Beyond checkpoint inhibition - Immunotherapeutical strategies in combination with radiation

Abstract

The revival of cancer immunotherapy has taken place with the clinical success of immune checkpoint inhibition. However, the spectrum of immunotherapeutic approaches is much broader encompassing T cell engaging strategies, tumour-specific vaccination, antibodies or immunocytokines. This review focuses on the immunological effects of irradiation and the evidence available on combination strategies with immunotherapy. The available data suggest great potential of combined treatments, yet also poses questions about dose, fractionation, timing and most promising multimodal strategies.

Keywords: Bispecific antibodies; CAR, chimeric antigen receptor; CAR-T-cells; CDN, cyclic dinucleotides; CTL, cytotoxic T lymphocyte; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; GM-CSF, granulocyte-monocyte colony stimulating factor; IR, irradiation; Immunocytokines; Immunotherapy; PD-1, Programmed cell death protein 1 receptor; PD-L1, PD-1 ligand; Radiotherapy; TCR, T cell receptor; Treg, regulatory T cells; Vaccination; bsAb, bispecific antibody; scFv, single chain variable fragment.

Fig. 1

Tumour irradiation leads to cell death and a release of danger molecules. The tumour microenvironment and cytokine milieu is also altered by irradiation. T cell priming and T cell recruitment is enhanced through irradiation. This is the rationale for combining irradiation with CAR T cells and bispecific antibodies. Vaccination might be enhanced by irradiation through neoantigen release and triggers anti-tumour immune responses. Immunocytokines are able to alter the tumour microenvironment to enhance anti-tumour immune responses and lead to T cell recruitment into the tumour.