small molecules
2026-09-30 | Metastatic Status Modifies the Survival Association of Neoadjuvant Radiotherapy in Malignant Peripheral Nerve Sheath Tumors: A Nationwide Analysis.
Malignant peripheral nerve sheath tumors (MPNSTs) are rare, aggressive sarcomas with poor overall survival (OS). Radiotherapy timing is extrapolated from other soft-tissue sarcomas, and no prior MPNST-specific analysis has formally tested whether neoadjuvant radiotherapy (NRT) effects are modified by metastatic status. We evaluated NRT's association with R0 resection and OS by metastatic status. Retrospective cohort of MPNST patients in the National Cancer Database (2005-2023). Multivariable logistic regression evaluated NRT and R0 resection. Cox proportional hazards models tested an NRT-by-metastatic status interaction, with hospital-level frailty terms addressing inter-facility correlation. Propensity score matching (1:1) reduced confounding. Sensitivity analyses addressed guarantee-time bias and confounding. Causal mediation evaluated R0 as a mediator of the NRT-survival relationship. Of 2241 patients, 24.2% received NRT. NRT increased the odds of R0 resection (OR 2.17, 95% CI 1.60-2.98; p < 0.001) but was not associated with improved survival overall. The NRT-survival association was modified by metastatic status (interaction p < 0.001): metastatic patients receiving NRT had better survival (matched HR 0.41, 95% CI 0.23-0.72; p = 0.004), whereas no survival benefit was seen in localized disease (worse in some analyses). This signal was consistent across guarantee-time sensitivity analyses but was not mediated by margins. NRT improves the odds of R0 resection in MPNST, but improved margins do not yield a uniform survival benefit. The NRT-survival association is modified by metastatic status; the metastatic signal, though robust to guarantee-time bias, was not mediated by margins and rests on a small subgroup. These findings are hypothesis-generating and warrant a prospective study.
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2026-09-24 | Therapeutic Vulnerabilities of the Key Genetic Drivers in Leiomyosarcoma.
Leiomyosarcoma (LMS) is a rare, aggressive soft-tissue sarcoma arising from smooth muscle cells. It has a high metastatic potential and limited therapeutic options. Despite advances in oncology, the molecular landscape of LMS remains incompletely understood, particularly regarding the genetic and epigenetic alterations that affect key signaling pathways. This review summarizes the current knowledge of mechanisms driving LMS pathogenesis, including somatic mutations in genes such as TP53 and RB1, chromosomal instability, dysfunction of DNA damage response and repair, aberrant DNA methylation, histone modifications, and non-coding RNAs. Emerging treatment strategies include inhibitors of PI3K/AKT/mTOR and CDK4/6 signaling, epigenetic drugs, immunotherapy, and combinations of these approaches. However, the coexistence of multiple genetic abnormalities complicates diagnosis, prognosis, and therapeutic selection. Companion diagnostic tools that test candidate therapies ex vivo or in vitro may help exclude potentially ineffective targeted treatments.
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2026-09-18 | Cardiac safety of L-Annamycin: a pooled analysis of five clinical trials.
Anthracyclines are highly effective chemotherapeutic agents but are limited by cumulative, dose-dependent cardiotoxicity, leading to strict lifetime exposure thresholds. L-Annamycin is a next-generation liposomal anthracycline designed to preserve antitumor efficacy while reducing cardiotoxicity. We performed a pooled analysis of cardiac safety data from five sponsor- and investigator-initiated clinical trials evaluating L-Annamycin in acute myelogenous leukemia (AML) and metastatic soft tissue sarcoma (STS). Cardiac monitoring included serial electrocardiograms, cardiac biomarkers (troponin I/T), and transthoracic echocardiography with left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) assessment. All cardiac data were independently evaluated by a cardio-oncology laboratory at the Cleveland Clinic. Ninety patients were included, with paired echocardiographic data available in 78. Median cumulative L-Annamycin dose was 660 mg/m2 (IQR 450-1,080). Baseline and post-treatment LVEF did not differ significantly (60.6% vs. 60%, p = 0.84). No associations were observed between change in LVEF and cumulative dose or age. Serial ECG, troponin, and GLS assessments showed no treatment-related cardiotoxicity. These findings were observed despite cumulative exposures exceeding conventional anthracycline lifetime limits. In this pooled analysis of patients with AML and STS, L-Annamycin was not associated with clinical or subclinical evidence of cardiotoxicity at cumulative doses exceeding traditional anthracycline thresholds. These data support continued clinical evaluation of L-Annamycin as a potentially safer anthracycline platform.
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2026-09-15 | Association of Prior Local Therapy with Outcomes Within Systemic Therapy Regimen Cohorts in Advanced Soft Tissue Sarcoma: A Retrospective Cohort Study.
