PD-1 BLOCKADE IN ADJUVANT OR NEOADJUVANT THERAPY FOR SARCOMA
Localized sarcomas are primarily managed with surgical resection. For patients with large and/or high-grade sarcomas, neoadjuvant and/or adjuvant therapies are often used to improve local control rates. As the results of PD-1 blockade monotherapy for patients with metastatic sarcomas are unsatisfactory, the combination of PD-1 blockade and other treatment modes has been explored. Radiotherapy is an effective local treatment and can upregulate PD-L1 expression in primary tumors.16–18 Patel et al, examined the expression of PD-L1 in tumor tissue from 46 patients with stage Ⅱ–Ⅲ STS before and after radiotherapy. No PD-L1 expression on tumor cells was observed in any patients before radiotherapy; however, PD-L1 expression on tumor cells was observed in five patients after radiotherapy.18 Moreover, the expression of PD-L1 on tumor-associated macrophages (TAMs) is also increased after radiotherapy, suggesting an increased risk of distant metastasis after surgery.18 This provides a rationale for perioperative PD-L1 blockade plus radiotherapy.
NCT03474094 is a multicenter, randomized Phase 2 study evaluating the sequence of radiotherapy and PD-L1 blockade in the perioperative period in patients with operable localized STS. The patients enrolled in this study will be allocated into three groups: the treatment sequence in group A includes radiotherapy followed by atezolizumab (an anti-PD-L1 antibody) therapy and operation; the treatment sequence in group B includes atezolizumab therapy followed by operation and radiotherapy; the treatment sequence in group C includes operation followed by atezolizumab therapy and radiotherapy. The primary endpoint is the influence of atezolizumab with or without radiotherapy on the pathological response in patients with STS, and the study is anticipated to be completed in 2021. Furthermore, CT03338959 is a Phase 1/2 study performed in patients with intermediate- or high-grade STS. The patients enrolled in this study will receive pembrolizumab plus radiation followed by surgery. The primary endpoint of this study is pathological response.
Based on the results of SARC028, MD Anderson Cancer Center sponsored a Phase 2 study (NCT03307616), which is an investigational study to determine whether nivolumab alone or in combination with ipilimumab before operation is effective for patients with surgically resectable UPS and dedifferentiated liposarcoma. Similar to NCT03307616, NCT03116529 is a Phase 1/2 study conducted in patients with high-risk STS and the purpose is to estimate the efficacy of radiotherapy plus duvalumab and tremelimumab before operation. The primary endpoints of NCT03116529 are safety and pathological responses. In addition, NCT03463408 is an early Phase 1 study in patients with resectable STS, the patients will be allocated to either of the two arms: the patients in arm 1 receive nivolumab and ipilimumab plus radiation before surgery, whereas the patients in arm 2 receive surgery without neoadjuvant or adjuvant therapy. The primary endpoint is safety. These clinical trials are currently recruiting patients.
PD-1 BLOCKADE COMBINED WITH OTHER AGENTS FOR THE TREATMENT OF SARCOMA
It was reported that the expression of PD-L1 is high and associated with poor prognosis in sarcoma patients.19–21 The expression of PD-L1 provides a potential therapeutic target for anti-PD-1 treatment of sarcomas. However, the expression of PD-L1 is dynamic and could be induced by many factors in the tumor microenvironment.22–24 PD-1 blockade alone is not effective enough in unselected sarcoma patients; thus, PD-1 blockade may be combined with other therapeutic agents.4,12
PD-1 blockade combined with radiotherapy
Preclinical animal studies have shown that immunological checkpoint inhibitor therapy combined with fractionated radiotherapy could induce the abscopal effect.25 Fractionated radiotherapy could enhance T cell trafficking into locally treated tumor sites and augment preexisting antitumor T cell responses, with the capacity to mediate regression of out-of-field tumor lesions when performed in combination with PD-1 blockade agents.26 PD-L1 expression in tumor tissue could be upregulated after radiotherapy.16–18 In UPS of the extremity and trunk (ET-UPS), infiltrating immune cells increase in the tumor microenvironment, and PD-L1 expression on tumor cells is upregulated after radiotherapy.18,27 This evidence provides a theoretical basis for PD-1 blockade plus radiotherapy. A case report showed remarkable tumor regression after combined nivolumab and radiation therapy in a patient with metastatic mediastinal leiomyosarcoma.28 PD-1 blockade combined with radiotherapy for localized sarcoma is discussed above in the “PD-1 blockade in adjuvant or neoadjuvant therapy for sarcoma” section. The NCT03548428 study was initiated to evaluate the efficacy of atezolizumab plus stereotactic body radiation therapy in sarcoma patients with oligometastases; the primary endpoint of this study is the PFS rate at 6 months. At present, the study has not begun to recruit patients.
PD-1 blockade combined with chemotherapy
Chemotherapy has immunomodulatory functions, which in turn enhance antitumor effects by several mechanisms. Firstly, cancer cell death caused by chemotherapy leads to the release of tumor-specific antigens, which are taken up by antigen-presenting cells. These cells present the antigens to T cells to allow for priming and activating of T cells.29 Secondly, chemotherapy might play several immune-potentiating roles including reduction of regulatory T cell (Treg) activity, selective depletion of myeloid-derived suppressor cells (MDSCs), induction of PD-L1 expression, and maturation of antigen-presenting cells.30,31 These findings form the rationale for the combination of PD-1 blockade and chemotherapy, which has demonstrated synergistic effects on advanced non-small cell lung cancer and nasopharyngeal cancer.14,32 Moreover, both immunological checkpoint inhibitors and metronomic chemotherapy have the potentiation to activate immune cells, and a preclinical study confirmed their synergy.33
NCT02406781 is a multicenter Phase 2 trial conducted to estimate the efficacy of pembrolizumab plus metronomic cyclophosphamide. Fifty-seven patients with advanced sarcomas enrolled in this study, 50 of which the efficacy could be evaluated. The four subtypes of sarcomas included in this study were leiomyosarcoma, UPS, other types of sarcoma, and gastrointestinal stromal tumor (GIST). Partial remission was achieved in three of the 50 patients. The PFS rates at 6 months in the four subtype groups were 0%, 0%, 14.3%, and 11.1%, respectively. The researchers of this study considered that the tumor microenvironment characterized by infiltration of macrophages might restrict the efficacy of treatment, based on analysis of biomarker expression in the tumor tissue.34 Although the clinical efficacy of this study was not remarkable, the analysis of molecular biomarkers revealed that the infiltrating macrophages expressing inhibitory enzyme indoleamine 2, 3-dioxygenase 1 (IDO1) may be related to poor clinical efficacy; thus, combination therapy with IDO inhibitors might improve the clinical efficacy.34 Clinical studies of PD-1 blockade combined with chemotherapy for the treatment of sarcomas registered on clinicaltrials.gov are listed in Table 1.
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