Current Landscape of Immunotherapy for Advanced Sarcoma
Abstract
:Simple Summary
Abstract
1. Introduction
2. Immunogenicity of Sarcoma: Anti-Tumor Response and Biomarkers
2.1. Innate Immunity and Release of Neoantigens
2.2. Antigenic Presentation and Activation of T Cells
2.3. Tumor Infiltration of Activated Lymphocytes
2.4. Immune-Suppressive Tumor Microenvironment
3. Immunotherapy for Sarcoma: Clinical Results
3.1. Immune Checkpoint Inhibitors (ICIs)
3.2. Combination of ICIs and Conventional Chemotherapy
3.3. Combination of ICIs and Tyrosine–Kinase Inhibitors
3.4. Combination of ICIs and Other Agents
3.5. Therapeutic Vaccines
3.6. Adoptive Cell Therapy
3.6.1. Engineered TCR
3.6.2. CAR T Cells
3.6.3. TIL Therapy
4. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Clinical Trial | Agent | Tumor | N | Age Range | Outcomes | Reported G3/G4 AEs |
---|---|---|---|---|---|---|
Immune checkpoint inhibitors (ICI) | ||||||
Maki et al. (phase I/II) [85] | Ipilimumab | Synovial sarcoma | 6 | 23–57 | ORR 0% mPFS 1.5 m mOS 8.8 m | Nausea (50%), diarrhea (33.3%), lymphopenia (33.3%), hyperbilirubinemia (16.7%), thrombopenia (16.7%) |
Merchant et al. (phase I) [86] | Ipilimumab | Pediatric sarcoma | 17 | 2–17 | ORR 0%; DCR 17.6% (3 SD) mPFS/mOS: NA | Diarrhea (9%), AST/ALT increase (6%), endocrinopathies (3%), other irAEs (9%) |
Ben-Ami et al. (phase II) [87] | Nivolumab | Uterine leiomyo-sarcoma | 12 | 29–73 | ORR 0% mPFS 1.8 m; mOS NA | Lipase/amylase increase (8.3%), fatigue (8.3%), abdominal pain (8.3%) |
Tawbi et al. (phase II) (SARC028) [54] | Pembrolizumab | BS cohort (22 OST, 13 ES, 5 CS) | 40 | 16–70 | mPFS 8 w; mOS 52 w OST: ORR 5%; DCR 32% (1 PR, 6 SD) ES: ORR 0%; DCR 15% (2 SD) CS: ORR 20%; DCR 40% (1 PR, 1 SD) | Interstitial nephritis (2%), infectious pneumonia (2%), bone pain (2%), pleural effusion (2%), hypoxia (2%) |
STS cohort (10 LMS, 10 LPS, 10 SS, 10 UPS) | 40 | 18–81 | mPFS 18 w; mOS 49 w LMS: ORR 0%; DCR 60% (6 SD) / LPS: ORR 20%; DCR 60% (2 PR, 4 SD)/SS: ORR 10%; DCR 30% (1 PR, 2 SD)/UPS: ORR 40%; DCR 70% (1 CR, 3 PR, 3 SD) | Pulmonary embolism (2%), adrenal insufficiency (2%), pneumonitis (2%) | ||
Blay et al. (phase II) (AcSé) [88] | Pembro-lizumab | Advanced rare sarcoma | 98 | >18 (NA) | ORR 15.3%; DCR 49% (1 CR, 14 PR, 33 SD); mDR 8.2 m; mPFS 2.8 m; mOS 19.7 m | NA |
Delyon et al. (phase II) [89] | Pembrolizumab | Classic/ endemic KS | 17 | NA | ORR 70.1%; DCR 88% (1 CR, 10 PR, 4 SD) | Reversible acute cardiac decompensation (6%) |
D’Angelo et al. (phase II) (Alliance A091401) [90] | Nivo/ipi vs. ipi | Advanced sarcoma (BS and STS) | 85 | 21–81 | ORR 16% vs. 5%; mDR 6.2 mmPFS 4.1 m vs. 1.7 m mOS 14.3 m vs. 10.7 m | Pain (7% vs. 5%), thrombopenia (0% vs. 2%), pulmonary edema (2% vs. 0%), respiratory failure (5% vs. 5%), skin infection (2% vs. 0%), intestinal obstruction (2% vs. 2%), spinal fracture (0% vs. 2%), thrombo-embolic event (2% vs. 2%), urinary tract infection (7% vs. 2%), urinary obstruction (0% vs. 5%), fistula (2% vs. 0%), vomiting (0% vs. 2%) |