Background/Objectives: Evidence regarding associations between local therapy before an indexed systemic regimen and subsequent outcomes in advanced soft tissue sarcoma (STS) remains limited. We evaluated outcomes within four regimen-defined cohorts and explored associations with prior local-therapy history. Methods: This retrospective cohort included 75 patients with recurrent or metastatic STS who contributed 155 treatment episodes: doxorubicin (n = 44), trabectedin (n = 31), pazopanib (n = 42), and eribulin (n = 38). Progression-free survival (PFS) and overall survival (OS) were measured from initiation of the indexed regimen. Surgery, local ablative therapy, and radiation therapy were assessed separately and in combined categories. Post hoc analyses were restricted to leiomyosarcoma. Results: Median PFS was 3.4, 3.1, 5.1, and 3.9 months, respectively. PFS was longer with any local therapy and surgery and/or ablation in the trabectedin cohort (p = 0.0342 and p = 0.0111) and with surgery and/or ablation in the eribulin cohort (p = 0.0352). Longer indexed-regimen OS was observed in surgery-containing categories in the doxorubicin and eribulin cohorts. In selected multivariable models, local therapy was associated with OS in doxorubicin- and eribulin-treated episodes and with PFS in eribulin-treated episodes. Leiomyosarcoma-restricted analyses did not consistently reproduce the full-cohort findings. Conclusions: Prior local-therapy history was associated with PFS or OS in selected within-cohort analyses. The associations may reflect local-treatment effects, differences among selected patients, or both; however, the study cannot distinguish these contributions. No between-regimen differences were formally tested. These findings support individualized multidisciplinary assessment and external validation.
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2026-09-15 | Radiological Response to Capecitabine and Temozolomide in an Elderly Patient with Metastatic Leiomyosarcoma: A Case Report.
Metastatic leiomyosarcoma (LMS) is characterized by limited treatment options beyond first-line therapy, and cross-resistance among cytotoxic agents is often assumed to exist. However, differential sensitivity to distinct chemotherapy mechanisms may exist. We report the case of an 81-year-old woman diagnosed with metastatic LMS of unknown primary origin presenting with extensive hepatic and pulmonary involvement. Following eight cycles of first-line gemcitabine plus docetaxel, the patient achieved stable disease without objective tumor shrinkage. Given this limited response, a significant radiological response to subsequent therapy was not anticipated. Second-line oral capecitabine and temozolomide (CAPTEM) was initiated, resulting in a marked radiologic regression at four months, with reductions in hepatic metastases and pulmonary nodules and no new lesions. Treatment was well tolerated, with no grade 3-4 toxicities. This case demonstrates a differential response to gemcitabine-based therapy and sensitivity to alkylating agents in LMS, supporting a more individualized, mechanism-driven treatment sequencing approach.
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proteins
2026-07-28 | Cytokine delivery and targeting strategies in pet dogs with cancer: a comparative immuno-oncology approach.
Cytokine therapies have long been hampered by a fundamental pharmacological problem: systemic absorption and distribution drives immune-related toxicity which precludes the achievement of therapeutic concentrations within tumors to mediate anti-tumor immunity. Engineering cytokines with tunable biodistribution properties to remain within or near the injection site has reinvigorated opportunities to explore cytokine-based immunotherapies for clinical evaluation. Pet dogs with spontaneous cancers offer a biologically rich and informative model system for investigating new therapeutic delivery strategies. Pet dogs develop tumors naturally in an immunocompetent setting, share key features of human tumor immunobiology and immune system architecture, and display similar pharmacodynamic immune biomarkers used for assessing tolerability and antitumor activities in human cancer patients. This mini review examines targeted cytokine delivery platforms evaluated in pet dogs with naturally occurring malignancies, including aluminum hydroxide-anchored IL-12, collagen-binding IL-2/IL-12 fusion proteins, antibody-cytokine immunocytokines (NHS-IL12 and hu14.18-IL2), PEGylated TNF-α, liposomal IL-2, plasmid IL-12 electrogene therapy, oncolytic viruses engineered to express IL-12 or IFN-β, and emerging delivery platforms. Solid malignancies studied in pet dogs include melanoma, soft tissue sarcoma, mast cell tumor, osteosarcoma, high-grade glioma, adenocarcinoma, fibrosarcoma, and urothelial carcinoma. Across diverse technological platforms, several pharmacodynamic patterns observed in dogs have also been recapitulated in first-in-human trials, emphasizing the potential wealth of a comparative oncology framework for evaluating novel immunomodulatory strategies. These parallels underscore the value of canine immuno-oncology trials in defining safety and biological activity for engineered cytokine constructs, with direct implications for guiding the development of dose selection and biomarker discovery in the human immuno-oncology field.
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2026-06-04 | Two-stage reconstruction using basic fibroblast growth factor -impregnated artificial dermis and acellular fish skin graft in a dog with distal extremity soft tissue sarcoma.
A 13-year-old Chihuahua presented with a distal forelimb soft tissue sarcoma and underwent surgical excision. To close the resulting large skin defect, a two-stage approach was performed using a basic fibroblast growth factor (bFGF)-impregnated artificial dermis composed of collagen gelatin sponge (CGS), followed by application of an acellular fish skin graft (FSG). After 10 days of bFGF-impregnated CGS application, uniform granulation tissue had formed, and an FSG was subsequently applied. Complete epithelialization was achieved 25 days after FSG placement without additional grafting. At 320 days postoperatively, no postoperative complications or local recurrence were observed. However, given the potential risk of promoting residual tumor cell proliferation, local bFGF use in malignant tumor-associated wounds should be restricted to carefully selected cases.
