Immunotherapy As a Future Treatment for Relapsed and Metastatic Primary Pulmonary Sarcomas

Journal of Cancer and Tumor International 3(4): 1-6, 2016, Article no.JCTI.26676 ISSN: 2454-7360

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Immunotherapy as a Future Treatment for Relapsed and Metastatic Primary Pulmonary Sarcomas

Vasa Jevremovic 1* and Alex Agelidis 2

1American Northwest University, Travnik, Bosnia and Herzegovina. 2University of Illinois at Chicago, Chicago, IL, USA.

Authors’ contributions

This work was carried out in collaboration between both authors. Authors VJ and AA contributed equally to the accumulation of background information and organization into the article. Authors VJ and AA contributed equally to the review and revision of the information included in this article.

Article Information

DOI: 10.9734/JCTI/2016/26676 Editor(s): (1) Pravin D. Potdar, Department of Molecular Medicine & Biology, Jaslok Hospital & Research Centre, Mumbai, Maharashtra, India. Reviewers: (1) Robin L. Jones, Fred Hutchinson Cancer Research Center, University of Washington, USA. (2) Anonymous, Universidade de São Paulo, Brazil. (3) Samuel Wagner, Bristol-Myers Squibb, USA. (4) Deepa Kolaseri Krishnadas, University of Louisville, USA. (5) Roumiana Todorova, IBPhBME-BAS, Sofia, Bulgaria. (6) Istvan Berczi, University of Manitoba, Winnipeg, Canada & The University of Aguascalientes, Aguascalientes, Mexico. Complete Peer review History: http://sciencedomain.org/review-history/15053

Received 28 th April 2016 th Commentary Accepted 13 June 2016 Published 17 th June 2016

ABSTRACT

Primary pulmonary sarcomas (PPS) are aggressive tumors that are ideally treated with complete surgical resection, although seldom possible. Chemotherapy and radiotherapy have proven to be inadequate as second-line in the majority of cases, requiring investigation into novel approaches to treatment. Due to the high rate of recurrence and advanced disease progression, immunotherapy is a future treatment modality that must be investigated in order to provide better prognosis. Studies predominantly focus on other soft tissue malignancies such as osteosarcoma, and thus research pertaining to PPS is limited.

Keywords: Pulmonary sarcoma; immunotherapy; relapse; metastasis.

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*Corresponding author: Email: [email protected];

Jevremovic and Agelidis; JCTI, 3(4): 1-6, 2016; Article no.JCTI.26676

1. INTRODUCTION the general population [13,14] as well as the stability of present disease with the use of non- Primary pulmonary sarcomas (PPS) are specific immunomodulators [15,16]. exceedingly uncommon, [1,2] yet there is speculation as to an increase in incidence High-dose treatment with interleukin (IL)-2 has associated with radiation treatment for other been investigated in numerous studies [15]. The malignancies [2]. Arising from the lung mechanism is based on stimulation of T and parenchyma, bronchi and pulmonary vasculature, natural killer (NK) cells, and has been FDA- [3] the three most common types include approved for treatment of metastatic melanoma leiomyosarcoma, malignant fibrous histiocytoma and renal cell carcinoma [16]. More recent and synovial sarcoma [4,5]. studies of metastatic solid tumors of various etiologies have demonstrated an unlikely relapse PPS often remains asymptomatic, but may after a follow-up period of 30 months without present with the same symptoms as lung disease, [16] although older reports of response carcinoma, [4,5] such as atelectasis, cough with rate vary from 0% to 33% [17,18]. IL-2 therapy is expectoration and hemoptysis [6]. Diagnosis not often employed for sarcomas, and is occurs when a sarcoma of an extrathoracic associated with high toxicity [16] but shows location is ruled out, as metastatic sarcoma to potential as an adjunct in the arsenal of therapy the lungs is much more common [7]. Computed for PPS. tomography imaging is crucial as a diagnostic modality in identifying these thoracic lesions [1,8], Interferon gamma has been investigated in the which may include areas of stippled calcification past as a potential immunotherapy for and focal areas of necrosis [3,9]. malignancy by potentiating immune cells and Immunohistochemistry for each sarcoma differs increasing presentation of antigens to T and overall structure is important in lymphocytes [15]. This antitumor activity is determination of grade and stage [3]. The ideal demonstrated by a report in which more than half management of disease is through curative of patients with osteosarcoma receiving surgical resection, [7] yet is seldom possible due interferon therapy had partial responses [19]. to unresectable disease or involvement of critical Similarly, a study in 1989 by Edmonson et al. structures [8]. In such cases, radiation and [20] demonstrated a 15% response rate using chemotherapy are used as next-line therapy, interferon for patients with metastatic bone most often producing suboptimal results [2,3,7]. It sarcomas. In 2003, Roozendaal and colleagues has been documented that second-line therapies [21] described a case of primary sarcoma in the provide a median survival of only 10-15 months calf with pulmonary metastasis refractory to [10]. In synovial sarcoma, the translocation of treatment with chemotherapy. High-dose t(X;18)(p11.2;q11.2) results in the fusion chemotherapy followed by peripheral stem cell products of either SYT-SSX1 or SYT-SSX2, in transplantation was considered too toxic, thus which the SYT-SSX1 variant is associated with a the patient was initiated on interferon therapy. higher mitotic rate, worse prognosis and After six months the patient showed a significant increased chance of relapse [2,3]. As this partial response. However, these interferon disease group is aggressive, and optimal studies predominantly focus on osteosarcoma, therapies are either not possible or inadequate, [16] and more investigation pertaining to the novel approaches are necessary to improve sarcoma subtypes of pulmonary origin are prognosis. needed.

