Immunotherapy in Sarcoma

A decade of immune-checkpoint inhibitors in cancer therapy.

Nat Commun. 11: 3801Maki R.G. Jungbluth A.A. Gnjatic S. et al.

A Pilot Study of Anti-CTLA4 Antibody Ipilimumab in Patients with Synovial Sarcoma.

Sarcoma. 2013: 168145Tawbi H.A. Burgess M. Bolejack V. et al.

Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial.

Lancet Oncol. 18: 1493-1501D'Angelo S.P. Mahoney M.R. Van Tine B.A. et al.

Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): two open-label, non-comparative, randomised, phase 2 trials.

Lancet Oncol. 19: 416-426Burgess M.A. Bolejack V. Schuetze S. et al.

Clinical activity of pembrolizumab (P) in undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated/pleomorphic liposarcoma (LPS): Final results of SARC028 expansion cohorts.

Jco. 37: 11015Chen J.L. Mahoney M.R. George S. et al.

A multicenter phase II study of nivolumab +/- ipilimumab for patients with metastatic sarcoma (Alliance A091401): Results of expansion cohorts.

Jco. 38: 11511Florou V. Rosenberg A.E. Wieder E. et al.

Angiosarcoma patients treated with immune checkpoint inhibitors: a case series of seven patients from a single institution.

J Immunother Cancer. 7: 213Momen S. Fassihi H. Davies H.R. et al.

Dramatic response of metastatic cutaneous angiosarcoma to an immune checkpoint inhibitor in a patient with xeroderma pigmentosum: whole-genome sequencing aids treatment decision in end-stage disease.

Cold Spring Harb Mol Case Stud. 5: a004408Sindhu S. Gimber L.H. Cranmer L. et al.

Angiosarcoma treated successfully with anti-PD-1 therapy - a case report.

J Immunother Cancer. 5: 58Painter C.A. Jain E. Tomson B.N. et al.

The Angiosarcoma Project: enabling genomic and clinical discoveries in a rare cancer through patient-partnered research.

Nat Med. 26: 181-187Wagner M.J. Othus M. Patel S.P. et al.

Multicenter phase II trial (SWOG S1609, cohort 51) of ipilimumab and nivolumab in metastatic or unresectable angiosarcoma: a substudy of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART).

J Immunother Cancer. 9: e002990Toulmonde M. Penel N. Adam J. et al.

Use of PD-1 Targeting, Macrophage Infiltration, and IDO Pathway Activation in Sarcomas: A Phase 2 Clinical Trial.

JAMA Oncol. 4: 93-97Le Cesne A. Marec-Berard P. Blay J.Y. et al.

Programmed cell death 1 (PD-1) targeting in patients with advanced osteosarcomas: results from the PEMBROSARC study.

Eur J Cancer. 119: 151-157Wilky B.A. Trucco M.M. Subhawong T.K. et al.

Axitinib plus pembrolizumab in patients with advanced sarcomas including alveolar soft part sarcoma: a single-arm, phase 2 trial.

Lancet Oncol. 20: 837-848Martin-Broto J. Hindi N. Grignani G. et al.

Nivolumab and sunitinib combination in advanced soft tissue sarcomas: a multicenter, single-arm, phase Ib/II trial.

J Immunother Cancer. 8: e001561Xie L. Xu J. Sun X. et al.

Apatinib plus camrelizumab (anti-PD1 therapy, SHR-1210) for advanced osteosarcoma (APFAO) progressing after chemotherapy: a single-arm, open-label, phase 2 trial.

J Immunother Cancer. 8Petitprez F. de Reyniès A. Keung E.Z. et al.

B cells are associated with survival and immunotherapy response in sarcoma.

Nature. 577: 556-560Cytlak U.M. Dyer D.P. Honeychurch J. et al.

Immunomodulation by radiotherapy in tumour control and normal tissue toxicity.

Nat Rev Immunol. 22: 124-138Wang Y.J. Fletcher R. Yu J. et al.

Immunogenic effects of chemotherapy-induced tumor cell death.

Genes Dis. 5: 194-203Livingston M.B. Jagosky M.H. Robinson M.M. et al.

