Evaluation of the efficacy and safety of immunotherapy in sarcoma: a two-center study

BackgroundSarcoma is a highly heterogeneous malignancy with a poor prognosis. Although chemotherapy and targeted therapy have improved the prognosis to some extent, the efficacy remains unsatisfactory in some patients. The efficacy and safety of immunotherapy in sarcoma need further evaluation.MethodsWe conducted a two-center study of sarcoma patients receiving PD-1 immunotherapy at Tianjin Medical University Cancer Institute and Hospital and Henan Provincial Cancer Hospital. The treatment regimens included PD-1 inhibitor monotherapy and combination therapy based on PD-1 inhibitors. The observed primary endpoints were median progression-free survival (mPFS) and median overall survival (mOS). Survival curves were compared using the Kaplan−Meier method.ResultsA total of 43 patients were included from the two centers. The median follow-up time for all patients was 13 months (range, 1-48 months). In the group of 37 patients with advanced or unresectable sarcoma, the mPFS was 6 months (95%CI: 5-12 months), and the mOS was 16 months (95%CI: 10-28 months). The ORR was 10.8% (4/37), and the DCR was 18.9% (7/37). Subgroup analysis showed no significant differences in mPFS (p=0.11) and mOS (p=0.88) between patients with PD-L1 negative/positive expression. There were also no significant differences in mPFS (p=0.13) or mOS (p=0.72) between PD-1 inhibitor monotherapy and combination therapy. Additionally, there were no significant differences in mPFS (p=0.52) or mOS (p=0.49) between osteogenic sarcoma and soft tissue sarcoma. Furthermore, the results showed no significant differences in mPFS (p=0.66) or mOS (p=0.96) between PD-1 inhibitors combined with targeted therapy and PD-1 inhibitors combined with AI chemotherapy. Among the 6 patients receiving adjuvant therapy after surgery, the mPFS was 15 months (95%CI: 6-NA months), and the mOS was not reached. In terms of safety, most adverse events were mild (grade 1-2) and manageable. The most severe grade 4 adverse events were bone marrow suppression, which occurred in 4 patients but resolved after treatment. There was also one case of a grade 4 adverse event related to hypertension.ConclusionImmunotherapy is an effective treatment modality for sarcoma with manageable safety. Further inclusion of more patients or prospective clinical trials is needed to validate these findings

Tumoral C2 Regulates the Tumor Microenvironment by Increasing the Ratio of M1/M2 Macrophages and Tertiary Lymphoid Structures to Improve Prognosis in Melanoma

Immunotherapy is an essential therapy for individuals with advanced melanoma. However, not all patients respond to such treatment due to individual differences. We conducted a multidimensional analysis using transcriptome data from our center, as well as publicly available databases. We found that effective nivolumab treatment led to an upregulation of C2 levels, and higher levels following treatment are indicative of a good outcome. Through bioinformatics analyses and immunofluorescence, we identified a correlation between C2 and M1 macrophages. To further investigate the role of C2 in melanoma, we constructed subcutaneous tumorigenic models in C57BL/6 mice. The tumors in the C2 overexpression group exhibited significantly smaller sizes. Flow cytometric analysis of the mouse tumors demonstrated enhanced recruitment of macrophages, particularly of the M1 subtype, in the overexpression group. Moreover, single-cell RNA sequencing analysis revealed that C2-positive tumor cells exhibited enhanced communication with immune cells. We co-cultured tumor cell supernatants with macrophages in vitro and observed the induction of M1 subtype polarization. In addition, we discovered a close correlation between C2 and tertiary lymphoid structures. C2 has been demonstrated to exert a protective effect, mediated by its ability to modulate the tumor microenvironment. C2 serves as a prognostic marker for melanoma and can be employed to monitor the efficacy of immunotherapy

The efficacies and biomarker investigations of anti-programmed 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 'FMB, TNB, MSI, IlLA-LOIL 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-beta signaling 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