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2026-02-27 | Tyrosine-Peptide Analog Modulates Extracellular Vesicles miRNAs Cargo from Mesenchymal Stem/Stromal and Cancer Cells to Drive Immunoregeneration and Tumor Suppression.
Soft tissue sarcoma remains challenging to treat due to its heterogeneity, stemness-associated survival programs, and resistance to conventional therapies. Extracellular vesicles (EVs) mediate tumor-stroma communication, yet how stemness-targeted therapies reshape EVs-associated miRNAs networks remains unclear. This study profiled EVs miRNAs cargo from infrapatellar fat pad mesenchymal stem/stromal cells (IFP-MSCs) and sarcoma cells (SCs) under basal conditions and following treatment with a synthetic tyrosine peptide analog (TPA). EVs were isolated, characterized, and subjected to miRNAs profiling and pathway enrichment analyses. TPA induced ≥2-fold regulation of 182 miRNAs, including 49 upregulated and 24 downregulated in IFP-MSC-EVs and 86 upregulated and 23 downregulated in SC-EVs. A conserved core of 149 miRNAs (67.1%) was shared across all EVs groups. Abundant species included miR-3960 and miR-21-5p, while TPA reduced tumor-associated miRNAs such as miR-1246 (~10-fold decrease in IFP-MSC-EVs). Pathway enrichment revealed consistent targeting of cancer, MAPK, Wnt, TGF-β, and immune signaling pathways, with modest increases in mapped gene coverage following TPA treatment. In silico analysis identified distinct EVs miRNA-gene interaction profiles, with VEGFA emerging as a recurrent predicted target. These results demonstrate that stemness-targeted modulation quantitatively reprograms EVs miRNA cargo in a cell-type-dependent manner, reshaping vesicle-mediated signaling networks in sarcoma.
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2026-02-20 | Trabectedin plus CD13-targeted tissue factor tTF-NGR against advanced relapsed or refractory soft tissue sarcoma: translational data, clinical safety and efficacy.
Trabectedin is standard for r/r soft tissue sarcomas. tTF-NGR accumulates in tumor vasculature leading to tumor vascular occlusion and tumor infarction. Both compounds in sequence could trap trabectedin inside tumors and increase its efficacy, which then optimizes the pro-coagulatory activity of tTF-NGR. This report summarizes translational data and results of the safety run-in patient cohort of the TRABTRAP trial combining trabectedin plus tTF-NGR. A dose of trabectedin of 1.5 mg/m2 (24 h, day 1) combined with 1.0 mg/m2 of tTF-NGR (1 h, days 2 and 3, q day 22) represents the approx. Maximum tolerated dose (MTD) and with 0.5 mg/m2 tTF-NGR (days 2 and 3) the recommended starting dose for the randomized part of TRABTRAP. None of the 6 patients on 0.5 mg/m2 tTF-NGR had dose-limiting toxicity (DLT). Higher doses or additional days of application of tTF-NGR led to grade 3 DLT including early troponin T high sensitivity increase, a reversible non-ST-elevation myocardial infarction in one patient, and reversible thromboembolic events. Pharmacokinetics explain the difference of the MTD between the phase I study and in TRABTRAP. Experimental and clinical efficacy and tolerability of the combination between trabectedin and tTF-NGR supports the active randomized part of TRABTRAP.
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2025-12-31 | Dual role of IFNγ in reprogramming the undifferentiated pleomorphic sarcoma cell line JBT19 towards cytotoxic chemotherapy and antitumor immunity.
Soft tissue sarcomas are therapeutically challenging. Among soft tissue sarcoma subtypes, undifferentiated pleomorphic sarcoma (UPS) exhibits one of the most pronounced disparities between its comparatively higher responsiveness to immunotherapy and its limited responsiveness to conventional cytotoxic chemotherapy. The interplay between immunotherapy and cytotoxic chemotherapy is still largely unknown. Interferon-γ (IFNγ) is a key player in antitumor immunity and contributes to the modulation of the tumor microenvironment, which impacts both immune and cancer cells. The mechanism by which this interplay can affect cancer cell chemosensitivity and immune sensitivity is difficult to predict. The present study aimed to investigate the interplay of IFNγ signaling in the UPS cell line JBT19. It was identified that IFNγ treatment significantly decreased the proliferation of JBT19 cells and increased the surface expression levels of cluster of differentiation (CD)44, CD47, CD95 (Fas), major histocompatibility complex (MHC)-I and programmed death-ligand 1 (PD-L1). In addition, IFNγ strongly upregulated surface expression levels of MHC-II and converted JBT19 cells into docetaxel-resistant cells. The IFNγ-induced changes were sustained but reversible after 3 weeks of cell culture without IFNγ. Regardless of IFNγ treatment, JBT19 cells could elicit and amplify the adaptive immune response in vitro. The in vitro JBT19-reactive lymphocytes effectively eliminated both IFNγ-treated and non-treated JBT19 cells, thus overcoming IFNγ-induced chemoresistance. To the best of our knowledge, the present study demonstrated a dual role of IFNγ towards cancer cell chemoresistance and immunostimulatory potential for the first time. The present study findings may have potential implications for combining immunotherapy with cytotoxic chemotherapy in cancer treatment in the future.