Somaiah et al. (phase II) [91] | Durva-lumab + tremeli-mumab | Advanced sarcoma (BS and STS) | 57 | 35–59 | mPFS 2.8 m; mOS: 21.6 m; PFS at 12 m (all): 28%; PFS at 12 m (ASPS): 80% ORR (irRECIST) (all): 12%; ORR (irRECIST) (ASPS): 40% | Lipase increase (7%), pneumonitis (6%), colitis (6%), myocarditis (4%), autoimmune disorders (4%), endocrine disorders (2%), diarrhea (2%), gastrointestinal disorders (2%), lung infection (2%), ALP increase (2%), amylase increase (2%), myositis (2%) |
Immune checkpoint inhibitors (ICI) + conventional CT | ||||||
Livingston et al. (phase II) [92] | Pembro + doxorubicin | Anthracy-cline naïve STS | 30 | NA | ORR 36.7%; DCR 80% (1 CR, 10 PR, 13 SD) mPFS 5.7 m; mOS 17 m PFS at 6 m: 44% PFS at 12 m: 62% | Neutropenia (36.7%), anemia (26.7%), febrile neutropenia (16.7%), arthralgia (13.3%), lymphopenia (13.3%), nausea (13.3%), fatigue (10.0%), hyponatremia (10.0%), vomiting (10.0%), lung infection (10.0%), muscle weakness (10.0%) |
Pollack et al. (phase I/II) [93] | Pembro + doxorubicin | Anthracy-cline naïve STS | 37 | 25–80 | ORR 19%; DCR 78% (7 PR, 22 SD); mPFS 8.1 m; mOS 27.6 m PFS at 12 m: 27% | Neutropenia (27.0%), oral mucositis (8.1%), anemia (5.4%), febrile neutropenia (5.4%), lymphopenia (5.4%), ejection fraction decrease (5.4%), anorexia (5.4%), diarrhea (2.7%), hypothyroidism (2.7%), nausea (2.7%), weight loss (2.7%) |
Toulmonde et al. (phase II) [79] | Pembro + mCP | Advanced STS | 50 | 18–84 | ORR 2%; DCR 34% (1 PR, 16 SD); PFS at 6 m: 0% (LMS, UPS), 11.1% (GIST), 14.3% (others) | Anemia (7.0%), fatigue (3.5%), lymphopenia (3.5%), oral mucositis (3.5%) |
Gordon et al. (phase I/II) (SAINT) [94] | Ipi/nivo + trabectedin (trab) | Advanced STS | 79 | NA | ORR 25.3%; DCR 87.3% (6 CR *, 14 PR, 49 SD) mPFS 6.7 m; mOS 24.6 m * One surgical CR | ALT increase (25%), fatigue (8.7%), AST increase (8.7%), decreased neutrophil count (5.4%), anemia (4.6%) |
Pink et al. (phase II) (NITRA-SARC) [95] | Nivo + trab | Advanced STS | 25 | NA | ORR 8%; DCR 48% (2 PR, 10 SD); mPFS 4 m | Leukopenia (47.2%), neutropenia (41.7%), thrombopenia (33.3%), increased ALT (30.6%), anemia (27.8%) |
Smrke et al. (phase I) [96] | Pembro + gemcitabine | LMS, UPS | 13 | 40–67 | LMS (11): DCR 73% (8 SD) UPS (2): DCR 100% (2 PR) | NA |
Nathenson et al. (phase II) [97] | Pembro + eribulin | LMS cohort | 19 | 48–80 | ORR 5.3%; DCR 26.3% (1 PR, 5 SD); mPFS 11 w | Most commonly, neutropenia, anemia, weight loss, diarrhea, lipase/ALP increase |
Wagner et al. (phase I/II) [98] | Avelumab + trab | LMS, LPS | 23 | NA | ORR 13%; DCR 56% (3 PR, 10 SD); mPFS 8.3 m | NA |
Toulmonde et al. (phase Ib) [99] | Durva + trab | Advanced STS cohort | 16 | NA | ORR 7%; PFS at 6 m: 28.6% | NA |
Immune checkpoint inhibitors (ICI) + tyrosine–kinase inhibitors/antiangiogenic drugs | ||||||
Martin-Broto et al. (phase I/II) (IMMU-NOSARC) | Nivo + suni-tinib | BS cohort (17 OST, 14 CS, 8 ES, 1 UPS) [100] | 40 | 21–74 | ORR 5%; DCR 60% (1 CR, 1 PR, 22 SD) mPFS 3.7 m; mOS 14.2 m | Neutropenia (10%), anemia (10%), AST/ALT increase (7.5%), fatigue (5%), oral mucositis (5%), hemorrhage (2.5%), dysphagia (2.5%), thrombopenia (2.5%), malaise (2.5%), thromboembolism (2.5%), pneumonitis (2.5%) |
