177P - Targeting of immune regulatory proteins through locoregional delivery of mAbs augments CD8 T cell mediated anti-tumour responses in vivo.

Background

Immune checkpoint blockade (ICB) has resulted in impressive clinical response rates in the treatment of melanoma and squamous cell carcinoma. Unfortunately, systemic administration of ICB therapy is associated with inconsistent patient responses alongside severe immune-related adverse events (iRAEs), resulting in discontinuation of treatment, especially when anti-PD-1 and anti-CTLA-4 mAb therapies are used in combination. Preclinical studies indicate that locoregional administration of ICB to internal solid tumours enhances immune responses with minimal toxicities, but this approach has not been fully explored in cutaneous tumours.

Methods

A triple combination (TC) of mAbs targeting (4-1bb/PD-1/VISTA) were injected peritumourally (10ug/mAb) or systemically (100ug/mAB) to C57BL/6J mice bearing TC-1 ears tumours, 3x over 9 days and compared to isotype control mAb treated mice. Tumour volumes, resistance to secondary tumour rechallenge, IFN-g ELISPOT and serum ALT assays and flow cytometry analysis of tumour bearing ears of therapy and isotype mAb treated mice was undertaken to characterize the mechanism, efficacy and safety following therapy administration.

Results

TC administered locally to ear tumours, induced potent anti-tumour responses and had superior efficacy to monotherapy. An abscopal effect was observed after one of two tumour bearing ears were administered TC therapy, resulting in 66% of treated mice regressing tumours in both ears. Surviving treated mice were resistant to subcutaneous TC-1 tumour rechallenge, implying the later induction of systemic immune memory. Mechanistically, the central role of CD8 T cells in driving therapy mediated anti-tumour responses was confirmed using systemic CD8 depletion. Increased proportions of Granzyme B+ CD8+ T cells and lower CD4+ T_regs were concurrently observed in TC treated animals compared to isotype control. While i.v. therapy resulted in elevated serum ALT and liver immune cell infiltrates, locally administered TC mAbs were well tolerated.

Conclusions

Our results demonstrate a novel, safe, dose-sparing strategy to administer combinations of checkpoint therapies for immune targeting of advanced, local cutaneous tumours.

Legal entity responsible for the study

The authors.

Funding

The University of Queensland Research Training Scholarship; Tour de Cure.

Disclosure

All authors have declared no conflicts of interest.