth control by combined vaccine-immune-checkpoint inhibition in MLH1-/- mice

Background

Previously, we initiated a proof-of-concept study in the MLH1-knockout model (Maletzki et al., 2017, Maletzki et al., 2019). These mice develop mismatch-repair deficient (MMR-D) tumours spontaneously. Repetitive therapeutic application of a whole tumour lysate prolonged overall survival along with reduced tumour burden. Assessment of tumour microenvironment not only revealed infiltration of CD8⁺ T-cells and granulocytes, but also upregulation of immune checkpoint molecules (LAG-3, PD-L1), likely constituting an escape mechanism. We therefore conducted a combined immunotherapeutic approach.

Methods

In this ongoing trial, MLH1-knockout mice with established gastrointestinal tumours received single or three injections of 6E11 (anti PD-L1 monoclonal antibody, 2.5 mg/kg bw, i.v.) either alone or in combination with the vaccine. Tumour growth was monitored by longitudinal PET/CT imaging, immune activation was analyzed via flow cytometric immune monitoring.

Results

6E11 monotherapy slightly increased median overall survival (mOS: 6.0 weeks vs. control 3.5 weeks). By increasing the injection intervals (3 injections, same dose), therapy outcome was improved (mOS: 9.2 weeks) and additionally boosted by combining 6E11 with the vaccine (mOS: 20 weeks vs. 10.2 weeks vaccine monotherapy). Accompanying PET/CT imaging confirmed tumour growth control in all treatment arms, with strongest growth inhibition in the combination group and complete remission in two cases resulting in long-term survival (>30 weeks) without evidence of tumour recurrence. Effects were accompanied by decreased levels of circulating myeloid-derived suppressor cells, PD-1, CTLA-4 and LAG-3-positive cells as well as and increased levels of cytotoxic T cells in spleens and residual tumours.

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 MMR-D-driven malignancies, which warrants further investigation.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

German Research Fundation (DFG).

Disclosure

All authors have declared no conflicts of interest.