Successful clinical translation of preclinical combinations of radiation and immunotherapy

Abstract

Ionising radiation (IR) can induce immunogenic cell death in tumours, an effect likely to contribute to the success associated with radiotherapy (RT) for cancer. Recent studies suggest that radiotherapy can be applied as a powerful adjuvant to immunotherapy, and can even contribute to converting the irradiated tumour into an in situ vaccine, resulting in specific immunity against metastases [1]. Importantly, preclinical models of syngeneic tumours have reliably predicted clinical success in several distinct tumour settings and with several different immunotherapy/radiation combinations. As a proof-of-principle trial, we have translated the preclinical evidence of a successful combination with Flt3 ligand and RT to a protocol of granulocyte–monocyte colony-stimulating factor (GM-CSF) and IR, and demonstrated out-of-field objective responses in 27% of patients with multiple metastases of solid tumours, defined as an abscopal effect [2] In-parallel mechanistic studies in the laboratory were conducted in the syngeneic mouse models of metastatic breast cancer. Results showed that radiation was synergistic with anti-CTLA-4 treatment, a strategy to break immune tolerance to the tumor. Multiple mechanisms contributed to thus synergy, including the RT-induced upregulation of a chemokine that promoted homing of effector T cells to the tumor. Intravital microscopy demonstrated that while both IR and CTLA-4 blockade given as monotherapy enhanced the motility of activated CD8 T cells infiltrating 4T1 tumours, IR with anti-CTLA-4 increased the arrest of T cells in contact with tumour cells, promoting the formation of an immune synapse between cytotoxic T cells and their targets. The latter required interaction between NKG2D on CD8+ T cells and its ligand, retinoic acid early inducible-1 (Rae-1), on the tumour cells, which was up-regulated by IR. Blocking NKG2D–Rae-1 interactions markedly increased the motility of anti-CTLA-4 treated T cells within irradiated tumours, inhibiting their contact with tumour cells and also abrogated immune-mediated tumour rejection [4]. The preclinical success of the combination of anti-CTLA-4 antibody and IR was mirrored by abscopal responses seen in metastatic melanoma and non-small-cell lung cancer (NSCLC) patients irradiated in one lesion during ipilimumab therapy. These clinical observations strongly suggest that the effects of IR identified in experimental models are relevant to patients. IR can stimulate the anti-tumor immune response, increasing the proportion of patients who respond to checkpoint blockade treatment, an hypothesis currently being tested in clinical trials. The same pattern of abscopal responses has been observed in preclinical models was also demonstrated in clinical cases of lymphomas and breast cancers treated by combinations of RT and toll-like receptor agonists. Finally, blocking tumour growth factor beta (TGF-beta) during RT preclinically has demonstrated abscopal effects that have been confirmed in one patient accrued to a trial of anti-human TGFb antibody fresolimumab and RT. While promising, this evidence remains preliminary and warrants more research to define the optimal combinations of immunotherapy and RT, to best exploit this novel role of ionising radiation [3].