Review of Adoptive Cellular Therapies for the Treatment of Sarcoma

Abstract

Sarcomas are a heterogeneous group of malignancies with limited therapeutic options, particularly in the metastatic setting. Adoptive cellular therapies (ACTs), including tumor-infiltrating lymphocyte (TIL) therapy, chimeric antigen receptor (CAR) T-cell therapy, and T-cell receptor (TCR) gene-modified T-cell therapy, offer promising novel approaches for these refractory tumors. TIL-based therapy has demonstrated early efficacy in melanoma and myeloma, with ongoing trials exploring its role in sarcoma. CAR T-cell strategies targeting HER2, GD2, and B7-H3 antigens are in development, though challenges such as tumor microenvironment-mediated resistance and antigen escape remain significant. Engineered TCRs, particularly those targeting MAGE-A4 and NY-ESO-1, have shown promising clinical results in synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCLS), leading to the recent FDA approval of afamitresgene autoleucel (afami-cel) and letetresgene autoleucel (lete-cel). Despite encouraging preliminary data, ACT implementation faces barriers including limited antigen specificity, off-tumor toxicity, immune evasion, and manufacturing scalability. Future research will focus on optimizing lymphodepleting regimens, mitigating toxicity, enhancing in vivo persistence, and combining ACT with other therapeutic agents. As clinical trials expand, ACT holds the potential to revolutionize sarcoma treatment by offering durable, targeted therapies for previously refractory disease.

Keywords: adoptive cellular therapy; chimeric antigen receptor; engineered T-cell receptor; sarcoma; tumor infiltrating lymphocyte.

Figure 1

Production of TILs. Tumor tissue is first resected or biopsied, and tissue is then processed to isolate TILs. Lymphocytes showing strong anti-tumor activity are selected and expanded in vitro. Finally, patients receive lymphodepleting chemotherapy followed by TIL infusion. Created in BioRender.com. https://BioRender.com/k76w677.

Figure 2

Production and Mechanism of Action of CAR T-Cells. T lymphocytes are first collected by leukapheresis, then a CAR construct is added via a viral vector. Cells are then expanded in vitro. Following cell expansion and quality control checks, patients receive lymphodepleting chemotherapy followed by CAR T-cell infusions. Cytotoxic activity is achieved by recognition of cell surface antigens by CAR T-cells leading to immune-mediated destruction of tumor cells. Created in BioRender.com. https://BioRender.com/q22d481.

Figure 3

Production and mechanism of action of TCR gene-modified T-cells. T-cells are first isolated by leukapheresis; then, a tumor-specific TCR gene is introduced using a viral vector. The cells are then expanded in vitro and rigorously assessed for safety and efficacy with quality control measures. Following lymphodepletion, patients receive infusions of TCR-modified T-cells. Cytotoxic activity is achieved by recognition of MHC class I molecules displaying the target intracellular peptide leading to immune-mediated destruction of tumor cells. Created in BioRender.com. https://BioRender.com/e59a255.