DISCUSSION
primary tumor, tumor, primary tumors, tumors
REGRESSION, TUMOR, PRIMARY TUMORS, CANCER PROGRESSION, RECURRENT DISEASE, BRAIN TUMORS, PRIMARY TUMOR, TUMORS, CYTOTOXICITY, MALIGNANT GLIOMAS
GC1118 is a novel anti‐EGFR monoclonal antibody, which specifically binds to EGFR and inhibits the downstream cascades of the EGFR pathway.The major difference between the experimental condition of the previous in vivo study and the clinical trial arises from the timely acquisition of specimens for genomic analysis. Unlike the preclinical study, we conducted genomic analysis using primary tumors while we treated the patients for their recurrent disease. Timely obtaining tumor specimens is important to make accurate molecular diagnoses, but usually impracticable in case of brain tumors.We hypothesized that tumor evolution might contribute to this failure. We defined the temporal interval—time interval between primary tumor acquisition and GC1118 initiation—and compared it between two patients' group stratified by tumor regression. Interestingly, tumor‐regression group showed longer intervals compared to the rest (mean ± s.d., 593 ± 428 vs. 357 ± 140, respectively, Not only physical temporal interval, but also therapeutics may influence the evolutionary trajectory by affecting genomic integrity.Previously, many studies depicted the significance of therapeutics on the genomic evolution of malignant gliomas.In the context of tumor evolution under therapy, A recent study by the GLASS consortium found that the classical subtype, enriched with There are additional reasons besides tumor evolution that can account for the failure of this trial. Although we adopted the strict eligibility criteria based on FISH to select the patients with EGFR amplification, the threshold of high EGFR amplification might not be sufficient. In two cases, copy number profiles of tumors were not matched, which signifies 90% agreement of two distinct methods. This disagreement is acceptable according to literatures as whole exome sequencing normalizes copy number across the tissue sample instead of on a cell‐by‐cell basis as with FISH.Coexisting Interestingly, we identified that the tumor‐regression group was enriched with immune‐related pathways by transcriptomic analysis. In a previous study, we suggested that antibody‐dependent cellular cytotoxicity might play an important role in eliciting antitumor effects of GC1118 in in vivo models.Antibody‐dependent cellular cytotoxicity driven by anti‐EGFR antibodies can induce cross talk among immune cells, especially NK cells and dendritic cells; this cross talk can prime antitumor cellular immunity.Moreover, γδ‐T cell and NK cells were upregulated in the tumor‐regression group according to deconvolution analysis. These cells are involved in the innate immune response and function as cytotoxic lymphocytes. Although γδ‐T cells have a dual effect regarding cancer progression, they can directly kill the tumor cells by diverse mechanisms including antibody‐dependent cellular cytotoxicity or indirectly induce an antitumor effect by interacting with multiple immune counterparts such as B cells, dendritic cells, and NK cells.Collectively, our study fail to show a survival benefit of GC1118 against GBMs with We observed that immune‐related genomic signatures were upregulated in tumors with regression. This finding is similar in the context to a recent study, which suggests a hazardous effect of EGFR amplification in response to immunotherapy. These collectively suggest a potential synergism of combining GC1118 and immunotherapy. Albeit speculative, this hypothesis is worth of being explored and should be investigated in the future prospective study.