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cell therapies
2026-07-02 | GPNMB-directed CAR T cell therapy against MiT/TFE-family fusion-driven solid tumors.
Chimeric antigen receptor (CAR) T cell therapy for solid tumors is constrained by the scarcity of safe, uniformly expressed cell-surface targets. Here we identify glycoprotein NMB (GPNMB)-an MiT/TFE-family fusion-driven protein-as being highly, homogeneously and stably expressed in primary and relapsed alveolar soft-part sarcoma (ASPS) and translocation renal cell carcinoma. We develop a GPNMB-directed CAR T cell product, GCAR1, which demonstrates potent activity against patient-matched cells, organoids and xenograft models. Post hoc interim analysis of a first-in-human open-label, individual-participant trial ( NCT07104682 ) for a participant with relapsed/refractory, metastatic ASPS showed that GCAR1 induces stable disease for up to 3 months, accompanied by resolution of many nontarget lesions (primary endpoint), and is well tolerated. GCAR1 T cells expand in peripheral blood as a polyclonal population and remain detectable for 1 month. Spatial transcriptomics identified immunosuppressive niches in a treatment-resistant lesion and immune checkpoint blockade synergized with GCAR1 in a xenograft model. Altogether, our data provide a proof of concept for treating GPNMB-expressing solid tumors with GCAR1 and more broadly targeting surface antigens driven by oncogenic gene fusions with CAR T cell therapies.
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2026-06-24 | Optimized L1CAM-CAR T cells enhance activity against moderate-antigen-density rhabdomyosarcoma models.
Rhabdomyosarcoma (RMS), the most common pediatric soft tissue sarcoma, remains difficult to treat in relapsed, metastatic, or refractory disease. Chimeric antigen receptor (CAR) T cell therapy has demonstrated promising results in hematological diseases, but its application to solid tumors including RMS is limited by antigen heterogeneity, on-target/off-tumor toxicity, and insufficient activity against moderate antigen density. We investigated L1 cell adhesion molecule (L1CAM) as a candidate CAR T cell target in RMS by profiling expression in cell lines, patient-derived xenografts, and healthy tissues. Using the CE7-derived single-chain variable fragment, we engineered and compared L1CAM-CAR constructs differing in hinge and costimulatory domains, including the clinically tested 4-1BB-based CE7-CAR configuration. Functional activity was assessed across fusion-positive and fusion-negative RMS models in vitro and in orthotopic mouse models, with B7-H3-CAR T cells included as a benchmark. L1CAM was expressed at variable but specific levels across RMS models, with more prominent expression in fusion-positive RMS and limited expression in healthy tissues. Among constructs, the CD28-based L1CAM.III-CAR showed the strongest cytotoxicity and IFN-γ release, including partial activity in a low-L1CAM model. In vivo, L1CAM.III-CAR T cells improved expansion, delayed tumor progression, and prolonged survival compared with the clinical-reference L1CAM.CT construct, although responses were incomplete and less pronounced than those achieved with B7-H3-CAR T cells. These findings support L1CAM as a rational target for L1CAM-positive RMS cases and demonstrate that CAR optimization can enhance activity against moderate-density antigens. The potent antitumor activity and favorable selectivity profile of L1CAM.III-CAR T cells support their development for pediatric sarcoma immunotherapy.
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2026-02-19 | CAR-T cell immunotherapy in rhabdomyosarcoma.
BACKGROUND: Rhabdomyosarcoma, the most common pediatric soft tissue sarcoma, remains a therapeutic challenge due to its aggressive nature and poor outcomes in high-risk patients. Herein, we explore the potential of CAR-T cell therapy as a transformative approach for rhabdomyosarcoma, focusing on target antigens such as HER2, CD276, FGFR4, PDGFR-α, and others. MAIN BODY: While preclinical studies are promising, antitumor activity in clinical studies to date has been limited. Significant clinical hurdles include antigen heterogeneity, immunosuppressive tumor microenvironments, and logistical barriers in manufacturing. Innovative strategies like dual-targeting CARs, combinatorial checkpoint blockade, and allogeneic platforms are discussed to address these limitations. Additionally, we highlight emerging modalities such as immune checkpoint inhibitors, oncolytic viruses, and small molecule inhibitors that may synergize with CAR-T cell therapy. CONCLUSIONS: By integrating these advances, rationally designed multimodal therapies could overcome resistance mechanisms and improve outcomes for refractory rhabdomyosarcoma, offering hope for a historically incurable malignancy.
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2026-01-09 | Vascular Reconstruction in Extremity Soft Tissue Sarcomas: A Systematic Review and Single-Arm Meta-Analysis.
