Anti-tumor activity of cetuximab plus avelumab in non-small cell lung cancer patients involves innate immunity activation: findings from the CAVE-Lung trial

Journal of Experimental & Clinical Cancer Research

Flora Cimmino¹  Jing Wang²  Lixia Diao²  Lauren Byers³  Robert Cardnell³  Carl M. Gay³  Kavya Ramkumar³  Morena Fasano⁴  Floriana Morgillo⁴  Vincenza Ciaramella⁴  Erika Martinelli⁴  Stefania Napolitano⁴  Fortunato Ciardiello⁴  Davide Ciardiello⁴  Concetta Tuccillo⁴  Carminia Maria Della Corte⁴  Giuseppe Viscardi⁴  Teresa Troiani⁴  Vincenzo Famiglietti⁴  Giulia Martini⁴  Raimondo Di Liello⁴ 

[1] CEINGE Institute;Department of Bioinformatics & Computational Biology, The University of Texas MD Anderson Cancer Center;Department of Thoracic Head and Neck Medical Oncology, University of Texas, MD Anderson Cancer Center;Medical Oncology, Department of Precision Medicine, Università degli Studi della Campania “Luigi Vanvitelli”;

关键词: Innate immunity;    STING;    NK cells;    Cetuximab;    Avelumab;   

DOI  :  10.1186/s13046-022-02332-2

来源: DOAJ

【 摘 要 】

Abstract Background We recently conducted Cetuximab-AVElumab-Lung (CAVE-Lung), a proof-of-concept, translational and clinical trial, to evaluate the combination of two IgG1 monoclonal antibodies (mAb): avelumab, an anti-PD-L1 drug, and cetuximab, an anti-epidermal growth factor receptor (EGFR) drug, as second- or third-line treatment in non-small cell lung cancer (NSCLC) patients. We have reported clinically relevant anti-tumor activity in 6/16 patients. Clinical benefit was accompanied by Natural Killer (NK) cell-mediated antibody-dependent cell cytotoxicity (ADCC). Among the 6 responding patients, 3 had progressed after initial response to a previous treatment with single agent anti-PD-1, nivolumab or pembrolizumab. Methods We report long-term clinical follow-up and additional findings on the anti-tumor activity and on the immune effects of cetuximab plus avelumab treatment for these 3 patients. Results As of November 30, 2021, 2/3 patients were alive. One patient was still on treatment from 34 months, while the other two patients had progression free survival (PFS) of 15 and 19 months, respectively. Analysis of serially collected peripheral blood mononuclear cells (PBMC) revealed long-term activation of NK cell-mediated ADCC. Comprehensive genomic profile analysis found somatic mutations and germline rare variants in DNA damage response (DDR) genes. Furthermore, by transcriptomic analysis of The Cancer Genome Atlas (TCGA) dataset we found that DDR mutant NSCLC displayed high STING pathway gene expression. In NSCLC patient-derived three-dimensional in vitro spheroid cultures, cetuximab plus avelumab treatment induced additive cancer cell growth inhibition as compared to single agent treatment. This effect was partially blocked by treatment with an anti-CD16 mAb, suggesting a direct involvement of NK cell activation. Furthermore, cetuximab plus avelumab treatment induced 10-, 20-, and 20-fold increase, respectively, in the gene expression of CCL5 and CXCL10, two STING downstream effector cytokines, and of interferon β, as compared to untreated control samples. Conclusions DDR mutations may contribute to DDR-induced STING pathway with sustained innate immunity activation following cetuximab plus avelumab combination in previously treated, PD-1 inhibitor responsive NSCLC patients.

【 授权许可】

Unknown