STS cohort [101] | 43 | 19–77 | ORR 9.3%; DCR 69.3% (1 CR, 3 PR, 26 SD); mPFS 5.9 m; mOS not reached (follow up 6.1 m) | AST increase (11.8%), ALT increase (9.8%), neutropenia (9.8%), fatigue (5.9%), thrombopenia (3.9%), diarrhea (3.9%), renal failure (3.9%) | ||
Wilky et al. (phase II) [102] | Pembro + axitinib | 12 ASPS, 6 LMS, 5 UPS, 2 DDLPS, 8 others (2 BS) | 33 | 27–62 | ORR 25%; DCR 53.1% (8 PR, 9 SD); mPFS (all): 4.7 m; mOS (all): 18.7 m; mPFS (ASPS): 12.4 m; mPFS (others): 3.0 m. | Hypertension (15%), autoimmune toxic effects (15%), nausea (6%), ALT/AST increase (3%), oral mucositis (3%), diarrhea (3%), abdominal pain (3%), hemoptysis (3%), hyperlipidemia (3%) |
Xie et al. (phase II) [103] | Camre-lizumab + apatinib | CT-refractory OST | 43 | 11–43 | ORR 20.1% (9 PR) mDR 6.2 m mPFS 6.2 m; mOS 11.3 m | Wound dehiscence (14%), ALP increase (9.3%), AST/ALT increase (9.3%), blood bilirubin increase (9.3%), hypertriglyceridemia (7.0%), anorexia (7.0%), weight loss (7.0%), pneumothorax (7.0%), platelet count decrease (4.7%), diarrhea (4.7%), PPS (4.7%), limb pain (4.7%), leukopenia (4.7%), rash (4.7%), oral mucositis (4.7%), hypertension (4.7%), toothache (4.7%), nausea (4.7%), non-cardiac chest pain (4.7%), hypothyroidism (2.3%), LDH increase (2.3%), proteinuria (2.3%), cough (2.3%), hemorrhage (2.3%), fatigue (2.3%), peripheral neuroinflammation (2.3%) |
Kim et al. (phase II) [104] | Durva + pazopanib | Advanced STS | 47 | NA | ORR 28.3% (1 CR, 12 PR) mPFS 8.6 m | NA |
Cousin et al. (phase II) [105] | Avelumab + regorafenib | Advanced STS | 43 | NA | ORR 9.3%; DCR 48.8% (4 PR, 17 SD); mDR 7.8 m; mPFS 1.8 m; mOS 15.1 m | PPS (12.2%), fatigue (10.2%), diarrhea (10.2%) |
Kelly et al. (phase II) [106] | Pembro + epacadostat | Advanced STS | 29 | 24–78 | ORR 3%; DCR 48% (1 PR, 13 SD); mPFS 8 w; PFS at 24 w 27.9%; mOS NA | AST increase (10%), ALT increase (3%), anemia (3%), hypophosphatemia (3%), lipase increase (3%) |
Schöffski et al. (phase Ib) [107] | Pembro + olaratumab | Advanced STS | 28 | NA | ORR 21.4%; DCR 53.5%; mDR 16.2 m; mPFS 2.7 m; mOS 14.8 m | NA |
Immune checkpoint inhibitors (ICI) + other agents | ||||||
Kelly et al. (phase II) [108] | Pembro + T-VEC | Advanced STS | 20 | 24–90 | ORR 35%; DCR 70% (7 PR, 7 SD); mPFS 17.1 w | Pneumonitis (5%), fever (5%), anemia (5%) |
Chawla et al. (phase II) [109] | Trabectedin + nivo + T-VEC | Advanced sarcoma | 36 | NA | ORR 8.3%; DCR 86.1% (3 PR, 27 SD); mPFS 5.5 m; mOS 9.0 m; OS at 6 m 73% | Anemia (33.3%), ALT increase (22.2%), fatigue (11.1%), thrombopenia (11.1%), neutropenia (11.1%) |
D’Angelo et al. (phase I) [110] | Nivo + bempegal-desleukin | Advanced STS | 84 | 13–80 | ORR 10.4% (PR: 3/8 in AS, 1/4 in ASPS, 2/10 in UPS, 1/10 in LMS, 1/10 in CS); mDR 9.3 m | Anemia (10%), lipase increase (10%), amylase increase (7%), hypertension (7%), pain (8%), thromboembolic events (5%) |
Somaiah et al. (phase I) [111] | LV305 | STS (13 SS, 6 MRCL) | 24 | 25–72 | ORR 4.2%; DCR 62.5% (1 PR, 14 SD); mPFS 4.6 m; mOS 33 m | No G3/G4 adverse events |
Rosenbaum et al. (phase I) [112] | Avelumab + DCC-3014 | Advanced STS (7 LMS) | 13 | 32–71 | DCR 23% (3 SD); decreased circulating MDSCs in 5/7 patients (median 26.9%) | ALT/AST increase (31%), CK increase (23%), amylase/lipase increase (16%), anemia (8%), hypertension (8%) |
