An injectable signal-amplifying device elicits a specific immune response against malignant glioblastoma.

Acta Pharmaceutica Sinica B 2023;13(12):5091e5106 Chinese Pharmaceutical Association Institute of Materia Medica, Chinese Academy of Medical Sciences Acta Pharmaceutica Sinica B w w w. e l s ev i e r. c o m / l o c a t e / a p s b w w w. s c i e n c e d i r e c t . c o m ORIGINAL ARTICLE An injectable signal-amplifying device elicits a specific immune response against malignant glioblastoma Qiujun Qiua, Sunhui Chenb, Huining Hed, Jixiang Chena, Xinyi Dinga, Dongdong Wanga, Jiangang Yanga, Pengcheng Guoa, Yang Lia, Jisu Kima, Jianyong Shenga, Chao Gaoa,f, Bo Yine, Shihao Zhengg, Jianxin Wanga,c,* a Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai 201203, China b Department of Pharmacy, Fujian Provincial Hospital & Provincial Clinical Medical College of Fujian Medical University, Fuzhou 350001, China c Institute of Materia Medica, Academy of Chinese and Western Integrative Medicine, Fudan University, Shanghai 201203, China d Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China e Department of Radiology, Huashan Hospital, Fudan University, Shanghai 200040, China f Institute of Tropical Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, China g Department of Neurosurgery, Fujian Provincial Hospital & Provincial Clinical Medical College of Fujian Medical University, Fuzhou 350001, China Received 15 March 2023; received in revised form 4 June 2023; accepted 5 June 2023 KEY WORDS Immunotherapy; Glioblastoma; Antigen-capturing nanoparticles; Recombinant chemokines; Immune signal-amplifying Abstract Despite exciting achievements with some malignancies, immunotherapy for hypoimmunogenic cancers, especially glioblastoma (GBM), remains a formidable clinical challenge. Poor immunogenicity and deficient immune infiltrates are two major limitations to an effective cancer-specific immune response. Herein, we propose that an injectable signal-amplifying nanocomposite/hydrogel system consisting of granulocyte-macrophage colony-stimulating factor and imiquimod-loaded antigen-capturing nanoparticles can simultaneously amplify the chemotactic signal of antigen-presenting cells and the “danger” signal of GBM. We demonstrated the feasibility of this strategy in two scenarios of GBM. In *Corresponding author. E-mail address: (Jianxin Wang). Peer review under responsibility of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. https://doi.org/10.1016/j.apsb.2023.06.010 2211-3835 ª 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 5092 system; Postoperative relapse; Biomaterial; Vaccine Qiujun Qiu et al. the first scenario, we showed that this simultaneous amplification system, in conjunction with local chemotherapy, enhanced both the immunogenicity and immune infiltrates in a recurrent GBM model; thus, ultimately making a cold GBM hot and suppressing postoperative relapse. Encouraged by excellent efficacy, we further exploited this signal-amplifying system to improve the efficiency of vaccine lysate in the treatment of refractory multiple GBM, a disease with limited clinical treatment options. In general, this biomaterial-based immune signal amplification system represents a unique approach to restore GBM-specific immunity and may provide a beneficial preliminary treatment for other clinically refractory malignancies. ª 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 1. Introduction Immunotherapy for various hypoimmunogenic cancers presents a formidable clinical challenge, especially for glioblastoma (GBM), the most aggressive and immunoevasive tumour occurring in the central nervous system (CNS); GBM currently has an extremely poor prognosis and no curative treatment options1. Surgical resection is the primary approach to excise the tumour bulk, however, tumour recurrence is inevitable after surgery2e4. Immunotherapies with mild toxicity and durable responses have changed the treatment landscape of various malignancies5e7 but not that of GBM8, which can be attributed to poor immunogenicity and inadequate immune infiltrates in that area of the body7,9. The CNS parenchyma has historically been recognized as being immune privileged (Fig. 1A). The absence of lymphatic drainage accompanied by the paucity of antigen-presenting cells (APCs) poses the greatest challenge for GBM immunotherapy7,10. However, the discovery of functional lymphatic vessels in the meninges refutes this classic dogma and provides a pathway for antigen drainage from the brain and APCs entry into peripheral lymph nodes11,12. Produced in the bone marrow and attracted to the central lesion during the disease process, dendritic cells (DCs) are the most potent APCs and play a key role in the initiation of anti-GBM immune responses13. Granulocyte-macrophage colonystimulating factor (GM-CSF) is one of the most important factors in the recruitment and proliferation of DCs. Porous biomaterial scaffolds loaded with GM-CSF have proven to be a promising strategy to increase the chemotactic signal and replenish DCs against multiple tumours and could have an effect on GBM14e16. However, classified as a cold tumour immune milieu, GBM is poorly immunogenic and prone to immune escape17,18, which is another cause of immunotherapy failure. Systemic therapeutic strategies, including immune checkpoint inhibition and combination chemotherapy, have been attempted to treat GBM by externally boosting the immune response, but limited intracerebral penetration (ordinarily under 1% of the total dose)19e21 leads to severe off-target effects and myelosuppression22,23, which in turn counteracts the outcome of the immunotherapy. To alleviate these two major obstacles, we propose an injectable nanocomposite/hydrogel system (DOX/RAcNPs@GM gel) consisting of doxorubicin (DOX), granulocyte-macrophage colony-stimulating factor (GM-CSF) and imiquimod-loaded antigencapturing nanoparticles (RAcNPs) to simultaneously amplify the chemotactic signal of antigen-presenting cells and the “danger” signal of GBM antigens (Fig. 1B). Surgical debulking is the first clinical intervention for GBM patients24, resulting in a cavity for therapeutic implantation to circumvent both the bloodebrain barrier and systemic side effects25. Early recurrence of GBM normally occurs near the resection site; thus, the fast release of the chemotherapeutic agent DOX after implant (...truncated)