The management of extremity soft tissue sarcomas (STS) involving major vessels presents unique challenges, historically leading to amputation. Advances in vascular reconstruction have enabled limb-sparing surgery (LSS), but outcomes and perioperative risks remain uncertain. This systematic review and meta-analysis aimed to evaluate oncologic results following LSS with vascular reconstruction in extremity STS. A systematic review and single-arm meta-analysis were performed according to PRISMA guidelines, with registration in PROSPERO. PubMed, Embase, and Cochrane Library were searched from inception to June 2025 for studies reporting outcomes in patients with extremity STS undergoing LSS with vascular reconstruction. Pooled analyses estimated limb salvage, survival, and complication rates using random-effects models. Thirty-one studies comprising 520 patients were included. Approximately 58% were male, with a mean age ranging from 29.3 to 59 years. The most common tumor localizations were the thigh (59.5%), inguinal region (15.9%), and popliteal fossa (8.6%). Liposarcoma (24.0%), synovial sarcoma (19.6%), and osteosarcoma (14.8%) were the most frequent histological subtypes. The pooled limb salvage rate was 89% (95% CI, 86%-92%), while amputation occurred in 10% (95% CI, 8%-14%). One- and 5-year overall survival rates were 89% and 62%, respectively, with disease-free survival rates of 74% and 55%. Major complications included graft thrombosis (19%), wound complications (29%), and wound infection (22%). Limb-sparing surgery with vascular reconstruction is effective for extremity STS involving major vessels, enabling high limb salvage and favorable long-term survival without compromising oncologic outcomes. However, substantial perioperative morbidity persists, underscoring the need for multidisciplinary care, careful patient selection, and prospective studies to refine indications and enhance quality of life.
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2025-11-19 | Generation of an iPSC-derived alveolar rhabdomyosarcoma cell line during directed endothelial differentiation.
Alveolar rhabdomyosarcoma (ARMS) is an aggressive soft tissue sarcoma typically driven by the oncofusion protein PAX3::FOXO1 (P3F). Despite ARMS tumor histology and transcriptome resembling skeletal muscle, these tumors arise in areas devoid of skeletal muscle, indicating that non-myogenic cells can give rise to ARMS. Our lab demonstrated that endothelial progenitors are a cell of origin for rhabdomyosarcoma. Here we provide a protocol for generating iPSC-derived alveolar rhabdomyosarcoma cells (iARMS) during endothelial directed differentiation through enforced expression of P3F. This model allows for dissection of how P3F mediates transformation of endothelial progenitors into aggressive myogenic tumors.
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antibodies
2026-09-19 | A partial response to atezolizumab in alveolar soft part sarcoma with near-complete resolution of extensive pulmonary metastases: a case report.
Alveolar soft part sarcoma (ASPS) is a rare soft tissue sarcoma with high metastatic potential and limited response to systemic therapy. Biomarkers that predict which patients may benefit from emerging immune checkpoint inhibitors (ICIs) continue to surface. We report a case of stage IV ASPS with extensive pulmonary metastases and high PD-L1 expression that exhibited a marked response to atezolizumab, a PD-L1 antagonist. A 35-year-old man presented to an outside institution in October 2023 with a painless, progressively enlarging left thigh mass. Magnetic resonance imaging (MRI) demonstrated a 7.5 × 4.5 × 14 cm heterogeneous intramuscular lesion. Chest computed tomography (CT) revealed innumerable bilateral pulmonary metastases. Transthoracic biopsy of a pulmonary nodule confirmed stage IV ASPS with strong nuclear TFE3 positivity, Cathepsin K positivity, retained INI1 expression, and PD-L1 expression in 90-100% of malignant cells. The primary lesion was not characterized separately. Following transfer to our institution, atezolizumab was initiated in December 2023. At 3 months, chest CT demonstrated a marked regression of pulmonary metastases. Many resolved completely while others showed significant interval decrease in size. At 8 months, chest CT demonstrated further regression in size, number, and density of the pulmonary metastases. Only micronodules remained. At 12 months, chest CT demonstrated that all remaining pulmonary micronodules were stable without new or progressive disease. The primary lesion was treated with neoadjuvant hypofractionated radiotherapy and wide local resection. Post-operative histopathology of the primary lesion demonstrated >99% tumor necrosis with negative margins. This patient achieved a partial response of the primary thigh mass per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and an immune partial response per immune RECIST (iRECIST). Moreover, this patient experienced a near-complete resolution of pulmonary metastatic disease sustained for 27 months despite an extensive metastatic burden. This case illustrates that substantial disease burden does not preclude meaningful, durable response to ICIs. Moreover, it raises the possibility that high PD-L1 expression may contribute to immune evasion. However, this observation was based on a metastatic biopsy. Prospective acquisition of standardized PD-L1 assay data, fusion-variant genotyping, and tumor-infiltrating lymphocyte profiles in future cases could inform individualized prognostication.
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2026-08-13 | Immunotherapy in the Treatment of Soft Tissue Sarcoma Since SARC028: An NCDB Analysis.
The publication of SARC028 in late 2017 revolutionized soft tissue sarcoma (STS) treatment by demonstrating promising response to anti-PD1 immunotherapy in undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (DDLPS). Data on immunotherapy efficacy and outcomes in larger cohorts and with longer follow-up remain limited. 31 672 cases of UPS, DDLPS, alveolar soft part sarcoma, and myxofibrosarcoma were extracted from the NCDB. Factors associated with the use of immunotherapy were evaluated using logistic regression, and survival analysis was performed with Kaplan-Meier curves and Cox proportional hazards models. Patients diagnosed with STS after 2017 were 3.67 times more likely to receive immunotherapy. Immunotherapy was associated with an approximately 20% reduction in mortality in stage IV STS, which was driven by cases of UPS. This survival benefit was observed in male, but not female, patients. There was no survival benefit in stage III STS. These data are consistent with a survival benefit with immunotherapy in stage IV STS, predominantly in UPS, supporting the findings of SARC028. Benefit in stage III STS was not observed, limiting concordance with later trials like SARC032. Further prospective data on long-term outcomes and immunotherapy efficacy according to histology and sex are needed.
