PD-1 blockade combined with targeted agents

Angiogenesis plays a central role in tumor growth and metastasis. Vascular endothelial growth factor (VEGF), an endothelial cell-specific mitogen found both in normal and tumor tissues, promotes new blood vessels formation by regulating (or dysregulating) angiogenesis.35 VEGF regulates the tumor microenvironment by several ways, such as activation of the hypoxia-mediated signal pathway; direct impairment of the antigen presentation mechanism; and binding with VEGF receptor (VEGFR) on MDSCs, Tregs, TAMs, and cytotoxic T lymphocytes, all of which support the formation of the immunosuppressive tumor microenvironment.22,36 Blocking the VEGF/VEGFR signaling pathway could interrupt neovascularization and exert antitumor effects. The synergistic effect of PD-1 blockade and anti-angiogenesis has been demonstrated in lung cancer, hepatocellular carcinoma, and renal cancer.15,37,38

Pazopanib is an oral multi-target tyrosine kinase inhibitor targeting VEGFR1–3 and platelet-derived growth factor receptor (PDGFR)1–3. In a retrospective study of pazopanib combined with nivolumab in 14 patients with advanced sarcomas, partial response was achieved in two patients, stable disease was observed in five patients, and seven patients were diagnosed with progressive disease. Grade 3/4 adverse events occurred in five patients, including one case of diarrhea, one case of pneumonitis, and three cases of liver function tests. Nonetheless, this combined regimen was tolerated well, with no treatment-related death.7

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Apatinib is an oral small-molecule VEGFR2 inhibitor that has shown antitumor activity in many kinds of tumors including gastric cancer, melanoma, lung cancer, breast cancer, and STS.39–41 PD-1 blockade plus apatinib has demonstrated promising activity in hepatocellular carcinoma and gastric or esophagogastric junction cancer.42 Two Phase 2 clinical studies to assess the activity of PD-1 blockade plus apatinib in sarcomas are underway. NCT03359018 is a trial designed to estimate the efficacy of SHR-1210 (an anti-PD-1 antibody) plus apatinib in 43 enrolled patients with advanced osteosarcoma. The primary endpoint is PFS and overall survival. The recruitment ended and results are pending. NCT03711279 is a multicenter, randomized, open Phase 2 study that is designed to compare the clinical efficacy of SHR-1210 plus apatinib with chemotherapy (doxorubicin combined with ifosfamide or doxorubicin alone) in advanced STS. This study is currently recruiting patients.

Axitinib is an orally administered potent and selective inhibitor of VEGFR1–3 that has been demonstrated to have good clinical efficacy alone or in combination with pembrolizumab in advanced renal cell cancer.15,43 NCT02636725 is an open-label Phase 2 study of pembrolizumab plus axitinib in patients with advanced alveolar STS and other STS. The primary endpoint of this study is the PFS rate at 3 months. The midterm results of this study were reported at the 2018 American Society of Clinical Oncology meeting. Thirty-three patients received at least one dose of study drugs, with 30 patients eligible for evaluation at the primary endpoint. The median PFS was 5.4 months, and the best objective response rate was 21.9%. In patients with alveolar soft part sarcoma, the PFS rate at 3 months was 90.9%, and the best objective response rate was 45.5%. This combination treatment is tolerated well with promising activity in alveolar STS.44 One study revealed the deletion mutation of a mismatch repair (MMR) gene that might be one cause of the good clinical efficacy of PD-1 blockade in alveolar soft part sarcoma.45

Sunitinib is a highly potent selective inhibitor of certain protein tyrosine kinases, including VEGFR1–3, PDGFRα, and PDGFRβ. Clinical data demonstrated the antitumor activity of sunitinib in renal cell cancer, hepatocellular carcinoma, and GIST.46–48 NCT03277924 is a Phase 1/2 study in which the antitumor activity of nivolumab plus sunitinib in patients with advanced sarcomas after the failure of first-line therapy will be estimated; the primary endpoint of this study is the PFS rate at 6 months. Olaratumab is a recombinant human IgG1 MoAb that specifically binds with PDGFRα and has demonstrated antitumor activity in STS.49 NCT03126591 is a Phase 1 study that aims to evaluate the safety of olaratumab plus pembrolizumab in patients with previously treated advanced STS. This study is now recruiting participants.

