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Immunotherapeutic Strategies for Sarcoma

Jul 28, 2022 1:30:00 PM / by Champions Oncology

3-D rendering of human cancer cells

Sarcomas are a group of aggressive heterogeneous tumors for which more than 100 histological subtypes have been defined[1]. Sarcomas are found in a variety of solid tissues, including bone and gastrointestinal stromal cells. Current treatment options include radiotherapy, surgical resection, targeted therapies, and chemotherapy, but these treatments have had limited efficacy on intermediate to high grade tumors. Investigations into the molecular and cellular mechanisms that drive sarcomas have helped identify potential biomarkers that can serve as potential therapeutic targets. In addition, recent studies have also focused on the tumor microenvironment (TME) within sarcomas and the roles of different immune cell subsets creating an immunosuppressive microenvironment. These observations directly inform novel immunotherapeutic approaches that are being examined in preclinical and clinical studies.


Sarcoma TME and Immune Checkpoint Blockade

In general, sarcoma TMEs are highly immunosuppressive environments, and a recent analysis of the Ewing’s sarcoma family of tumors (ESFT) showed poor overall survival correlated with tumors that had a TME with elevated expression of hypoxia-inducible factor 1-α and were enriched with immunosuppressive M2 macrophages and neutrophils[2]. The presence of tumor-associated macrophages has also been linked to growth and metastasis of sarcomas, and elevated expression of the immune checkpoint molecule PD-L1 also correlated with metastasis and poor overall survival[3,4]. These observations led to clinical trials that evaluated the efficacy of immune checkpoint blockade for treating sarcomas, but treatments that targeted PD-1/PD-L1 or CTLA-4 showed limited clinical efficacy and did not meet primary endpoints for overall survival[5,6].


ICI blockade coupled with chemotherapy has been tested in clinical trials for many cancers that do not respond well to ICI blockade alone. One recent single-center, single-arm phase II study evaluated treatment outcomes in patients with soft tissue sarcoma treated with anti-PD-1 (pembrolizumab) and doxorubicin, and initial results have indicated this combination has manageable toxicity and favorable trends with respect to overall survival and progression-free survival[7]. Another recent retrospective analysis of advanced soft-tissue sarcoma patients treated with pembrolizumab, and cyclophosphamide revealed that the presence of tertiary lymphoid structures within tumors correlated with better treatment outcomes[8]. These findings indicate that ICI blockade has the potential to have therapeutic effects when used in combination with other treatment modalities.


Targeted Therapies

Genomic studies of sarcomas have been critical to identifying mutations associated with tumor growth, angiogenesis, and metastasis. These findings led to clinical trials examining the efficacy of tyrosine kinase inhibitors or inhibitors that target vascular endothelial growth factor or insulin-like growth factor-1, but most of these trials failed to meet overall survival endpoints [9,10]. More recent genomic studies have indicated that mutations associated with different tumors occur in the same genes as some of the targeted therapies, but the mutations differ sufficiently to render these therapies ineffective[11].

syringe with vial labeled "targeted therapy"


Cellular Immunotherapy

Cell-based immunotherapies have shown great promise in treating hematologic malignancies and are being explored for solid tumors. Chimeric antigen receptor (CAR) T cells have been of particular interest as they are patient-derived T cells engineered to express a tumor-specific receptor, and thus can target tumors without being detected as foreign cells. Preclinical studies suggested that sarcoma-specific CAR T cells may be effective, but clinical trials have failed due to poor penetration and function of CAR T cells in the immunosuppressive TME[12].

Recent and ongoing studies are exploring the effects of multi-CAR T cell strategies that target different tumor antigens, as well as the effects of using modified dendritic cells or natural killer cells or combining treatment modalities[13].

Effective and lasting treatment options for sarcomas continue to be elusive but advances in genomic analysis and immune-based treatments are slowly improving outcomes. Like other cancers, clinical studies exploring treatment combinations are also showing promise and may provide critical breakthroughs for some of the most aggressive sarcomas.


