Opinion statement
Bone and soft tissue sarcoma are rare cancers of mesenchymal origin with the characteristics of heterogeneity and diversity that account for less than 1% of solid malignant cancers. Conventional chemotherapy remains standard of care with response rates of 10–15% that are usually dependent on histologic subtype as some subtypes are chemotherapy resistant. There remains a large unmet clinical need for new and novel options promoting the development of promising therapeutic options such as immunotherapy. With more than 80 different subtypes, the heterogeneity of sarcoma requires thoughtful clinical trial design. In the sarcoma field, recent breakthroughs have occurred in the context of histology-specific approach based on underlying tumor biology. To that end, immunotherapy approaches will need to take a similar approach. Oncolytic viruses (OVs) have emerged as a promising treatment for many solid tumors and shown encouraging results in sarcoma. This review mainly focuses on collective clinical data highlighting the role of OVs as immunotherapy being used in soft tissue sarcoma (STS) and bone sarcomas. Combining OVs with T cell-activating checkpoint inhibition, adoptive cell therapy or targeted therapies may yield increased potency, improve antitumor efficacy of oncolytic virotherapy, and offer a new prospect for the treatment of sarcoma.
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References and Recommended Reading
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Macedo N, Miller DM, Haq R, et al. Clinical landscape of oncolytic virus research in 2020. Journal for ImmunoTherapy of Cancer. 2020;8:e001486.
Cripe TP, Mackall CL. Exploiting genetic alterations to design novel therapies for cancer. Hematol Oncol Clin North Am. 2001;15:657–75.
Birdi HK, Jirovec A, Cortés-Kaplan S, et al. Immunotherapy for sarcomas: new frontiers and unveiled opportunities. J Immunother Cancer. 2021;9(2):e001580. https://doi.org/10.1136/jitc-2020-001580.
Howells A, Marelli G, Lemoine NR, Wang Y. Oncolytic viruses—interaction of virus and tumor cells in the battle to eliminate cancer. Front Oncol. 2017;7:195. https://doi.org/10.3389/fonc.2017.00195.
Andtbacka RH, Kaufman HL, Collichio F, et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015;33(25):2780–8.
Kelly CM, Antonescu CR, 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. 2020, 6(3):402–8. https://doi.org/10.1001/jamaoncol.2019.6152 Recent phase II clinical study reporting the endpoints in advanced sarcoma with the use of T-VEC plus PD-1 inhibitor.
Tawbi HA, 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. 2017;18(11):1493–501.
Lazar AJ, et al. Comprehensive and integrated genomic characterization of adult soft tissue sarcomas. Cell. 2017;171(4):950–65.
Alexandrov LB, Jones PH, Wedge DC, Sale JE, Campbell PJ, Nik-Zainal S, et al. Clock-like mutational processes in human somatic cells. Nat Genet. 2015;47:1402–7.
Streby KA, et al. Intratumoral injection of HSV1716, an oncolytic herpes virus, is safe and shows evidence of immune response and viral replication in young cancer patients. Clin Cancer Res. 2017;23(14):3566–74.
Veldwijk MR, Berlinghoff S, Laufs S, et al. Suicide gene therapy of sarcoma cell lines using recombinant adeno-associated virus 2 vectors. Cancer Gene Ther. 2004;11(8):577–84. https://doi.org/10.1038/sj.cgt.7700718.
Opyrchal M, Aderca I, Galanis E. Phase I clinical trial of locoregional administration of the oncolytic adenovirus ONYX-015 in combination with mitomycin-C, doxorubicin, and cisplatin chemotherapy in patients with advanced sarcomas. Methods Mol Biol. 2009;542:705–17.
Dobner T, Horikoshi N, Rubenwolf S, Shenk T. Blockage by adenovirus E4orf6 of transcriptional activation by the p53 tumor suppressor. Science. 1996;272(5267):1470–3.
Martinez-Velez N, Xipell E, Jauregui P, et al. The oncolytic adenovirus Δ24-RGD in combination with cisplatin exerts a potent anti-osteosarcoma activity. J Bone Miner Res. 2014;29(10):2287–96.
Bone and soft-tissue sarcoma: a new target for telomerase-specific oncolytic virotherapy. Extensive review of hTERT promoter-driven oncolytic adenoviruses against bone and soft-tissue sarcoma cells with telomerase activity.
