Introduction
Natural killer/T-cell lymphoma (NKTL) is a rare and distinct subtype of non-Hodgkin’s lymphoma (NHL), which predominantly occurs in East Asia and Latin America (1, 2). Appropriately 60% of NKTL cases are initially diagnosed as stage I/II disease in the upper aerodigestive tract (1). Radiotherapy has been widely used in localized NKTL, and the combined strategy of radiotherapy systematic treatment has greatly improved the clinical outcome of these patients (3, 4). Asparaginase and pegaspargase are key agents for NKTL treatment, and asparaginase/pegaspargase containing regimens (P-GEMOX, SMILE and DDGP) are highly effective in the combined treatment strategy (5–9). However, these chemotherapy regimens consist of multiple toxic agents and inevitably have some hematological toxicity and risk of infection (5–9). Meanwhile, severe toxicities would hamper the completion of combined radiotherapy and reduce patients’ medical compliance, which limits their usefulness in fragile patients and concurrent radiotherapy. Therefore, there is an unmet need for a more tolerable chemoradiotherapy regimen with comparable efficacy for localized NKTL.
Epstein–Barr virus (EBV) has been reported to increase the expression of programmed death-1 (PD-1) in various types of cancer, including NKTL (10–12). Therefore, it is reasonable to use anti-PD-1 antibody in NKTL patients. Several anti-PD-1 antibodies, including pembrolizumab, nivolumab and sintilimab, have been explored in refractory/relapsed NTKL, with impressive antitumoral effects in previously heavily treated patients (13–15). Such encouraging results in relapsed/refractory NKTL have provided the opportunity to explore anti-PD-1 antibodies in the frontline treatment of NKTL. Recently, Cai et al. explored the efficacy of anti-PD-1 antibodies with the P-GEMOX regimen in 9 advanced NKTL patients, with a complete response rate of 66.7% (16). The latter exploratory study indicated the potential promising therapeutic role of immune checkpoint inhibitors in first-line treatment of NKTL.
Currently, antiangiogenic treatments are widely used in multiple malignancies. Overexpression of genes related to angiogenesis have been observed in NKTL (17). In particular, overexpression of both vascular endothelial growth factor A (VEGF-A) and its receptor VEGFR2 has been detected in NKTL tissues and cell lines at the mRNA and protein levels (17). These findings provided a rationale to further explore the effect of antiangiogenic treatment in NKTL (17). Anlotinib is a small molecule tyrosine kinase inhibitor (TKI) targeting vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR) and platelet-derived growth factor receptor (PDGFR), with promising antitumor effect in lung cancer and sarcoma (18, 19). Moreover, a recent study demonstrated anlotinib could potentiate the therapeutic effect of PD-1 blockade by optimizing antitumor innate immunity in lung cancer (20). In addition, the potential synergistic effects of immune checkpoint inhibitors and antiangiogenic agents have been reported in hepatocellular, cervical and lung cancers (21–25). However, data regarding the combination therapy of anti-PD-1 antibody and anti-angiogenesis agents in NKTL are scarce.
Taken together, herein we proposed a novel systematic combination regimen of anti-PD-1 antibody, anlotinib and pegaspargase “sandwich” with radiotherapy for localized NKTL and reported retrospective results of 8 patients in our institution.
Discussion
To the best of our knowledge, this is the first study to report the efficacy and safety of anti-PD-1 antibody-based regimen in the frontline treatment of localized NKTL. The results suggested that the novel triple-agent regimen (anti-PD-1 antibody, anlotinib and pegaspargase) could be a highly active combination for untreated patients with localized NKTL. Moreover, this regimen had mild toxicity and showed a favorable safety profile when “sandwich” with radiotherapy, suggesting it as a feasible and promising treatment approach in the clinical setting.
Conventional anthracyclines-containing regimens have no favorable efficacy in NKTL due to frequent expression of P-gp (28), which could be partly overcome by L-asparaginase and pegaspargase (5–9). In the past decade, L-asparaginase and pegaspargase have been established as cornerstone in the therapy of NKTL patients, and several L-asparaginase and pegaspargase combining regimens have been explored and recommended as standard of care for NKTL (5–9). Pegaspargase is more feasible and has relatively lower risk of allergy compared with L-asparaginase and is therefore widely used in our institution (29). Thus, we consider pegaspargase an indispensable and cornerstone drug in the frontline treatment of localized NKTL.
Recent studies have demonstrated that anti-PD-1 antibody is an effective and revolutionary salvage treatment in relapsed/refractory NKTL. In our study, three distinct anti-PD-1 antibodies were used, all of which showed remarkable efficacy in relapsed/refractory NKTL. In 2017, Kwong et al. reported seven relapsed/refractory NKTL patients who all responded to pembrolizumab (5 CR and 2 PR) for the first time (13). Li et al. then demonstrated that pembrolizumab is highly effective in relapsed/refractory NKTL, with an ORR of 57% (15). Low dose nivolumab was also found to be effective in relapsed/refractory NKTL by Chan et al. (14). Sintilimab was reported to achieve an ORR of 67.9% and a 1-year OS of 82.1% in relapsed/refractory NKTL in the Orient-4 study (30). Nevertheless, anti-PD-1 antibody has also shown encouraging antitumor activity in the frontline therapy of NKTL (16).
