A sizeable fraction of individuals with non-small cell lung cancer (NSCLC) develop primary or acquired resistance to immune checkpoint inhibitor (ICI) therapy (eg, pembrolizumab). Some of these patients are said to have immunologically cold tumors, defined by a low tumor mutation burden (TMB; <300 mutations per exome), null programmed cell death protein 1 ligand 1 (PD-L1) expression, or presence of mutations in the Wnt pathway. These immunologically cold NSCLC tumors are typically less likely to regress with ICI when administered as monotherapy. Previous research has shown that immunostimulatory effects of radiotherapy may help to mediate rejection of the irradiated tumor and non-irradiated metastatic sites (known as the abscopal effect), and it has been suggested that radiotherapy may thus be able to help mitigate ICI resistance. An article published in Nature Cancer featured results of a study that focused on putatively immunologically cold tumors, leveraging the randomized, phase II PEMBRO-RT clinical trial of pembrolizumab after stereotactic body radiation therapy (SBRT) compared with pembrolizumab monotherapy to better understand the immunomodulatory effects of radiotherapy and to identify the subset of patients who may benefit most from these approaches. Their results suggest that radioimmunotherapy may circumvent immunotherapy primary resistance of these tumors.
Examination of serial non-irradiated tumor and peripheral blood samples from patients treated with pembrolizumab alone or in combination with SBRT suggested a radiation-driven abscopal effect. Radiotherapy was shown to drive immunogenic cell death and to have immunosuppressive effects at the irradiated tumor site through induction of PD-L1 expression on tumor cells. Therefore, addition of the anti–PD-1 antibody pembrolizumab may be synergistic by counteracting this negative effect on the antitumor immune response and help explain why abscopal effects by radiotherapy alone are rare in the clinical setting.
Collectively, the findings from this research support the induction of systemic immune responses involving both T- and B-cell immunity and suggest a potential cold-to-hot conversion of the tumor microenvironment with radioimmunotherapy. Interestingly, induction of B-cell responses on therapy was unique to the SBRT arm, highlighting the potential role of humoral adaptive responses in driving tumor regression after radioimmunotherapy. In conclusion, this study supports the abscopal effect of radioimmunotherapy in patients with metastatic NSCLC, including those with immunologically cold tumors, and suggests that radioimmunotherapy may be a promising avenue of further exploration for patients with therapeutic resistance to ICI.
High level
The immunomodulatory effects of radiation create a path forward for radioimmunotherapy as a potential strategy to overcome immunotherapy resistance. Future studies are needed to validate the role of radioimmunotherapy in tumors with overlapping characteristics of immunotherapy resistance, given the multifaceted nature of immunologically cold tumors. Participant selection remains key, together with SBRT dose and timing. The findings of this study may inform patient selection for radioimmunotherapy approaches, including the subset of patients with primary resistance to immunotherapy who currently lack effective treatment options. Additional trials are also needed to investigate the benefit of radioimmunotherapy vs immunochemotherapy or in overcoming immunotherapy resistance in patients with immunologically cold tumors.
Ground level
These results provide a step toward identifying patients who may benefit from a combination of ICI and radiotherapy. In patients with immunologically cold tumors, the systemic immune-stimulatory benefits of radioimmunotherapy coincided with significantly improved therapeutic response and longer survival in the combination therapy arm when compared with pembrolizumab alone. The lack of these associations among participants with immunologically hot tumors (ie, with high TMB or high PD-L1 expression) suggest that the addition of SBRT to pembrolizumab may have limited benefit for this population.
