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18NANOMEDICINE IN CANCER PHOTOIMMUNOTHERAPY
XIAO-LONG LIU1'2, MING WU1,2, DA ZHANG1,2 AND ZHIXIONG CAI1,2
1 Mengchao Hepatobiliary Hospital of Fujian Medical University, P. R. China 2 Department of Translational Medicine, Xiamen Institute of Rare Earth Materials, Chinese Academy of Sciences,
P. R. China [email protected]
Abstract
Cancer immunotherapy has become one of the most promising therapeutic approach for cancer treatment through harnessing and boosting the patient's own immune system to eliminate both the primary and metastatic tumor cells [1]. Although it has achieved great success in clinic recently, the objective response rate (ORR) of immunotherapy including checkpoint inhibitors such as PD-1 or PD-L1 antibodies and chimeric antigen receptor T-cell (CAR-T) therapy in most solid tumors, is still extremely limited due to that most solid tumors are featured as cold tumor, characterized as tumor heterogeneity [2], hypoxic microenvironment [3], restricted tumor-infiltrating lymphocytes [2], weak immunogenicity[3], and high expression of immune-inhibiting molecules [4]. Therefore, there is an urgent need to develop new strategies to reverse the "cold" state of solid tumors, and combined with other treatment paradigm to improve the therapeutic outcomes of immunotherapy.
Our group is focusing on developing novel nanomedicine to combine immunotherapy with other therapeutic modalities, such as photodynamic therapy (PDT) or photothermal therapy (PTT) to improve the response rate of different immunotherapy paradigm. PDT has been extensively studied in solid tumor treatment, while it usually aggravates tumor hypoxia, which promotes the survival and metastasis of residue cancer cells; although it has been reported that PDT also could induce immunogenic death of cancer cells to activate host anti-tumor responses, but such responses were generally week and not enough to eliminate the residue cancer cells; therefore, the tumors always suffer fast recurrence after PDT treatment. To resolve these problems, we designed metal-organic framework (MOF) based nanoparticles to combine PDT, anti-hypoxic signaling, and CpG adjuvant as in-situ immunostimulant to boost the host anti-tumor responses after PDT. The MOF based nanoparticles were self-assembled through the coordination of photosensitizer (H2TCPP) and Zirconium ions (named as PCN); the HIF-1a inhibitor acriflavine (ACF) was loaded into the pores of PCN, and the immunologic adjuvant CpG was successively coated on the surface; afterwards, the hyaluronic acid (HA) was coated on the out surface. The aggravated hypoxic survival signaling after PDT could be blocked by ACF to inhibit the HIF-1a induced survival and metastasis. With the help of CpG adjuvant, the tumor associated antigens generated from PDT based cancer cell destruction could initiate strong antitumor immune responses to eliminate residue cancer cells. By integrating these strategies, our designed novel MOF system could significantly improve the cancer therapeutic efficiency both in vitro and in vivo (Figure 1 Left)[3].
Figure 1: (Left) Schematic illustration of the preparation procedure and the working principle of PCN-ACF-CpG@HA to integrate PDT, anti-hypoxic signaling and CpG adjuvant as in-situ immunostimulant. (Right) Schematic illustration of the mechanism of BFVs that generate robust antitumor immune responses.BFVs synergistically improve immunotherapy by converting immune cold into hot.
To systematically converting the immune cold tumor to hot tumor, we developed biosynthetic functional vesicles (BFVs) to integrate strategies including overcome hypoxia, induce immunogenic cell death and immune checkpoint inhibition to boost systematic antitumor immunity. The BFVs presents PD1 and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on the surface, while loads catalase into its inner core. The TRAIL can specifically induce immunogenic death of cancer cells to initiate immune response, which is further synergistically strengthened by blocking PD1/PDL1 checkpoint signal through ectogenic PD1 proteins on BFVs. The catalase can catalyze high level of H2O2 in tumor microenvironment to produce O2 to overcome tumor hypoxia, in turn to increase infiltration of effector T cells while deplete immunosuppressive cells in tumor. The comprehensive immuno-modulating ability of BFVs elicits robust and systematic antitumor immunity, as demonstrated by significant regression of tumor growth, prevention of abscopal tumors and excellent inhibition of lung metastasis (Figure 1 Right) [2].