Nemunaitis J, Tong AW, Nemunaitis M, et al. A phase I study of telomerase-specific replication competent oncolytic adenovirus (telomelysin) for various solid tumors. Mol Ther. 2010;18(2):429–34. https://doi.org/10.1038/mt.2009.262.
Zhu Z, et al. Co-expression network analysis identifies four hub genes associated with prognosis in soft tissue sarcoma. Front Genet. 2019;10:37.
Woo Y, et al. The oncolytic activity of myxoma virus against soft tissue sarcoma is mediated by the overexpression of ribonucleotide reductase. Clin Med Insights: Oncol. 2021;15:1179554921993069 Preclinical study showing a direct correlation between myxoma virus oncolysis and RRM2 RNA levels in STS.
Le Boeuf, F, et al. Oncolytic maraba virus MG1 as a treatment for sarcoma Int J Cancer 141.6 (2017): 1257-1264
Monga V, Skubitz KM, Maliske S, Mott SL, Dietz H, Hirbe AC, et al. A retrospective analysis of the efficacy of immunotherapy in metastatic soft-tissue sarcomas. Cancers. 2020.
Katz D, Palmerini E, and Pollack SM. More than 50 subtypes of soft tissue sarcoma: paving the path for histology-driven treatments Am Soc Clin Oncol Educ Book 38 (2018): 925-938.
Zamarin D, et al. PD-L1 in tumor microenvironment mediates resistance to oncolytic immunotherapy. J Clin Invest. 2018;128(4):1413–28.
Fridlender ZG, et al. Chemotherapy delivered after viral immunogene therapy augments antitumor efficacy via multiple immune-mediated mechanisms. Mol Ther. 2010;18(11):1947–59.
Curiel TJ. Regulatory T cells and treatment of cancer. Curr Opin Immunol. 2008;20(2):241–6.
Raj S, Miller LD, and Pierre L. Triozzi. Addressing the adult soft tissue sarcoma microenvironment with intratumoral immunotherapy Sarcoma 2018 (2018).
Hamacher R, and Bauer S. Preclinical models for translational sarcoma research Curr Opin Oncol 29.4 (2017): 275-285.
Penn I. "Sarcomas in organ allograft recipients." Transplantation 60.12 (1995): 1485-1491.
Angelo SPD’, Tap WD, Schwartz GK, Carvajal RD, "Sarcoma immunotherapy: past approaches and future directions", Sarcoma, vol. 2014, Article ID 391967, 13 pages, 2014. A review focusing on innovative future directions in sarcoma that could help design combinational therapeutic study designs with OVs.
Pollack SM, Ingham M, Spraker MB, Schwartz GK. Emerging targeted and immune-based therapies in sarcoma. J Clin Oncol: Off J Am Soc Clin Oncol. 2018;36(2):125–35.
Lettieri CK, Hingorani P, Kolb EA. Progress of oncolytic viruses in sarcomas. Expert Rev Anticancer Ther. 2012;12(2):229–42.
Sharma, Anu, et al. Radiotherapy of human sarcoma promotes an intratumoral immune effector signature Clin Cancer Res 19.17 (2013): 4843-4853
Boxberg M, Steiger K, Lenze U, Rechl H, von Eisenhart-Rothe R, Wörtler K, et al. PD-L1 and PD-1 and characterization of tumor-infiltrating lymphocytes in high grade sarcomas of soft tissue-prognostic implications and rationale for immunotherapy. Oncoimmunology. 2017;7(3):e1389366.
D’Angelo SP, et al. Prevalence of tumor-infiltrating lymphocytes and PD-L1 expression in the soft tissue sarcoma microenvironment. Hum Pathol. 2015;46(3):357–65.
Chalmers ZR, Connelly CF, Fabrizio D, et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 2017;9:34.
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Hira Chaudhary and Sandra D’Angelo each declare no potential conflicts of interest.
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Chaudhary, H., D’Angelo, S. Role of Virus-Directed Therapy in Soft Tissue Sarcoma. Curr. Treat. Options in Oncol. 23, 404–414 (2022). https://doi.org/10.1007/s11864-022-00956-2
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DOI: https://doi.org/10.1007/s11864-022-00956-2