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2026-08-13 | Dual Inhibition of LAG-3 and PD-1 with IBI110 and Sintilimab in Advanced Alveolar Soft Part Sarcoma: A Single-Center, Phase II Trial.
Alveolar soft part sarcoma (ASPS) is an ultra‑rare soft tissue sarcoma. Current standard therapy with PD‑1/PD‑L1 inhibitors achieves limited response rates (<40%). Lymphocyte‑activation gene 3 (LAG‑3) is co‑expressed with PD‑1 on exhausted T cells, and dual blockade has shown synergy in some solid tumors but remains unexplored in sarcoma. This trial evaluated the efficacy of IBI110 (anti‑LAG‑3) plus sintilimab (anti‑PD‑1) in advanced ASPS. This open‑label, phase II study enrolled 28 patients from July 2022 to September 2023 (median follow‑up 33.6 months). Both drugs were given intravenously at 200 mg every 3 weeks. The primary endpoint was overall response rate (ORR) by RECIST v1.1. Among 28 patients, 8 (28.6%) were resistant to prior immune checkpoint inhibitors (ICIs) and 20 (71.4%) were ICI‑naïve. The overall ORR was 51.8% (14/27 evaluable), including 4 complete responses and 10 partial responses. During a median follow-up of 33.6 months, the median PFS and OS were not reached in the whole population. In ICI‑naïve patients, ORR was 60% with median PFS/OS not reached; in ICI‑resistant patients, ORR was 25% with median PFS of 14.9 months and median OS of 25.4 months. Median time to response was 3.3 months; median DoR was not reached. Grade 3-4 treatment‑related adverse events occurred in 9 patients (32.1%), with no treatment‑related deaths. Exploratory analysis showed that responders had significantly higher baseline LAG‑3⁺ cell density in tumor specimens. Dual LAG‑3/PD‑1 blockade demonstrated promising and durable antitumor activity with manageable safety in both ICI‑naïve and ICI‑resistant advanced ASPS, warranting further investigation.
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2026-07-23 | Intratumoral TIGIT blockade augments antitumor responses and bypasses increased functionality of peripheral TIGIT+ NK cells in mouse and human models of bone and soft tissue sarcoma.
TIGIT (T cell immunoreceptor with Ig and ITIM domains) has emerged as a key exhaustion marker of intratumoral natural killer (NK) cells, but results from clinical trials with TIGIT blockade have been largely negative. Recent data have suggested that a subset of TIGIT-expressing NK cells can show increased functionality. We hypothesized that there are differences in function between peripheral and intratumoral TIGIT-expressing NK cells in patients with sarcoma and preclinical sarcoma models, which undermine the efficacy of systemic TIGIT blockade. We sought to investigate differences in TIGIT+ NK cells using systemic versus intratumoral TIGIT-blocking strategies. Peripheral and intratumoral NK cells were analyzed from human patients and mice with osteosarcoma (OSA) and soft tissue sarcoma (STS). NK phenotype and function were evaluated using flow cytometry, immunohistochemistry, live-cell imaging, and RNA sequencing. Mouse antimouse-IgG1 TIGIT blockade was delivered systemically or intratumorally in flank models of OSA (K7M2) and STS (MCA-205). Clinical and genomic data were evaluated using Caris CODEai. Expression of the TIGIT ligand CD155 on myeloid and tumor cells was evaluated as a marker of TIGIT function. Using multiple readouts, TIGIT+ NK cells from the spleen of tumor-bearing mice or peripheral blood of patients with STS and OSA showed increased functionality compared with TIGIT- NK, while TIGIT+ NK cells from the sarcoma tumor microenvironment (TME) of mice and humans were dysfunctional, with upregulated senescence and inhibitory gene pathways. Systemic TIGIT blockade reinvigorated intratumoral NK cell function but inhibited peripheral NK cells, while intratumoral administration of TIGIT blockade significantly delayed tumor growth and prolonged survival with partial reversal of NK dysfunction in the TME. Clinical and genomic data demonstrated that more NK cell infiltration in human STS was prognostic of improved overall survival only when intratumoral CD155 expression was low, indicating that elevated CD155 expression is correlated with greater NK cell dysfunction. We identified a cross-species role of TIGIT expression dependent on location, where peripheral TIGIT+ NK cells showed evidence of enhanced functionality, while intratumoral TIGIT+ NK cells were dysfunctional. These differences impacted antitumor effects of TIGIT blockade, suggesting that intratumoral delivery of TIGIT blockade may be a novel translational strategy in high-risk bone and soft tissue sarcomas.