Chawla et al. (phase I) [113] | Avelumab + SNK01 | Advanced sarcoma | 15 | 20–75 | ORR 13.3%; DCR 33.3% (2 PR, 3 SD); mPFS 11.1 w | No G3/G3 adverse events related to SNK01 |
Therapeutic vaccines | ||||||
Kawaguchi et al. (phase I) [114] | SYT-SSX vaccine | SS | 21 | 21–69 | DCR 50% (6 SD out of 12 assessable patients) | NA |
Takahashi et al. (phase II) [115] | Peptide vaccine | Advanced sarcoma | 20 | 23–75 | DCR 30% (6 SD); mOS 9.6 m | NA |
Pipia et al. (phase I/II) [116] | DC vaccine | Advanced STS | 74 | NA | Cohort 1 (adj/maint): mOS 24.4 m; cohort 2 (mono): mOS 14.2 m | NA |
Chawla et al. (phase II) [117] | Atezo +/− CMB305 | SS, MLS | 89 | NA | mPFS 2.6 m vs. 1.6 m mOS 18 m in both groups | 4 G3/G4 events in each group (not specified) |
Adoptive cell therapy | ||||||
Robbins et al. (phase II) [118] | NY-ESO1 TCR | SS | 18 | 19–65 | ORR 61% (1 CR, 10 PR); PFS 3–47 m; estimated 3-y OS: 38% | No toxicities attributed to the transferred cells * |
D’Angelo et al. (phase II) [119] | NY-ESO1 TCR | SS | 45 | NA | ORR 33% (1 CR, 14 PR); mPFS 8.6–22.4 w | No toxicities attributed to the transferred cells * |
Van Tine et al. (phase I) [120] | MAGE-A4 TCR | SS | 8 | NA | ORR 50%; DCR 87.5% (4 PR, 3 SD) | No toxicities attributed to the transferred cells * |
D’Angelo et al. (phase II) [121] | MAGE-A4 TCR | STS (23 SS,2 MLS) | 25 | 24–73 | ORR 40%; DCR 84% (2 CR, 8 PR, 11 SD) | CRS (5%) * |
Ahmed et al. (phase I/II) [122] | Her2-CAR T cells | Advanced sarcoma (16 OST, 3 others) | 19 | 7–29 | DCR 23.5% (4 SD); mOS 10.3 m | Anemia (5.3%), muscle weakness (5.3%), back pain (5.3%) |
Navai et al. (phase I) [123] | Her2-CAR T cells | Advanced sarcoma (5 OST, 5 others) | 10 | 4–54 | ORR 20%; DCR 50% (2 CR, 3 SD) (CR in 1 OST and 1 RMS) | No toxicities attributed to the transferred cells * |
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Albarrán, V.; Villamayor, M.L.; Pozas, J.; Chamorro, J.; Rosero, D.I.; San Román, M.; Guerrero, P.; Pérez de Aguado, P.; Calvo, J.C.; García de Quevedo, C.; et al. Current Landscape of Immunotherapy for Advanced Sarcoma. Cancers 2023, 15, 2287. https://doi.org/10.3390/cancers15082287
Albarrán V, Villamayor ML, Pozas J, Chamorro J, Rosero DI, San Román M, Guerrero P, Pérez de Aguado P, Calvo JC, García de Quevedo C, et al. Current Landscape of Immunotherapy for Advanced Sarcoma. Cancers. 2023; 15(8):2287. https://doi.org/10.3390/cancers15082287
Chicago/Turabian StyleAlbarrán, Víctor, María Luisa Villamayor, Javier Pozas, Jesús Chamorro, Diana Isabel Rosero, María San Román, Patricia Guerrero, Patricia Pérez de Aguado, Juan Carlos Calvo, Coral García de Quevedo, and et al. 2023. "Current Landscape of Immunotherapy for Advanced Sarcoma" Cancers 15, no. 8: 2287. https://doi.org/10.3390/cancers15082287
APA StyleAlbarrán, V., Villamayor, M. L., Pozas, J., Chamorro, J., Rosero, D. I., San Román, M., Guerrero, P., Pérez de Aguado, P., Calvo, J. C., García de Quevedo, C., González, C., & Vaz, M. Á. (2023). Current Landscape of Immunotherapy for Advanced Sarcoma. Cancers, 15(8), 2287. https://doi.org/10.3390/cancers15082287