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Original Article OX40 Agonist Combined with Irreversible Am J Cancer Res 2021;11(6):2782-2801 www.ajcr.us /ISSN:2156-6976/ajcr0128762 Original Article OX40 agonist combined with irreversible electroporation synergistically eradicates established tumors and drives systemic antitumor immune response in a syngeneic pancreatic cancer model Qi-Wei Zhang*, Xiao-Xia Guo*, Yu Zhou, Qing-Bing Wang, Qin Liu, Zhi-Yuan Wu, Xiao-Yi Ding Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin Er Road, Shanghai 200025, China. *Equal contributors. Received December 22, 2020; Accepted April 25, 2021; Epub June 15, 2021; Published June 30, 2021 Abstract: In this study, we intended to explore a novel combination treatment scheme for pancreatic cancer, using irreversible electroporation (IRE) and OX40 agonist. We further aimed to investigate the capacity and mechanism of this combination treatment using an in vivo mouse aggressive pancreatic cancer model. To this end, mice subcuta- neously injected with KPC1199 pancreatic tumor cells were treated with IRE, followed by intraperitoneal injection of OX40 agonist. Tumor growth and animal survival were observed. Flow cytometry analysis, immunohistochemistry, and immunofluorescence were used to evaluate the immune cell populations within the tumors. The tumor-specific immunity was assessed using ELISpot assay. Besides, the cytokine patterns both in serum and tumors were iden- tified using Luminex assay. After combination therapy with IRE and OX40 agonist, 80% of the mice completely eradicated the established subcutaneous tumors, during the 120 days observation period. Rechallenging these tumor-free mice at day 120 with KPC1199 tumor cells leads to complete resistance to tumor growth, suggest- ing that the combination therapy generated long-term-specific antitumor immune memory. Moreover, combination therapy significantly delayed the growth of contralateral untreated tumors, and significantly prolonged animal sur- vival, suggesting that a potent systematic anti-tumor immunity was induced by combination therapy. Mechanically, combination therapy amplified antitumor immune response induced by IRE, as manifested by the increased quality and quantity of CD8+ T cells trigged by IRE. Together, these results provide strong evidence for the clinical assess- ment of the combination of IRE and OX40 agonist in patients with pancreatic cancer. Keywords: Pancreatic cancer, OX40, irreversible electroporation, immunotherapy, combination treatment Introduction cal therapy. Moreover, after surgical resection, the recurrence rate remains high despite Pancreatic cancer (PC) remains one of the most adjuvant chemotherapy [3-5]. Recently, the deadly solid cancers in the world and one of the advances made in systemic chemotherapy and most difficult to diagnose and cure, making it radiation therapy have contributed to modest the seventh leading cause of cancer-related improvements in patient survival [6-8]. Besides, deaths [1]. However, in all PC cases, more than immunotherapy, including immune checkpoint 90% are pancreatic ductal adenocarcinoma inhibitors (ICIs), chimeric antigen receptor T (PDAC). Furthermore, the 5-year survival rate cells (CAR-T), or cancer vaccines, has demon- has been reported less than 9% for all stages strated promising results for many cancers but among patients diagnosed with PDAC [2]. did not include PC [9]. To achieve superior ther- Complete surgical resection of the tumor apeutic effects against PC, new strategies are remains a potentially curative treatment, but needed. unfortunately, nearly 80% of patients with PDAC are diagnosed at locally advanced or dis- As a member of the tumor necrosis factor tant metastasis stages, meaning that these receptor (TNFR) superfamily, the costimulatory patients miss the opportunity for radical surgi- molecule OX40 is chiefly expressed in activated Combined irreversible electroporation with OX40 agonist against pancreatic cancer CD8+ and CD4+ T cells, which regulate multiple residual tumor and preventing disease progres- functions of T cells [10-12]. The proliferation, sion. Therefore, the immune response caused differentiation, survival, and effector function by IRE requires augmentation by other thera- of T cells and the generation of memory T cells pies to exert an effective anti-tumor immunity. can be enhanced by OX40 costimulation [13- 16]. Manipulation of OX40 signaling using To this end, we hypothesized that IRE induces recombinant soluble OX40 ligand (OX40L) or the exposure of tumor antigens that could the anti-OX40 agonist monoclonal antibody serve as tumor vaccination in situ, which might (anti-OX40 mAb), either alone or in combination further activate T cells in vivo and upregulate with other treatments, is an efficient approach the expression