Figure 2:(Left) Schematic illustration of Artifical engineeredNK cells combined with anti heat endurance strategy for improving the therapeutic efficiency of PTT. (Right) (a) Schematic illustration of CSP@IL-12 nanocomplex synthesis. (b) The mechanism of anti-tumor effects of CSP@IL-12 nanocomplex for synergistic PTT and IL-12 cytokine therapy by tumor local administration.
PTT has also been pre-clinically applied in solid tumor treatment, while the incomplete tumor removal of PTT and heat endurance of tumor cells would induce significant tumor relapse after treatment. To overcome these shortages, we designed a programmable therapeutic strategy that integrated PTT agents (PTAs) for MRI guided phototherapy, DNAzymes for anti-heat endurance, and artificial engineered natural killer (A-NK) cells for adoptive immunotherapy. The novel PTAs exhibited excellent light-to-
heat conversion ability, tumor micro-environment enhanced T1-MRI guiding ability, and anti-heat endurance ability through activating DNAzymes by released Mn2+ after PTT to cleave HSP70 mRNA. Furthermore, the artificial engineered NK cells could specifically eliminate any possible residual tumor cells after PTT, to systematically enhance the therapeutic efficacy of PTT and avoid tumor relapse. Overall, we highlighted the potential of A-NK cells combined with anti-heat endurance as powerful adjuvant for immuno-enhancing photothermal therapy efficiency of solid tumors (Figure 2 Left) [4]. Furthermore, a novel photothermal and gene co-delivery nanoparticle, with CuS inside the SiO2 pore channels and PDMAEMA polycation on the outside of SiO2 surface, is also explored for tumor localized NIR II PTT and in situ immunotherapy through local generation of IL-12 cytokine. The resultant CSP integrated with the plasmid encoding IL-12 gene (CSP@IL-12) exhibited excellent gene transfection efficiency, outstanding NIR-II PTT effect and excellent therapeutic outcomes both in vitro and in vivo. Such an in situ synergistic therapy modality could significantly induce systemic immune responses including promoting DC maturation, CD8+ T cell proliferation and infiltration to efficiently eliminate possible metastatic lesions through abscopal effects. Hence, this creative synergistic strategy of NIR-II PTT and IL-12 cytokine therapy might provide a more efficient, controllable and safer alternative strategy for future photo-immunotherapy (Figure 2 Right).
References
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[2] M Wu, D Zheng, D Zhang, P Yu, L Peng, F Chen, Z Lin, Z Cai, J Li, Z Wei, X Lin, J Liu, X Liu. Converting Immune Cold into Hot by Biosynthetic Functional Vesicles to Boost Systematic Antitumor Immunity. iScience, 23(7): 101341, 2020.
[3] Z Cai, F Xin, Z Wei, M Wu, X Lin, X Du, G Chen, D Zhang, Z Zhang, X Liu, C Yao. Photodynamic Therapy Combined with Antihypoxic Signaling and CpG Adjuvant as an In Situ Tumor Vaccine Based on Metal-Organic Framework Nanoparticles to Boost Cancer Immunotherapy. Adv Healthcare Materials, 9( 1): e1900996,2020.
[4] Zhang D, Zheng Y, Lin Z, Lan S, Zhang X, Zheng A, Li J, Liu G, Yang H, Liu X, Liu J. Artificial Engineered Natural Killer Cells Combined with Antiheat Endurance as a Powerful Strategy for Enhancing Photothermal-Immunotherapy Efficiency of Solid Tumors. Small, 15(42): e1902636, 2020.
