New therapeutics for soft tissue sarcomas: Overview of current immunotherapy and future directions of soft tissue sarcomas

Abstract

Soft tissue sarcoma is a rare and aggressive disease with a 40 to 50% metastasis rate. The limited efficacy of traditional approaches with surgery, radiation, and chemotherapy has prompted research in novel immunotherapy for soft tissue sarcoma. Immune checkpoint inhibitors such as anti-CTLA-4 and PD-1 therapies in STS have demonstrated histologic-specific responses. Some combinations of immunotherapy with chemotherapy, TKI, and radiation were effective. STS is considered a ‘cold’, non-inflamed tumor. Adoptive cell therapies are actively investigated in STS to enhance immune response. Genetically modified T-cell receptor therapy targeting cancer testis antigens such as NY-ESO-1 and MAGE-A4 demonstrated durable responses, especially in synovial sarcoma. Two early HER2-CAR T-cell trials have achieved stable disease in some patients. In the future, CAR-T cell therapies will find more specific targets in STS with a reliable response. Early recognition of T-cell induced cytokine release syndrome is crucial, which can be alleviated by immunosuppression such as steroids. Further understanding of the immune subtypes and biomarkers will promote the advancement of soft tissue sarcoma treatment.

Innovative Breakthroughs for the Treatment of Advanced and Metastatic Synovial Sarcoma

“…Additional studies potentially including SyS have been planned, for example, pembrolizumab combined with Lenvatinib, a multiple kinase inhibitor of VEGFR1-2-3, FGFR1-2-3-4, PDGFR alpha, c-kit, and Ret in the NCT04784247 trial; or nivolumab (anti-PD1) plus gemcitabine/doxorubicin/docetaxel (GALLANT, NCT04535713); or sintilimab (anti-PD-1) plus doxorubicin/ifosfamide (NCT04356872); or camrelizumab (anti-PD-1) plus doxorubicin/ifosfamide (NCT04606108) [60]. Radiation therapy is another local therapy able to increase tumor immunogenicity and activate the immune microenvironment in tumors.…”

“…Radiation therapy is another local therapy able to increase tumor immunogenicity and activate the immune microenvironment in tumors. Several ongoing trials are aimed at evaluating the effect of radiation in addition to ICI [60].…”

Immunotherapy Plus Radiotherapy for the Treatment of Sarcomas: Is There a Potential for Synergism?

“… 16 , 17 The efficacy of adoptive cellular therapies in other subtypes of STS are limited. 11 Similarly, cancer vaccines only have promising efficacy in synovial sarcoma and myxoid/round cell liposarcoma. 18 Overall, the efficacy of immunotherapy alone in STS is disappointing.…”

“…9,10 At present, the widely used immunotherapies in clinical practice include programmed death receptor-1 (PD-1)/programmed death protein ligand-1 (PD-L1) inhibitors and cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitors, and the new types of immunotherapy include adoptive cellular therapies and cancer vaccines. 11,12 PD-1/L1 and CTLA-4 inhibitors have promising efficacy (with a response rate of 10-28%) in the treatment of a few pathological subtypes of STS (undifferentiated pleomorphic sarcoma, dedifferentiated liposarcoma, alveolar soft part sarcoma and angiosarcoma), and their efficacy in the treatment of other subtypes of STS are limited. 11,[13][14][15] Among approaches of adaptive cellular therapies, only engineered T-cell receptor (TCR) therapy has achieved remarkable efficacy in synovial sarcoma, with a response rate of over 50%.…”

“…11,12 PD-1/L1 and CTLA-4 inhibitors have promising efficacy (with a response rate of 10-28%) in the treatment of a few pathological subtypes of STS (undifferentiated pleomorphic sarcoma, dedifferentiated liposarcoma, alveolar soft part sarcoma and angiosarcoma), and their efficacy in the treatment of other subtypes of STS are limited. 11,[13][14][15] Among approaches of adaptive cellular therapies, only engineered T-cell receptor (TCR) therapy has achieved remarkable efficacy in synovial sarcoma, with a response rate of over 50%. 16,17 The efficacy of adoptive cellular therapies in other subtypes of STS are limited.…”