PD-1 blockade combined with other immunomodulatory agents

PD-1 blockade has shown substantial clinical antitumor activity.7,32,37,38,42,45 As immunological checkpoints are non-redundant and could inhibit T cell activation, proliferation, and effector function within lymph nodes and/or the tumor microenvironment, PD-1 signal pathway blockade combined with other immunomodulatory agents might produce greater antitumor activity than PD-1 blockade alone.50 PD-1 blockade combined with CTLA-4 blockade has shown better clinical efficacy than when used alone in melanoma, lung cancer, renal cell cancer, and sarcoma.5,6,12,51 Clinical studies of PD-1 blockade combined with other immunomodulatory agents registered on the clinicaltrials.gov are listed in Table 2.

Publishers Alliance Table 2

(To view a larger version of Table 2, click here.)


Tumor cells can utilize immunosuppressive factors in the tumor microenvironment, including immune checkpoint molecules, cytokines, and immunosuppressive cells, to escape immune surveillance. The incidences of angiosarcoma and Kaposi sarcoma are high in patients with human immunodeficiency virus infection and those receiving transplantation. Expression of tumor-associated antigens and the initiation of the immune system are also observed in sarcomas. The response to PD-1 blockade depends on the interaction between immune cells and tumor cells in the tumor microenvironment. Currently, the detection of PD-L1 expression by immunohistochemistry is widely used in clinic to predict the efficacy of PD-1 blockade.52 According to PD-L1 expression, the tumor microenvironment is categorized into four distinct types: type I represents tumors without expression of PD-L1 on tumor cells and with tumor-infiltrating lymphocytes (TILs) in the tumor tissue; type II represents tumors with both PD-L1 expression on tumor cells and TILs in the tumor tissue; type III represents tumors with TILs but no expression of PD-L1 on tumor cells; type IV represents tumors with PD-L1 expression on tumor cells and without TILs in the tumor tissue.53 In STS, intratumor infiltration of PD-1-positive lymphocytes and PD-L1 expression was observed in 65% and 58% of the cases, respectively, and multivariate analysis indicated that both PD-1 positivity and PD-L1 positivity were independent prognostic indicators of overall survival and event-free survival.23 Approximately 50% of the sarcomas, notably leiomyosarcomas, chondrosarcomas, liposarcomas, and UPS, expressed PD-L1 based on immunohistochemistry and presented PD-1+ TILs.54 These results suggested that sarcomas may be an indication of PD-1 blockade therapy; however, PD-1 blockade alone did not show promising efficacy clinically.4,12

The expression of PD-L1 is not limited to tumor cells; PD-L1 expression is observed on TAMs, Tregs, and MDSCs in the tumor microenvironment. Noguchi et al, confirmed that PD-L1 expression on tumor cells plays an important role in promoting tumor immune escape.24 Induction of PD-L1 on tumor cells was interferon gamma-dependent and transient, whereas induction of PD-L1 on TAMs was of greater magnitude, only partially interferon gamma-dependent, and stable over time. PD-L1 expression on either tumor cells or host immune cells could lead to tumor escape from the immune system, indicating that total PD-L1 expression in the tumor microenvironment may represent a more accurate biomarker for predicting response to PD-1/PD-L1 blockade therapy, compared with PD-L1 expression on tumor cells alone.24

Tumor mutation burden (TMB) is an emerging biomarker for PD-1 blockade therapy. High TMB predicts a better response to PD-1 blockade55,56 and may induce the formation of tumor-specific neoantigens, which could trigger a more robust immune response driven by TILs.56 One study reported a favorable response to pembrolizumab in one patient with classic Kaposi sarcoma with high TMB.57 More studies on TMB and the efficacy of PD-1 blockade in sarcomas are needed.

Microsatellite instability (MSI) is known as a condition of genetic hypermutability resulting from impaired DNA MMR. The presence of MSI indicates that the MMR function is abnormal. High MSI and deletion mutation of MMR genes are present in a subset of tumors and appear to be biomarkers that predict response to PD-1 blockade therapy.58 In pleomorphic rhabdomyosarcoma and alveolar soft part sarcoma, patients with MSI-high tumors could benefit from PD-1 blockade therapy.45,59 In addition, it was reported that deletion mutation of MMR genes correlates with PD-L1 overexpression.59

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