Such an approach in recent focus is Another immunostimulatory therapy is liposomal- immunotherapy. The basis for this method stems muramyl tripeptide phosphatidyl-ethanolamine from the observation made by Coley in 1891, (L-MTP), which is a synthetic analog of the when a recurrence of small cell sarcoma receded bacterial cell wall [15]. In vitro studies have following erysipelas infection and further local shown that L-MTP increases tumor cell killing by injections of pathogen [11,12]. This was thought mononuclear cells, quantified by measurement of to occur as the malignant cells were caught in tumor necrosis factor (TNF)-alpha and IL-6 as crossfire between the immune system and immunomodulatory markers [16]. Furthermore, L- pathogen, subject to the antitumor effects elicited MTP in laboratory models had shown a reduction in the process [11]. This is supported by the fact in the metastatic tumor burden, demonstrating a that sarcomas occur three times more often in possible approach in aggressive and advanced immunosuppressed patients when compared to malignancies as discussed [22]. Unfortunately,

Jevremovic and Agelidis; JCTI, 3(4): 1-6, 2016; Article no.JCTI.26676

this approach predominantly focused on indicated by one study, with especially elevated osteosarcoma, yet has potential for other soft levels in malignant fibrous histiocytomas [32]. tissue malignancies such as PPS [23]. L-MTP This presents an interesting approach for may function similarly to IL-2 and interferon as a immunotherapy of PPS by molecular profiling of non-specific immunomodulator in cancer receptor expression via in situ hybridization [32] treatment. and treatment with agents such as tamoxifen and toremifen [33]. This vector of immune therapy An interesting therapy in development is both prevents tumor growth and sensitizes tumor vaccination for sarcomas. Vaccines targeting cells to cytotoxic immune lysi [33]. Cure rates for gangliosides GD2, GD3 and GM2 in patients with mastocytoma in a study by Baral et al. [34] had solitary metastases excised in combination with been up to 75% when IL-2-activated NK cells GM-CSF or IL-2 have the potential to stimulate and cytotoxic T cells were administered in the immune response to lysate sarcoma cells conjunction with anti-estrogen agents. [16,24]. Furthermore, it has been observed that Such agents could be used in combination with this therapy has no major toxicities, [24] an other treatments when indicated by a positive important advantage over chemo-radiation. A receptor profile, as in malignant fibrous phase II trial using bivalent vaccination with GD2 histiocytoma. and GD3 demonstrated a positive serologic response when compared to control groups, in Programmed death receptor (PD-1) present on T patients that are surgically disease-free, cells is a target for cancer cells to dampen an receiving adjuvant therapy and are still being immune response through expression of PD-1 followed-up for survival and presence of ligands PD-L1 and PD-L2 [35]. Thus, this recurrence (NCT01141491) [16,25,26]. Although immune escape mechanism expressed in 19% to studies have focused on neuroblastoma and 92% of malignant cells is associated with a poor other sarcomas, vaccination is of great interest prognosis.[36] PD-L1 ligand was associated with for PPS as it highly expresses GD2 and GD3 [15]. deep seated sarcoma, distant metastases, high More specifically targeted toward synovial histological grade and tumor necrosis in one sarcomas, a vaccine has been developed using study, [35] all of which occur frequently with PPS HLA-A24-optimized SYT-SSX peptide [16,27]. histologies [2]. Targeting PD-1 with inhibitors is a Bloom et al. [27] completed a trial determining potential mechanism to prevent immune that this vaccine could be safely administered to suppression by these advanced sarcomas. A synovial sarcoma patients, resulting in significant closed phase II trial is underway investigating the stabilization of aggressive disease. Stability was efficacy of pembrolizumab as a PD-1-antibody documented with a two-fold increase in cytotoxic inhibitor in advanced soft tissue sarcomas T-lymphocytes in the group receiving the (NCT02301039) [37]. Another target for immune vaccination and lack of progression in serial checkpoint inhibitors is cytotoxic T-lymphocyte- computed tomography scans [27]. Vaccination associated protein (CTLA4), a T cell surface seems to be a developing future direction of receptor that when engaged transmits an treatment for aggressive sarcomatous disease. inhibitory signal to T cells [38]. Ipilimumab is an antibody to CTLA4 that had been Cancer testis antigens are proteins that are not investigated in the past as a potential expressed in somatic cells and are typically agent for preventing immune evasion of synovial found in association with sarcoma tumor cells sarcomas, yet the results were not promising [39]. and germline tissues [15]. More specifically, 80% However, an ongoing phase II trial is of synovial sarcomas express NY-ESO, [15,28] investigating the new agent nivolumab with or 100% of synovial sarcomas express PRAME [29] without ipilimumab in the treatment of and 14% of non-uterine leiomyosarcomas unresectable metastatic sarcoma express MAGE-A3 [30]. These antigens are (NCT02500797) [40]. Unfortunately, these recognized by cytotoxic T-lymphocytes [15] and studies focus on Ewing sarcoma and are thus possible targets in sarcoma treatment. osteosarcoma without discussion pertaining to Adoptive transfer of autologous T cells other sarcomatous etiologies. expressing one of the aforementioned peptides is a promising approach, and D’Angelo et al. [31] have recently reported a 50% response rate with 2. CONCLUSION engineered T cell persistence. Mainstay surgical resection is not always Estrogen receptors are expressed in soft tissue possible, and second-line therapies are often sarcomas with a rate of 37.5% to 43.3%, as suboptimal. Thus, it may in the future be

Jevremovic and Agelidis; JCTI, 3(4): 1-6, 2016; Article no.JCTI.26676

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