Phase II study of pembrolizumab in combination with doxorubicin in metastatic and unresectable soft tissue sarcoma.

Clin Cancer Res. 27: 6424-6431Pollack S.M. Redman M.W. Baker K.K. et al.

Assessment of Doxorubicin and Pembrolizumab in Patients With Advanced Anthracycline-Naive Sarcoma: A Phase 1/2 Nonrandomized Clinical Trial.

JAMA Oncol. 6: 1778-1782Zhang S. Kohli K. Black R.G. et al.

Systemic Interferon-γ Increases MHC Class I Expression and T-cell Infiltration in Cold Tumors: Results of a Phase 0 Clinical Trial.

Cancer Immunol Res. 7: 1237-1243

The role of PD-L1 expression as a predictive biomarker: an analysis of all US Food and Drug Administration (FDA) approvals of immune checkpoint inhibitors.

J Immunother Cancer. 7: 278Zheng C. You W. Wan P. et al.

Clinicopathological and prognostic significance of PD-L1 expression in sarcoma: A systematic review and meta-analysis.

Medicine (Baltimore). 97: e11004Italiano A. Bellera C. D'Angelo S.

PD1/PD-L1 targeting in advanced soft-tissue sarcomas: a pooled analysis of phase II trials.

J Hematol Oncol. 13: 55Zhu M.M.T. Shenasa E. Nielsen T.O.

Sarcomas: Immune biomarker expression and checkpoint inhibitor trials.

Cancer Treat Rev. 91: 102115Keung E.Z. Burgess M. Salazar R. et al.

Correlative Analyses of the SARC028 Trial Reveal an Association Between Sarcoma-Associated Immune Infiltrate and Response to Pembrolizumab.

Clin Cancer Res. 26: 1258-1266Italiano A. Bessede A. Bompas E. et al.

PD1 inhibition in soft-tissue sarcomas with tertiary lymphoid structures: A multicenter phase II trial.

Jco. 39: 11507

Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas.

Cell. 171 (): 950.e28Campbell B.B. Light N. Fabrizio D. et al.

Comprehensive Analysis of Hypermutation in Human Cancer.

Cell. 171 (): 1042.e10Doyle L.A. Nowak J.A. Nathenson M.J. et al.

Characteristics of mismatch repair deficiency in sarcomas.

Mod Pathol. 32: 977-987Campanella N.C. Penna V. Ribeiro G. et al.

Absence of Microsatellite Instability In Soft Tissue Sarcomas.

Pathobiology. 82: 36-42Dufresne A. Lesluyes T. Ménétrier-Caux C. et al.

Specific immune landscapes and immune checkpoint expressions in histotypes and molecular subtypes of sarcoma.

Oncoimmunology. 9: 1792036Hu C. Chen B. Huang Z. et al.

Comprehensive profiling of immune-related genes in soft tissue sarcoma patients.

J Transl Med. 18: 337Jungbluth A.A. Antonescu C.R. Busam K.J. et al.

Monophasic and biphasic synovial sarcomas abundantly express cancer/testis antigen NY-ESO-1 but not MAGE-A1 or CT7.

Int J Cancer. 94: 252-256Hemminger J.A. Ewart Toland A. Scharschmidt T.J. et al.

The cancer-testis antigen NY-ESO-1 is highly expressed in myxoid and round cell subset of liposarcomas.

Mod Pathol. 26: 282-288Garrido F. Aptsiauri N. Doorduijn E.M. et al.

The urgent need to recover MHC class I in cancers for effective immunotherapy.

Curr Opin Immunol. 39: 44-51D'Angelo S.P. Melchiori L. Merchant M.S. et al.

Antitumor Activity Associated with Prolonged Persistence of Adoptively Transferred NY-ESO-1 (c259)T Cells in Synovial Sarcoma.

Cancer Discov. 8: 944-957

Hong, D.S. Phase I dose escalation and expansion trial to assess the safety and efficacy of ADP-A2M4 SPEAR T cells in advanced solid tumors. 2020. ASCO Virtual Scientific Program: American Society of Clinical Oncology. J Clin Oncol, 38, no. 15_suppl. 2020. 102-102.

Rosenbaum E. Seier K. Bandlamudi C. et al.