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2026-07-21 | Immunotherapy in Soft Tissue Sarcomas—An Ongoing Quest
Soft tissue sarcomas (STSs) are rare and heterogeneous mesenchymal malignancies characterized by diverse molecular profiles and immune landscapes. Although immunotherapy has revolutionized the treatment of specific solid tumors, its efficacy in STSs remains limited and variable across histotypes. This review explores the panorama of biomarkers of immunotherapy sensitiveness in STSs, with particular emphasis on tumor-intrinsic features and on tumor microenvironment (TME) signatures. Current evidence highlights low tumor mutational burden, rare microsatellite instability, heterogeneous antigen expression, and epigenetic suppression of antigen presentation as hallmarks of the immune resistance that is characteristic of many STSs. However, growing evidence underlines TME composition as a major determinant of response to different types of immunotherapy. Indeed, the presence of B-cell-rich tertiary lymphoid structures and certain traits of adaptive immune responses are provenly associated with enhanced sensitivity to immunotherapy and enhanced outcomes. We further discuss emerging strategies aimed at enhancing STS immunogenicity, either by increasing intrinsic tumor immunogenicity or remodeling TME composition and functional profile. Collectively, the available data support a paradigm shift from a sarcoma cell-centered approach toward a multi-compartment TME-including strategy, providing a framework for the development of more effective and personalized immunotherapeutic strategies in STS.
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other
2026-08-25 | Head and Neck Rhabdomyosarcoma in Children: An Otolaryngological Perspective on Diagnostic and Therapeutic Approaches.
Head and neck rhabdomyosarcoma (HNRMS) is the most common soft-tissue sarcoma in children, with approximately 30-40% of cases arising in the head and neck region. Due to its anatomical complexity, histopathological diversity, and molecular heterogeneity, HNRMS remains a major diagnostic and therapeutic challenge in pediatric otolaryngology. This review aims to summarize current evidence regarding the epidemiology, clinical presentation, diagnostic strategies, contemporary treatment modalities, and long-term complications associated with pediatric HNRMS. Recent advances in molecular pathology have significantly improved risk stratification in rhabdomyosarcoma, particularly through the identification of FOXO1 fusion status as a key prognostic marker. Modern imaging techniques, especially magnetic resonance imaging and PET-based assessment, have enhanced diagnostic precision and evaluation of local tumor extension. Contemporary multimodal treatment protocols combining chemotherapy, conservative surgery, and proton beam radiotherapy have improved survival outcomes while reducing treatment-related morbidity. Furthermore, growing attention has been directed toward survivorship issues, including craniofacial deformities, endocrine dysfunction, hearing impairment, and secondary malignancies. The prognosis of pediatric HNRMS depends strongly on tumor location, histological subtype, and molecular characteristics. Orbital tumors are associated with favorable outcomes, whereas parameningeal lesions continue to pose substantial therapeutic difficulties because of delayed diagnosis and proximity to critical anatomical structures. Early recognition, accurate histopathological and molecular diagnosis, and individualized multidisciplinary treatment are essential to optimize survival and minimize long-term complications. Ongoing developments in targeted therapy and proton radiotherapy may further improve both oncological outcomes and quality of life in affected children. This review is important because it integrates current molecular, diagnostic, and therapeutic advances in pediatric HNRMS from an otolaryngological perspective, highlighting both survival outcomes and long-term quality-of-life considerations. Moreover, it emphasizes the need for early multidisciplinary management in anatomically complex head and neck tumors, which remains crucial for improving prognosis and reducing treatment-related morbidity.
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2026-07-12 | Outcomes of Talimogene Laherparepvec in Soft Tissue Sarcoma.
Talimogene laherparepvec (T-VEC), an intralesional therapy designed to elicit an immunogenic anti-tumor response, has a favorable safety profile in phase II trial and may be an effective second-line therapeutic in sarcoma; however, there is a paucity of data on its therapeutic efficacy. We present a case series of patients who received T-VEC for sarcoma at a high-volume sarcoma center. A total of four patients who had prior progression of disease on immune checkpoint inhibitors (ICI) received a median of 9.5 (range, 4-15) doses of T-VEC over 26.5 (range, 10-49) weeks with a median progression free-survival of 9 weeks (range, 9-10). Only one patient experienced toxicity, which presented as mild flu-like symptoms. This case series of patients receiving T-VEC for sarcoma adds to the literature of intralesional therapies for this rare disease. Our experience suggests that T-VEC may be administered safely and may provide local tumor control in select patients with sarcoma who have failed prior therapy with ICI.
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2026-05-27 | First-in-human dose escalation trial of an engineered salmonella delivering L-methioninase in advanced bone and soft tissue sarcomas.