Currently, anti-PD-1 antibody plus antiangiogenic tyrosine kinase inhibitor (TKI) has been explored in a variety of clinical trials of multiple solid tumors, demonstrating impressive synergistic antitumor effects (21–25). Vascular endothelial growth factor (VEGF) has been found to play an important role in systemic and local immunosuppression in tumor models (31). Increased levels of VEGF in tumor microenvironment could change the expression of adhesion molecules to directly inhibit the function of T cell, prevent T-cell activation, reduce the T cell-mediated anticancer immune response, and promote the recruitment and proliferation of immunosuppressive cells (31, 32). As a multitarget antiangiogenic TKI, anlotinib could firstly inhibit the VEGFR to normalize the tumor vessels, reducing tissue hypoxia and enhancing the delivery of other antitumor agents such as immune checkpoint inhibitor (32). Secondly, monotherapy of anlotinib was found to upregulate the expression of PD-L1 in the tumor microenvironment (TME), which could increase the antitumor effect of anti-PD-1 antibody (31, 32). Finally, anlotinib was identified to reprogram the immunosuppressive TME into an immunostimulatory TME by enhancing the infiltration of immune effector cells and the antigen presentation function (20). In addition, TME vessel normalization could conversely be promoted by immune checkpoint inhibitors (33). Collectively, strong reasons exist to support the multidimensional synergetic effects of anlotinib combined with anti-PD-1 antibodies. In a series of prospective and observational studies, the encouraging efficacy data of anti-PD-1 antibody plus anlotinib have been reported (22, 34–36). In this study, interim analysis after 2 cycles of treatment showed a CR rate (CRR) of 50% and an ORR of 100%, indicating that this regimen could induce a rapid remission in NKTL. Notably, the CRR increased to 87.5% when “sandwich” with radiotherapy. L-asparaginase/pegaspargase containing cytotoxic regimens, including SMILE, AspaMetDex and P-GEMOX/GELOX, have been previously explored in untreated and relapsed/refractory NKTL patients, exhibiting ORRs of 78%-96% and CRRs of 45%-74% (5–9, 29, 37). When concurrently, sequentially or “sandwich” combined with radiation, the CRRs of these regimens could be further increased to 70%-80%. Based on these findings, we suggested that our novel regimen and traditional cytotoxic regimens have comparable efficacies.
The combination of immune checkpoint inhibitors (ICI) and radiotherapy has recently been recognized as a breakthrough therapy in multiple malignancies. Beside the direct disruption of chemical bonds within the bases in the DNA of tumor cells, radiotherapy-induced abscopal effect, such as the reconstruction of tumor immune microenvironment, could play an important role in antitumor effects (38, 39). Radiotherapy could induce immunogenic cell death (ICD) to release new tumor antigens, upregulate MHCI molecules, activate dendritic cells, and reduce the abundance of immunosuppressive cells (38, 39). Accumulating evidence, both preclinical and clinical, indicates that anti-PD-1 antibodies combined with radiotherapy have synergistic effects in lung cancer, pancreatic cancer, prostate cancer and melanoma (38, 40, 41). Considering that radiotherapy remains the cornerstone of localized NKTL, anti-PD-1 antibody might show a potential synergetic effect when combined with radiotherapy. In this study, three patients who obtained PR in interim analysis ultimately achieved CR after radiotherapy. These promising data suggest that prospective studies are warranted to confirm the potential benefits and safety of the combination of radiotherapy and anti-PD-1 antibody-containing regimens in localized NKTL.
The major superior feature of our regimen is the encouraging safety profile, which is consistent with known safety profiles of anti-PD-1 antibodies, anlotinib or pegaspargase alone. No new safety signal was reported. Generally, grade 3/4 TRAEs were identified in only one patient (12.5%), whereas the incidence rates of grade 3/4 TRAEs were generally above 70% for traditional cytotoxic regimens (5–9, 29, 37). In previous cytotoxic regimens, the incidence of grade 3/4 hematological toxicity was generally above 50%, which was the major concern of scheduled radiotherapy. In this study, half of the participants didn’t suffer from any grade hematological toxicity, and no grade 3/4 hematological toxicity was reported. Meanwhile, immune-related AE and antiangiogenic AE were also mild. All TRAEs were alleviated within 3 months after the last dose. No dose reduction, treatment discontinuation or radiotherapy delay was reported due to TRAEs. According to the safety data, our regimen is a feasible and promising chemoradiotherapy regimen which can be well tolerated in fragile and elderly patients.
There were several limitations in this study. First, this study was limited by its nonrandomized nature with a relatively small sample size. Secondly, efficacy analyses were preliminary, and long-term follow-up is still needed. Finally, we could not carry out prognostic analysis of biomarkers in this study. To overcome these shortcomings, a prospective, single arm, phase II trial evaluating the safety and efficacy of sintilimab, anlotinib and pegaspargase for localized NKTL has been initiated in multiple centers (NCT03936452).
In conclusion, these preliminary findings indicate that anti-PD-1 antibody combined with anlotinib and pegaspargase is a promising regimen “sandwich” with radiotherapy for localized NTKL, with encouraging efficacy, mild toxicity and good tolerance. Future prospective studies with large sample sizes could provide more accurate data on the efficacy and safety of this regimen and could further identify predictive biomarkers of this novel therapy in NKTL patients.