Kickstarting Immunity in Cold Tumours: Localised Tumour Therapy Combinations With Immune Checkpoint Blockade.

Elizabeth Appleton,Anna Wilkins,Masahiro Ono,Jehanne Hassan,Nanna Sivamanoharan,Adel Samson,Erik Wennerberg,Kevin J Harrington,Alan Melcher,Charleen Chan Wah Hak

doi:10.3389/fimmu.2021.754436

Abstract

Cancer patients with low or absent pre-existing anti-tumour immunity (“cold” tumours) respond poorly to treatment with immune checkpoint inhibitors (ICPI). In order to render these patients susceptible to ICPI, initiation of de novo tumour-targeted immune responses is required. This involves triggering of inflammatory signalling, innate immune activation including recruitment and stimulation of dendritic cells (DCs), and ultimately priming of tumour-specific T cells. The ability of tumour localised therapies to trigger these pathways and act as in situ tumour vaccines is being increasingly explored, with the aspiration of developing combination strategies with ICPI that could generate long-lasting responses. In this effort, it is crucial to consider how therapy-induced changes in the tumour microenvironment (TME) act both as immune stimulants but also, in some cases, exacerbate immune resistance mechanisms. Increasingly refined immune monitoring in pre-clinical studies and analysis of on-treatment biopsies from clinical trials have provided insight into therapy-induced biomarkers of response, as well as actionable targets for optimal synergy between localised therapies and ICB. Here, we review studies on the immunomodulatory effects of novel and experimental localised therapies, as well as the re-evaluation of established therapies, such as radiotherapy, as immune adjuvants with a focus on ICPI combinations.

Highlights

The last decade has seen a revolution in the field of immunooncology (IO), driven most notably by the approval and clinical implementation of immune checkpoint inhibitor (ICPI) therapy
Monoclonal antibody therapy targeting immune checkpoint pathways was shown to be a potent method of anti-cancer T cell re-invigoration, effectively releasing the brakes that are imposed on effector function by checkpointmediated immunosuppression
Despite huge advances in recent years, ICPI therapy remains largely ineffective in the treatment of immunologically cold tumours

Summary

INTRODUCTION

The last decade has seen a revolution in the field of immunooncology (IO), driven most notably by the approval and clinical implementation of immune checkpoint inhibitor (ICPI) therapy. Local treatments have been shown to exert a systemic influence on TME composition and anti-cancer immunity, even in non-treated tumours Examples of such effects include stimulation of immune cell influx, enhanced immune cell priming and increased expression of checkpoint targets (such as PD-1 or PD-L1). A two-part phase I study of ONCOS102 in combination with concurrent or sequential anti-PD-1 therapy provided evidence of the ability of OV to overcome ICPI resistance This trial recruited advanced melanoma patients that were refractory to prior anti-PD-1 therapy, and reported a 35% ORR in an early analysis (NCT03003676). Antonia et al reported a pronounced benefit in PFS with Durvalumab treatment compared with placebo (16.8 months vs 5.6 months respectively) [116], highlighting the potential for upfront combination therapy in the definitive management of TABLE 5 | A non-exhaustive representative summary of key clinical trials evaluating radiotherapy in combination with immune checkpoint inhibition

Findings

DISCUSSION AND FUTURE