of OX40 in T cells. Therefore, to treating multiple preclinical tumor models, therapy using anti-OX40 mAb might augment including PC [13, 17-24]. However, in clinical and prolong the tumor-specific adaptive settings, anti-OX40 mAb has shown limited immune responses induced by IRE. Ultimately, efficacy against advanced solid tumors [25, these effects might stimulate the immune sys- 26]. One of the potential reasons is the lack of tem to attack residual microscopic tumor or OX40 expression at baseline, which might limit micrometastases, and systemic benefits for the anti-tumor efficiency of anti-OX40 mAb. distant tumors might be obtained from such Therefore, there is increasing interest in com- combination therapy. To test our hypothesis, bining anti-OX40 mAb with additional strate- this study assessed the efficacy and mecha- gies to enhance antigen availability or the nisms of the combination of IRE therapy and expression of OX40 in T cells. anti-OX40 mAb in a PC model. Currently, a novel ablation strategy, irreversible Materials and methods electroporation (IRE), has emerged as a non- Tumor cells and animals thermal minimally invasive ablation technique against multiple solid tumors. Unlike conven- The KPC1199 cell line is a mouse PC cell line, tional ablation methods, IRE relies on high-volt- which was isolated from a spontaneous age electrical pulses across the target tissues PDAC mouse model (LSL-KrasG12D, Pdxcre, LSL- aimed to kill tumor cells by producing irrevers- TP53R172H) on a C57BL/6 background [39], and ible nanopores in cellular membranes. These was kindly provided by Dr. Liwei Wang (Renji nanopores result in increased transmembrane Hospital, Shanghai Jiao Tong University School transport and loss of homeostasis, while there of Medicine, Shanghai, China). Cells were cul- is less damage to surrounding normal tissues, tured in DMEM medium (ThermoFisher, Wal- such as blood vessels, intestines, and bile tham, MA, USA) supplemented with 1% peni- ducts. These unique advantages make IRE an cillin-streptomycin (PS) solution (Gibco, New ideal choice for the treatment of PC, which is York, NY, USA), 10% fetal bovine serum (FBS) not suitable for traditional ablation methods (ThermoFisher) at 37°C, and 5% CO2 in a [27, 28]. In clinical settings, IRE has shown humidified atmosphere. Male 6-8-week-old promising results in treating PC [29-33]. Prior C57BL/6 mice were obtained from SLAC clinical studies demonstrated that apart from Laboratory Animal Co. Ltd. (Shanghai, China). the primary function of IRE to ablate PC, IRE And, all mice were housed under specific patho- has also shown immunomodulatory properties gen-free conditions. All our studies were per- [34, 35]. Besides, previous studies reported formed in line with the Guidelines for the Care that IRE ablation might invoke a more robust and Use of Laboratory Animals of Shanghai Jiao immune response than conventional ablation Tong University School of Medicine. methods, such as radiofrequency ablation or cryoablation [36-38]. However, micrometasta- Establishment of subcutaneous PC mouse ses, recurrence after incomplete ablation, or model and treatment protocol residual microscopic tumor remain the prob- lematic aspects of delivering curative treat- For therapeutic efficacy studies, all-male wild- ment by IRE in clinical settings. This reality type (WT) C57BL/6 mice aged 6-8 weeks implies that the immunomodulatory effects underwent a subcutaneous injection of 4×106 induced by IRE therapy might be weak and tran- KPC1199 tumor cells into the right flank. This sitory which are incapable of eradicating the first injection into the right flank was done to 2783 Am J Cancer Res 2021;11(6):2782-2801 Combined irreversible electroporation with OX40 agonist against pancreatic cancer Figure 1. Efficacy of IRE and anti-OX40 mAb treatment of mouse subcutaneous pancreatic tumors. A. The schema for animal experiments using unilateral tumor mouse model. N = 10 per group. B. Volume changes in tumors in uni- lateral tumor mouse model following the indicated treatments. C. Tumor-free rates in IRE vs. IRE+Anti-OX40 groups after treatment initiation. D. Survival rates in unilateral tumor-bearing mice in the indicated treatment groups up to 120 days after initiating treatment. E. The schema for animal experiments using bilateral tumor mouse model. N = 10 per group. F. Volume changes of the untreated secondary tumors in bilateral tumor-bearing mice following the indicated treatments. G. Survival rates in bilateral tumor-bearing mice in the indicated treatment groups. N = 10 per group. ***P < 0.001. IRE, irreversible electroporation. simulate the primary tumor. To further assess the right flank reached a volume of approxi- the effects of IRE+anti-OX40 mAb combination mately 200 mm3 or
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