The efficacies and biomarker investigations of antiprogrammed death-1 (anti-PD-1)-based therapies for metastatic bone and soft tissue sarcoma

Objective:Sarcomas are a group of rare malignancies with various subtypes.Patients with metastatic sarcoma who have failed traditional treatments can possibly achieve better prognoses from using novel therapies,including anti-programmed death-1(PD-1)-based therapies.Methods:We retrospectively analyzed clinical data of 24 metastatic sarcoma patients from June 15,2016 to December 30,2019.These patients mainly received angiogenesis inhibitors combined with anti-PD-1 therapy after they became resistant to traditional treatments.Furthermore,8 patients underwent panel DNA and whole transcript sequencing.Results:Six patients received 2 cycles of anti-PD-1 therapy and were included in the safety evaluation only group.The median follow-up time was 5.77 months.The median progression-free survival was 7.59 months,the overall response rate was 16.7%and the disease control rate was 55.6%.Based on whole exome and transcript sequencing data,there was no association between TMB,TNB,MSI,HLA-LOH,and PD-L1 expressions and sarcoma types with clinical responses.Immunotherapy efficacy and bioinformatics analyses indicated higher intratumoral heterogeneity(ITH)in progressive disease(PD)patients and lower ITH in partial response(PR)and stable disease patients.A higher percentage of immune cell infiltration,especially monocytes,was observed in PR patients.Active stromal gene expression was increased in PD patients but decreased in PR patients.Enrichment analysis revealed that an increased TGF-βsignaling pathway was reversely correlated with anti-PD-1 efficacy,while a decreased inflammatory response signaling pathway was positively correlated with anti-PD-1 efficacy.Conclusions:Our study showed PD-1 inhibitors combined with anti-angiogenesis agents were effective and well-tolerated.ITH,monocyte ratio,stroma subtypes,and the status of immune-associated signaling pathways may be related with anti-PD-1 based therapy.

Personalized neoantigen pulsed dendritic cell vaccine for advanced lung cancer

Neoantigens are considered to be ultimate target of tumor immunotherapy due to their high tumor specificity and immunogenicity.Dendritic cell(DCs)vaccines based on neoantigens have exciting effects in treatment of some malignant tumors and are a promising therapeutic modality.Lung cancer is a lethal disease with the highest morbidity and mortality rate in the world.Despite the rapid development of targeted therapy and immune checkpoint inhibitors for lung cancer in recent years,their efficacy is still unsatisfactory overall.Therefore,there is an urgent unmet clinical need for lung cancer treatment.Here,we attempted to treat lung cancer using a personalized neoantigen peptide-pulsed autologous DC vaccine and conducted a single-arm,2 medical centers,pilot study initiated by the investigator(ChiCTR-ONC 16009100,NCT02956551).The patients enrolled were patients with heavily treated metastatic lung cancer.Candidate neoantigens were derived from whole-exome sequencing and RNA sequencing of fresh biopsy tissues as well as bioinformatics analysis.A total of 12 patients were enrolled in this study.A total of 85 vaccine treatments were administered with a median value of 5 doses/person(range:3-14 doses/person).In total,12-30 peptide-based neoantigens were selected for each patient.AIl treatment-related adverse events were grade 1-2 and there were no delays in dosing due to toxic effects.The objective effectiveness rate was 25%;the disease control rate was 75%;the median progression-free survival was 5.5 months and the median overall survival was 7.9 months.This study provides new evidence for neoantigen vaccine therapy and new therapeutic opportunities for lung cancer treatment.

Whole-exome sequencing in a patient with synchronous triple primary malignancies involving lung cancer:a case report

The incidence of multiple primary malignancies(MPMs)has been increasing rapidly in recent years,however,the genetic pathogenesis is largely unknown on account of rare cases,especially for those patients who are diagnosed with three or more tumors.Under these circumstances,whole-exome sequencing(WES)may help to provide more comprehensive genomic information and guidance to proper therapeutic strategies.Here,we presented a rare case of a 66-year-old Chinese male patient who was diagnosed with synchronous triple primary malignancies:esophageal squamous cell carcinoma(ESCC),lung adenocarcinoma(LA),and hepatocellular carcinoma(HCC).Tumors were surgically removed within 3 months.WES was performed when the patient suffered from cancer recurrence and tumor-specific neoantigens were predicted.Each tumor displayed a distinct somatic mutation profile,providing direct evidence of independent origins.No shared driver gene mutation or neoantigen was detected among the three tumors.Two germline alterations of cancer susceptibility genes—SPINK1 c.194+2T>C and JAK3 c.425G>A were identified.This case is the first report of synchronous primary triple cancers covering the esophagus,lung,and liver.Our findings highlight the complexities of MPMs that even when under identical germline genetic backgrounds,the occurrence of MPMs can be a random event and driven by distinct somatic gene mutations.Synchronous multiple primary cancers that originated from different organs may not have common therapeutic gene targets,and it can be difficult to find a treatment to cover all the tumors.