11530 Background: Advanced bone and soft-tissue sarcomas have limited treatment options. Tumor-selective methionine dependency is a known metabolic vulnerability. SGN1 is designed to deplete methionine locally within tumors via intratumoral colonization of an attenuated Salmonella vector expressing L-methioninase. Preclinical studies have demonstrated safety and targeted antitumor activity. Here, we report the results from the escalation and expansion phases of the Phase I study in patients (pts) with advanced bone and soft-tissue sarcomas. Methods: The Phase I study includes a dose-escalation phase where pts received intravenous (IV) (2.0×10⁸ to 4.0×10⁸ CFU) or intra-arterial (IA) infusion (2.0×10⁸ to 6.0×10⁸ CFU) once a week (QW) in 28-day cycles, followed by an expansion phase with the putative recommended Phase 2 dose (RP2D) (2.0×10⁸ CFU for IV or 6.0×10⁸ CFU for IA QW) in 6 cohorts, including pts with recurrent either bone or soft tissue sarcoma after at least 2 lines of chemo therapies. SGN1 was administered in combination with physician's choice systemic therapy. Administration of SGN1 was via one of three routes: IV, IA, or a combined IV/IA regimen. Efficacy was assessed by RECIST version 1.1. Results: At the cut-off of Aug 19, 2024, 25 pts with advanced bone and soft-tissue sarcomas were enrolled in the escalation and expansion phases (median follow-up of 5.6 months; range, 0.5-18.2), including pts with bone sarcoma (n=10) and soft tissue sarcoma (n=15). Treatment was administered via IV (n=13), IA (n=8), or a combined IV/IA (n=4) route. The disease control rate (DCR) was 76.0% (95% CI: 56.5, 93.0) in all, 70.0% (95% CI: 34.8, 93.3) in bone sarcoma, 80.0% (95% CI: 52.0, 95.6) in soft tissue sarcoma pts, and 69.2% (95% CI: 38.5, 90.9) in IV, 75.0% (95% CI: 34.8, 93.3) in IA, 100% in combined IV/IA route. Quantitative PCR analysis confirmed significant intra-tumoral colonization by SGN1 post-treatment. The median progression-free survival (mPFS) was 11.5 months (95% CI: 11.1, NE) in all, 11.1 months (95% CI: 1.1, NE) in bone sarcoma, not reached (NR) (95% CI: 3.2, NE) in soft tissue sarcoma pts, and NR (95% CI: 2.7, NE) in IV, 11.5 months (95% CI: 1.3, NE) in IA, NR (95% CI: 11.1, NE) in combined IV/IA route. Complete tumor necrosis was observed in at least two soft tissue sarcoma patients. In all pts, the most frequent treatment-related adverse events (TRAEs) were pyrexia (32.0%) and elevation of blood LDH increased (20.0%). No TRAEs leading to temporary drug discontinuation, no serious TRAEs resulting in withdrawal from the study, and no treatment-related deaths occurred. Conclusions: SGN1 exhibits a manageable safety profile, and showed encouraging clinical benefit in advanced bone and soft-tissue sarcoma, as evidenced by mPFS and DCR. The promising data from this phase I study supports further testing of SGN1 in Phase II studies. Clinical trial information: ChiCTR2400085361.
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2026-04-10 | Integrative Oncology Approach in Advanced Myxofibrosarcoma: A Case Report of Prolonged Survival with High-Dose Vitamin C and Viscum album.
Myxofibrosarcoma (MFS) is a rare and aggressive soft tissue sarcoma with high recurrence and metastasis rates. The prognosis in advanced metastatic disease is poor, with median survival time ranging from 12 to 24 months despite multimodal therapy. Integrative oncology approaches, such as high-dose vitamin C and Viscum album, are increasingly explored as adjuncts in both curative and palliative cancer care. We present the case of a 59-year-old male with high-grade unresectable MFS of the right buttock and spinal metastases. Standard palliative treatments (systemic chemo- and radiotherapy, followed by targeted and immunotherapy) were combined with high-dose intravenous vitamin C and V. album extracts given intravenously, subcutaneously, and intratumorally. Despite the progression of the disease and COVID-19 comorbidity, the patient survived for 48 months, exceeding conventional survival estimates. This case suggests that integrative oncology combining systemic anticancer therapy with high-dose vitamin C and V. album extracts may enhance tolerance and extend survival in advanced MFS. Further prospective studies are warranted to corroborate the value of complementary therapy in sarcoma management.
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2026-04-06 | Lenvatinib in Combination with PD-1 Blockades as Re-Challenging Treatment for Patients with Metastatic Soft Tissue Sarcoma Following TKI Treatment Failure: A Retrospective Study.
Previous research has demonstrated the effectiveness of lenvatinib and programmed death-1 (PD-1) blockades in the treatment of sarcoma. However, there is limited information regarding the efficacy and safety of combining lenvatinib with PD-1 blockades as a re-challenge therapy in patients with metastatic soft tissue sarcoma (STS) following prior treatment failure with tyrosine kinase inhibitors (TKIs). Between October 2019 and September 2024, 28 patients with metastatic STS who received rechallenge treatment with lenvatinib in combination with PD-1 blockades following progression on prior TKI treatment were included in this retrospective analysis. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS), and safety. Of the 28 patients, ORR and CBR were 0 and 64.3%, respectively. The median duration of follow-up was 26 months (range, 13.2-38.8). The median PFS was 4.8 months (95% CI: 2.7-6.9), while the median OS was 23 months (95% CI: 16.5-29.5). Approximately 96.4% of patients experienced adverse events of grade 1 or higher. Grade 3 adverse events were reported in 5 patients, accounting for 17.9%. Our findings indicate that patients with metastatic STS may potentially benefit from the combination of lenvatinib and PD-1 blockades following the failure of prior TKI therapy. The combination of lenvatinib and PD-1 blockade therapy showed encouraging survival results in patients with metastatic STS, with an acceptable and manageable safety profile.
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