Combination of pembrolizumab and radiotherapy induces systemic antitumor immune responses in immunologically cold non-small cell lung cancer
Menée à l'aide des échantillons tissulaires et sanguins de 293 patients atteints d'un cancer du poumon non à petites cellules de stade métastatique et inclus dans un essai de phase II, cette étude évalue l'intérêt, du point de vue de la réponse immunitaire et de la survie sans progression, d'ajouter une radiothérapie stéréotaxique à une immunothérapie à base de pembrolizumab chez les patients présentant des "tumeurs froides" (faible charge mutationnelle tumorale, absence d'expression de PD-L1 ou mutations dans la voie de signalisation Wnt)
The abscopal effects of radiation may sensitize immunologically cold tumors to immune checkpoint inhibition. We investigated the immunostimulatory effects of radiotherapy leveraging multiomic analyses of serial tissue and blood biospecimens (n = 293) from a phase 2 clinical trial of stereotactic body radiation therapy (SBRT) followed by pembrolizumab in metastatic non-small cell lung cancer (NCT02492568). Participants with immunologically cold tumors (low tumor mutation burden, null programmed death ligand 1 expression or Wnt pathway mutations) had significantly longer progression-free survival in the SBRT arm. Induction of interferon-γ, interferon-α and antigen processing and presentation gene sets was significantly enriched after SBRT in nonirradiated tumor sites. Significant on-therapy expansions of new and pre-existing T cell clones in both the tumor (abscopal) and the blood (systemic) compartments were noted alongside clonal neoantigen-reactive autologous T cell responses in participants with long-term survival after radioimmunotherapy. These findings support the systemic immunomodulatory and antitumor effects of radioimmunotherapy and may open a therapeutic window of opportunity to overcome immunotherapy resistance.
Nature Cancer , article en libre accès, 2025