Using immunotherapy to boost the abscopal effect

Abstract

More than 60 years ago, the effect whereby radiotherapy at one site may lead to regression of metastatic cancer at distant sites that are not irradiated was described and called the abscopal effect (from 'ab scopus', that is, away from the target). The abscopal effect has been connected to mechanisms involving the immune system. However, the effect is rare because at the time of treatment, established immune-tolerance mechanisms may hamper the development of sufficiently robust abscopal responses. Today, the growing consensus is that combining radiotherapy with immunotherapy provides an opportunity to boost abscopal response rates, extending the use of radiotherapy to treatment of both local and metastatic disease. In this Opinion article, we review evidence for this growing consensus and highlight emerging limitations to boosting the abscopal effect using immunotherapy. This is followed by a perspective on current and potential cross-disciplinary approaches, including the use of smart materials to address these limitations.

Figure 1. Historical timeline of some important developments regarding the abscopal effect

AE, abscopal effect; CTLA4, cytotoxic T lymphocyte-associated antigen; PDL1, programmed cell death 1 ligand 1.

Figure 2. Mechanism of the abscopal effect

Radiation generates neoantigens from tumour cells. Antigens from damaged tumour cells can be taken up by antigen-presenting cells (APCs), which travel to the lymph node to prime the T cell-mediated abscopal effect. Activated T cells directed against tumour-specific antigens then infiltrate the primary tumour and non- irradiated tumour metastases. The use of smart radiotherapy biomaterials (SRBs) and nanoparticles provides promising avenues to boost abscopal response rates. Nanoparticles can amplify damage to the tumour cells owing to radiation-induced emission of micrometre-range missile-like photoelectrons and Auger electrons. Immunotherapeutic agents loaded in the SRBs and/or nanoparticles can be sustainably released to boost abscopal responses by targeting different aspects of the immune-mediated abscopal response process. For example, anti-CD40 monoclonal antibody could be employed to increase activation of the APCs, while antibodies against cytotoxic T lymphocyte- associated antigen (CTLA4), programmed cell death protein 1 (PD1) or PD1 ligand 1 (PDL1) can act as immune checkpoint inhibitors, increasing the T cell activity directed against tumour cells at irradiated as well as non-irradiated tumour sites. Please note that the relative sizes of SRBs, nanoparticles and immunotherapeutic agents as depicted are notproportional. FASL, FAS ligand; MHCI, major histocompatibility complex class I.