HLA Genotyping in Synovial Sarcoma: Identifying HLA-A∗02 and Its Association with Clinical Outcome.

Clin Cancer Res. 26: 5448-5455Ramachandran I. Lowther D.E. Dryer-Minnerly R. et al.

Systemic and local immunity following adoptive transfer of NY-ESO-1 SPEAR T cells in synovial sarcoma.

J Immunother Cancer. 7: 276D'Angelo S.P. Noujaim J.C. Thistlethwaite F. et al.

IGNYTE-ESO: A master protocol to assess safety and activity of letetresgene autoleucel (lete-cel; GSK3377794) in HLA-A∗02+ patients with synovial sarcoma or myxoid/round cell liposarcoma (Substudies 1 and 2).

Jco. 39: TPS11582Ishihara M. Kageyama S. Miyahara Y. et al.

MAGE-A4, NY-ESO-1 and SAGE mRNA expression rates and co-expression relationships in solid tumours.

BMC Cancer. 20: 606Kakimoto T. Matsumine A. Kageyama S. et al.

Immunohistochemical expression and clinicopathological assessment of the cancer testis antigens NY-ESO-1 and MAGE-A4 in high-grade soft-tissue sarcoma.

Oncol Lett. 17: 3937-3943D'Angelo S.P. Van Tine B.A. Attia S. et al.

SPEARHEAD-1: A phase 2 trial of afamitresgene autoleucel (Formerly ADP-A2M4) in patients with advanced synovial sarcoma or myxoid/round cell liposarcoma.

Jco. 39: 11504June C.H. O'Connor R.S. Kawalekar O.U. et al.

CAR T cell immunotherapy for human cancer.

Science. 359: 1361-1365Brudno J.N. Kochenderfer J.N.

Toxicities of chimeric antigen receptor T cells: recognition and management.

Blood. 127: 3321-3330

The ErbB/HER family of protein-tyrosine kinases and cancer.

Pharmacol Res. 79: 34-74Ahmed N. Brawley V.S. Hegde M. et al.

Human Epidermal Growth Factor Receptor 2 (HER2) –Specific Chimeric Antigen Receptor–Modified T Cells for the Immunotherapy of HER2-Positive Sarcoma.

J Clin Oncol. 33: 1688-1696Navai S.A. Derenzo C. Joseph S. et al.

Abstract LB-147: Administration of HER2-CAR T cells after lymphodepletion safely improves T cell expansion and induces clinical responses in patients with advanced sarcomas.

Cancer Res. 79 ()Duan Z. Choy E. Harmon D. et al.

Insulin-like growth factor-I receptor tyrosine kinase inhibitor cyclolignan picropodophyllin inhibits proliferation and induces apoptosis in multidrug resistant osteosarcoma cell lines.

Mol Cancer Ther. 8: 2122-2130Tzanakakis G.N. Giatagana E.M. Berdiaki A. et al.

The Role of IGF/IGF-IR-Signaling and Extracellular Matrix Effectors in Bone Sarcoma Pathogenesis.

Cancers (Basel). 13Huang X. Park H. Greene J. et al.

IGF1R- and ROR1-Specific CAR T Cells as a Potential Therapy for High Risk Sarcomas.

PLoS One. 10: e0133152Wang Z. Zhao K. Hackert T. et al.

CD44/CD44v6 a Reliable Companion in Cancer-Initiating Cell Maintenance and Tumor Progression.

Front Cell Dev Biol. 6: 97Zhang Y. Ding C. Wang J. et al.

Prognostic significance of CD44V6 expression in osteosarcoma: a meta-analysis.

J Orthop Surg Res. 10: 187Leuci V. Casucci G.M. Grignani G. et al.

CD44v6 as innovative sarcoma target for CAR-redirected CIK cells.

Oncoimmunology. 7: e1423167Fernandez L. Valentin J. Zalacain M. et al.

Activated and expanded natural killer cells target osteosarcoma tumor initiating cells in an NKG2D-NKG2DL dependent manner.

Cancer Lett. 368: 54-63Lehner M. Götz G. Proff J. et al.

Redirecting T cells to Ewing's sarcoma family of tumors by a chimeric NKG2D receptor expressed by lentiviral transduction or mRNA transfection.

