Atezolizumab With Stereotactic Ablative Radiotherapy in Patients With Metastatic Tumours
Status:
Recruiting
Trial end date:
2020-10-01
Target enrollment:
Participant gender:
Summary
Although it is usually described as an immunosuppressive modality and not thought of as
immunotherapy, there are new preclinical evidences suggesting that high-dose ionizing
irradiation (IR) results in direct tumour cell death and augments tumour-specific immunity,
which enhances tumour control both locally and distantly. Importantly, IR effects exceed the
classical cytocidal properties by also causing phenotypic changes in the fraction of
surviving cells, markedly enhancing their susceptibility to T cell-mediated elimination.
However, not all IR-induced modifications of the tumour and its microenvironment favor immune
rejection. The tumour microenvironment is populated by various types of inhibitory immune
cells including Tregs, alternatively activated macrophages, and myeloid-derived suppression
cells (MDSCs), which suppress T cell activation and promote tumour outgrowth. Chiang et al.
showed the accumulation of pro-tumourigenic M2 macrophages in areas of hypoxia present in
irradiated tumours. IR then may also induced responses that are inadequate to maintain
antitumuor immunity.
Close interaction between IR, T cells, and the PD-L1/PD-1 axis exsit and provide a basis for
the rational design of combination therapy with immune modulators and radiotherapy. Deng et
al. demonstrate that PD-L1 was upregulated in the tumour microenvironment after IR. Moreover,
administration of anti-PD-L1 enhanced the efficacy of IR through a cytotoxic T cell-dependent
mechanism. Concomitant with IR-mediated tumour regression, IR and anti-PD-L1 synergistically
reduced the local accumulation of tumour-infiltrating MDSCs, which suppress T cells and alter
the tumour immune microenvironment. Finally, activation of cytotoxic T cells with combination
therapy mediated the reduction of MDSCs in tumours through the cytotoxic actions of TNF.
Sagiv-Barfi et al, also demonstrated in 5 patients receiving atezolizumab and radiation
therapy, at least stabilization of systemic progression in all patients and a RECIST partial
response at systemic sites in 1 patient. Transient, grade 1-2 inflammatory adverse events
(fevers, flu-like symptoms) occurred with no serious immune-related toxicities. Abscopal
out-field effects of irradiation has also been described in addition to a reduction in
circulating MDSCs in a melanoma patient treated with the anti CTLA-4 ipilimumab and
radiotherapy.
Lastly, recent evidence demonstrates that loco-regional curative treatment with stereotactic
ablative radiotherapy (SABR) is a good alternative as compared with conventional 3D RT for
patients with solid tumour, with durable remissions and a low toxicity profile. Many
non-randomised studies have shown that SBRT for oligometastases is safe and effective, with
local control rates of about 80%. Importantly, these studies also suggest that the natural
history of the disease is changing, with 2-5 year progression-free survival of about 20%. For
colorectal, non-small cell, and renal cell cancers, 1-year metastasis control rates ranged
from 67 to 91%. Moreover, abscopal reponses in the setting of immune checkpoints inhibitors
and radiotherapy combinations have been made in the setting of metastatic disease event in
patients with extensive tumor burden. The goal of SABR is to deliver appropriate metastasis
directed radiotherapy while minimizing exposure of surrounding normal tissues. Interestingly,
the dose and fractionation employed modulate RT ability to synergize with immunotherapy.
Vanpouille-Box et al, showed that immune response genes were differentially expressed in
irradiated tumours by 8Gyx3 but not 20Gyx1. This highlight the interest of hypofractionated
SABR acting as a "in situ tumour vaccine".
As hypofractionated SABR may, in addition to its good local control, increase the
effectiveness of anti PD-L1, investigators aimed to investigate the efficacy and the
tolerability of the combination of anti-PD-L1 antibody with SABR.