Kumar Amit, Bhoopathi Praveen, Mannangatti Padmanabhan, Maji Santanu, Pradhan Anjan K, Madan Esha, Klibanov Alexander L, Gogna Rajan, Limbrick David D, Emdad Luni, Das Swadesh K, Fisher Paul B
VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.
Department of Cellular, Molecular, and Genetic Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.
J Immunother Cancer. 2025 Jun 22;13(6):e011198. doi: 10.1136/jitc-2024-011198.
Glioblastoma (GBM) is a rapidly growing, aggressive brain tumor with very poor prognosis without currently effective therapies. The immunosuppressive nature of the tumor microenvironment (TME) in GBM hinders the development of effective tumor-eradicating immunotherapies. This hostile TME can be modulated by administering immune-activating cytokines in combination with agents inducing tumor cell death. To achieve these objectives, we sought to harness the cancer-selective cell death-inducing properties of an enhanced "Superkine" version of melanoma differentiation associated gene-7/interleukin-24, , and the immune-activating properties of to modulate the TME of GBM to maximize therapeutic outcomes.
A fusion "Superkine" () comprised of linked to was generated, and antitumor effects were evaluated when transduced by a type 5 adenovirus (Ad.5) in a GBM immunocompetent mouse tumor model. To target the delivery of Ad.5 systemically, we employed an innovative approach of focused ultrasound (FUS) paired with microbubbles (MBs), FUS-DMB (FUS plus double MB), to safely transport the engineered Ad.5 construct into mouse brain to overcome limitations of systemic viral delivery and selectivity of the blood-brain barrier.
The stimulated higher tumor regression and enhanced survival in vivo than the individual "Superkine" or cytokine in GBM cancer models. Apoptosis of GBM cells was induced, as well as increased tumor infiltration of T cells, dendritic cells, macrophages and natural killer (NK) cells. The antitumor-inducing activity of FSK is a consequence of induction of cancer-specific growth suppression and induction of apoptosis (IL-24S) as well as diverse effects on immune cells (IL-15 and IL-24S). Antibody neutralization indicates that a primary immune mediator of anticancer activity of FSK is through recruitment and activation of NK cells. Global cytokine analyses indicated no changes in inflammatory cytokines during therapy, suggesting that this strategy will be safe.
In summary, treatment with an , consisting of a fusion of to , promotes GBM cell killing and remodeling of the TME by recruiting and activating immune cells supporting the feasibility of developing safe and effective cancer immunotherapeutic fusion proteins and selective delivery in the brain for the therapy of GBM.
胶质母细胞瘤（GBM）是一种生长迅速、侵袭性强的脑肿瘤，预后极差，目前尚无有效的治疗方法。GBM肿瘤微环境（TME）的免疫抑制特性阻碍了有效的肿瘤根除免疫疗法的发展。通过联合使用免疫激活细胞因子和诱导肿瘤细胞死亡的药物，可以调节这种不利的TME。为了实现这些目标，我们试图利用增强型“超级细胞因子”版本的黑色素瘤分化相关基因-7/白细胞介素-24（ ）的癌症选择性细胞死亡诱导特性，以及 的免疫激活特性来调节GBM的TME，以最大限度地提高治疗效果。
构建了一种由 与 连接而成的融合“超级细胞因子”（ ），并在GBM免疫活性小鼠肿瘤模型中通过5型腺病毒（Ad.5）转导时评估其抗肿瘤作用。为了全身靶向递送Ad.5 ，我们采用了一种创新方法，即聚焦超声（FUS）与微泡（MBs）配对，FUS-DMB（FUS加双MB），以安全地将工程化的Ad.5构建体输送到小鼠大脑中，克服全身病毒递送的局限性和血脑屏障的选择性。
在GBM癌症模型中， 比单个“超级细胞因子”或细胞因子在体内刺激了更高的肿瘤消退率并提高了生存率。诱导了GBM细胞凋亡，同时增加了T细胞、树突状细胞、巨噬细胞和自然杀伤（NK）细胞的肿瘤浸润。FSK的抗肿瘤诱导活性是诱导癌症特异性生长抑制和凋亡（IL-24S）以及对免疫细胞（IL-15和IL-24S）产生多种作用的结果。抗体中和表明，FSK抗癌活性的主要免疫介质是通过招募和激活NK细胞。整体细胞因子分析表明治疗期间炎症细胞因子没有变化，这表明该策略是安全的。
总之，由 与 融合而成的 治疗可通过招募和激活免疫细胞促进GBM细胞杀伤和TME重塑，支持开发安全有效的癌症免疫治疗融合蛋白并在大脑中进行选择性递送以治疗GBM的可行性。