PLoS One. 7: e31210Fernandez L. Metais J.-Y. Escudero A. et al.

Memory T Cells Expressing an NKG2D-CAR Efficiently Target Osteosarcoma Cells.

Clin Cancer Res. 23: 5824-5835Rosenberg S.A. Yang J.C. Sherry R.M. et al.

Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy.

Clin Cancer Res. 17: 4550-4557Andersen R. Donia M. Ellebaek E. et al.

Long-Lasting Complete Responses in Patients with Metastatic Melanoma after Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes and an Attenuated IL2 Regimen.

Clin Cancer Res. 22: 3734-3745Besser M.J. Shapira-Frommer R. Itzhaki O. et al.

Adoptive transfer of tumor-infiltrating lymphocytes in patients with metastatic melanoma: intent-to-treat analysis and efficacy after failure to prior immunotherapies.

Clin Cancer Res. 19: 4792-4800Ben-Avi R. Farhi R. Ben-Nun A. et al.

Establishment of adoptive cell therapy with tumor infiltrating lymphocytes for non-small cell lung cancer patients.

Cancer Immunol Immunother. 67: 1221-1230Lee H.J. Kim Y.A. Sim C.K. et al.

Expansion of tumor-infiltrating lymphocytes and their potential for application as adoptive cell transfer therapy in human breast cancer.

Oncotarget. 8: 113345-113359Retèl V.P. Steuten L.M. Mewes J.C. et al.

Early Cost-Effectiveness Modeling for Tumor Infiltrating Lymphocytes (TIL) -Treatment Versus Ipilimumab in Metastatic Melanoma Patients.

Value Health. 17: A640Rosenberg S.A. Yannelli J.R. Yang J.C. et al.

Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2.

J Natl Cancer Inst. 86: 1159-1166Marabondo S. Kaufman H.L.

High-dose interleukin-2 (IL-2) for the treatment of melanoma: safety considerations and future directions.

Expert Opin Drug Saf. 16: 1347-1357

Toxicities Associated With Adoptive T-Cell Transfer for Cancer.

Cancer J. 21: 506-509Mullinax J.E. Hall M. Beatty M. et al.

Expanded Tumor-infiltrating Lymphocytes From Soft Tissue Sarcoma Have Tumor-specific Function.

J Immunother. 44: 63-70Guillerey C. Huntington N.D. Smyth M.J.

Targeting natural killer cells in cancer immunotherapy.

Nat Immunol. 17: 1025-1036Domagala J. Lachota M. Klopotowska M. et al.

The Tumor Microenvironment-A Metabolic Obstacle to NK Cells' Activity.

Cancers (Basel). 12Ljunggren H.G. Malmberg K.J.

Prospects for the use of NK cells in immunotherapy of human cancer.

Nat Rev Immunol. 7: 329-339Tonn T. Schwabe D. Klingemann H.G. et al.

Treatment of patients with advanced cancer with the natural killer cell line NK-92.

Cytotherapy. 15: 1563-1570Seliktar-Ofir S. Merhavi-Shoham E. Itzhaki O. et al.

Selection of Shared and Neoantigen-Reactive T Cells for Adoptive Cell Therapy Based on CD137 Separation.

Front Immunol. 8: 1211Inozume T. Hanada K. Wang Q.J. et al.

Selection of CD8+PD-1+ lymphocytes in fresh human melanomas enriches for tumor-reactive T cells.

J Immunother. 33: 956-964Riggan L. Shah S. O'Sullivan T.E.

Arrested development: suppression of NK cell function in the tumor microenvironment.

Clin Transl Immunol. 10: e1238Crowe N.Y. Smyth M.J. Godfrey D.I.

A critical role for natural killer T cells in immunosurveillance of methylcholanthrene-induced sarcomas.

J Exp Med. 196: 119-127Knochelmann H.M. Smith A.S. Dwyer C.J. et al.

CAR T Cells in Solid Tumors: Blueprints for Building Effective Therapies.

Front Immunol. 9: 1740Kelly C.M. Antonescu C.R. Bowler T. et al.

Objective Response Rate Among Patients With Locally Advanced or Metastatic Sarcoma Treated With Talimogene Laherparepvec in Combination With Pembrolizumab: A Phase 2 Clinical Trial.