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[1] Doyle LA. Sarcoma classification: an update based on the 2013 World Health Organization Classification of Tumors of Soft Tissue and Bone. Cancer. 2014 Jun 15;120(12):1763-74.

[2] Stahl D, Gentles AJ, Thiele R, Gütgemann I. Prognostic profiling of the immune cell microenvironment in Ewing’s Sarcoma Family of Tumors. Oncoimmunology. 2019 Dec 2;8(12):e1674113.

[3] Xiao W, Klement JD, Lu C, Ibrahim ML, Liu K. IFNAR1 controls autocrine type I IFN regulation of PD-L1 expression in myeloid-derived suppressor cells. J Immunol. 2018 Jul 1;201(1):264-77.

[4] Zhu Z, Jin Z, Zhang M, Tang Y, Yang G, Yuan X, Yao J, Sun D. Prognostic value of programmed death-ligand 1 in sarcoma: a meta-analysis. Oncotarget. 2017 Aug 29;8(35):59570.

[5] Maki RG, Jungbluth AA, Gnjatic S, Schwartz GK, D’Adamo DR, Keohan ML, Wagner MJ, Scheu K, Chiu R, Ritter E, Kachel J. A pilot study of anti-CTLA4 antibody ipilimumab in patients with synovial sarcoma. Sarcoma. 2013 Oct;2013.

[6] Zuo W and Lingdi Z. Recent advances and application of PD-1 blockade in sarcoma." Oncotargets and Therapy 2019; 12:6887.

[7] Livingston MB, Jagosky MH, Robinson MM, Ahrens WA, Benbow JH, Farhangfar CJ, Foureau DM, Maxwell DM, Baldrige EA, Begic X, Symanowski JT. Phase II Study of Pembrolizumab in Combination with Doxorubicin in Metastatic and Unresectable Soft-Tissue Sarcoma. Clinical Cancer Research. 2021 Dec 1;27(23):6424-31.

[8] Italiano A, Bessede A, Pulido M, Bompas E, Piperno-Neumann S, Chevreau C, Penel N, Bertucci F, Toulmonde M, Bellera C, Guegan JP. Pembrolizumab in soft-tissue sarcomas with tertiary lymphoid structures: a phase 2 PEMBROSARC trial cohort. Nature Medicine. 2022 May 26:1-8.

[9] Ray-Coquard IL, Domont J, Tresch-Bruneel E, Bompas E, Cassier PA, Mir O, Piperno-Neumann S, Italiano A, Chevreau C, Cupissol D, Bertucci F. Paclitaxel given once per week with or without bevacizumab in patients with advanced angiosarcoma: a randomized phase II trial. J. Clin. Oncol. 2015 Sep 1;33(25):2797-802

[10] Tap WD, Demetri G, Barnette P, Desai J, Kavan P, Tozer R, Benedetto PW, Friberg G, Deng H, McCaffery I, Leitch I. Phase II study of Ganitumab, a fully human anti–type-1 insulin-like growth factor receptor antibody, in patients with metastatic ewing family tumors or desmoplastic small round cell tumors. J. Clin. Oncol. 2012 May 20;30(15):1849-56.

[11] Trédan O, Wang Q, Pissaloux D, Cassier P, de la Fouchardière A, Fayette J, Desseigne F, Ray-Coquard I, de la Fouchardière C, Frappaz D, Heudel PE. Molecular screening program to select molecular-based recommended therapies for metastatic cancer patients: analysis from the ProfiLER trial. Ann. Oncol. 2019 May 1;30(5):757-65.

[12] Thanindratarn P, Dean DC, Nelson SD, Hornicek FJ, Duan Z. Chimeric antigen receptor T (CAR-T) cell immunotherapy for sarcomas: From mechanisms to potential clinical applications. Cancer Treatment Reviews. 2020 Jan 1; 82:101934.

[13] Patel S, Burga RA, Powell AB, Chorvinsky EA, Hoq N, McCormack SE, Van Pelt SN, Hanley PJ, Cruz CR. Beyond CAR T cells: other cell-based immunotherapeutic strategies against cancer. Front. Onc. 2019 Apr 10; 9:196.


Tags: Solid Tumor Oncology