JAMA Oncol. 6: 402-408

The potential of the CMB305 vaccine regimen to target NY-ESO-1 and improve outcomes for synovial sarcoma and myxoid/round cell liposarcoma patients.

Expert Rev Vaccin. 17: 107-114Somaiah N. Chawla S.P. Block M.S. et al.

A Phase 1b Study Evaluating the Safety, Tolerability, and Immunogenicity of CMB305, a Lentiviral-Based Prime-Boost Vaccine Regimen, in Patients with Locally Advanced, Relapsed, or Metastatic Cancer Expressing NY-ESO-1.

Oncoimmunology. 9: 1847846Chawla S.P. Van Tine B.A. Pollack S.M. et al.

Phase II Randomized Study of CMB305 and Atezolizumab Compared With Atezolizumab Alone in Soft-Tissue Sarcomas Expressing NY-ESO-1.

J Clin Oncol. : Jco2003452https://doi.org/10.1200/JCO.20.03452Dancsok A.R. Gao D. Lee A.F. et al.

Tumor-associated macrophages and macrophage-related immune checkpoint expression in sarcomas.

Oncoimmunology. 9: 1747340Chen L. Oke T. Siegel N. et al.

The Immunosuppressive Niche of Soft-Tissue Sarcomas is Sustained by Tumor-Associated Macrophages and Characterized by Intratumoral Tertiary Lymphoid Structures.

Clin Cancer Res. 26: 4018-4030

Chawla, S.P., et al. RESULTS FROM THE CHONDROSARCOMA PHASE 1 STUDY EXPANSION COHORT OF THE TETRAVALENT DEATH RECEPTOR 5 AGONIST INBRX-109. in Connective Tissue Oncology Society Annual Meeting. November 19, 2020.

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Kawai, A., et al., Efficacy and safety of nivolumab monotherapy in patietns with unresectable clear cell sarcoma and alveolar soft part sarcoma (OSCAR trial, NCCH1510): A multicenter, Phase 2 clinical trial., in Connective Tissue Oncology Society Annual Meeting. November 19, 2020.

Hindi N. Rosenbaum E. Jonczak E. et al.

Retrospective world-wide registry on the efficacy of immune checkpoint inhibitors in alveolar soft part sarcoma: Updated results from sixty patients.

Jco. 39: 11564Somaiah N. Conley A.P. Lin H.Y. et al.

A phase II multi-arm study of durvalumab and tremelimumab for advanced or metastatic sarcomas.

Jco. 38: 11509Naqash A.R. O'Sullivan Coyne G.H. Moore N. et al.

Phase II study of atezolizumab in advanced alveolar soft part sarcoma (ASPS).

Jco. 39: 11519Shi Y. Cai Q. Jiang Y. et al.

Activity and Safety of Geptanolimab (GB226) for Patients with Unresectable, Recurrent, or Metastatic Alveolar Soft Part Sarcoma: A Phase II, Single-arm Study.

Clin Cancer Res. 26: 6445-6452Yang J. Dong L. Yang S. et al.

Safety and clinical efficacy of toripalimab, a PD-1 mAb, in patients with advanced or recurrent malignancies in a phase I study.

Eur J Cancer. 130: 182-192D'Angelo S.P. Shoushtari A.N. Keohan M.L. et al.

Combined KIT and CTLA-4 Blockade in Patients with Refractory GIST and Other Advanced Sarcomas: A Phase Ib Study of Dasatinib plus Ipilimumab.

Clin Cancer Res. 23: 2972-2980Gordon E.M. Chua-Alcala V.S. Kim K. et al.

SAINT: Results of a phase 1/2 study of safety/efficacy using safe amounts of ipilimumab, nivolumab, and trabectedin as first-line treatment of advanced soft tissue sarcoma.

Jco. 37: 11016Palmerini E. Lopez-Pousa A. Grignani G. et al.

IMMUNOSARC: a collaborative Spanish (GEIS) and Italian (ISG) sarcoma groups phase I/II trial of sunitinib and nivolumab in advanced soft tissue and bone sarcoma: Results from the phase II part, bone sarcoma cohort.

Jco. 38: 11522

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