Vannini Andrea, Parenti Federico, Forghieri Cristina, Romagnoli Elisabetta, Massaro Daniela, Zaghini Anna, Campadelli-Fiume Gabriella, Gianni Tatiana
Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
J Immunother Cancer. 2025 Jul 22;13(7):e011812. doi: 10.1136/jitc-2025-011812.
Cancer immunotherapy includes vaccines generated through distinct approaches, each with advantages and limitations. Those made of autologous or allogeneic whole cells do not require prior identification of antigens, that is, immunize against undetermined (agnostic) tumor antigens. However, they often exhibit low adjuvanticity and modest antigenicity. Viruses have emerged as elicitors and enhancers of immune responses. Oncolytic viruses are replicating anticancer agents, most often administered intratumorally. They derepress the immunosuppressive tumor microenvironment through different mechanisms, and some promote antitumor immunity-a strategy termed oncolytic immunotherapy. Tropism-retargeted oncolytic herpes simplex viruses (here ReHVs), generated in our laboratory, specifically target a tumor-associated antigen (TAA) of choice that serves as receptor for ReHV entry into the cancer cell. ReHVs do not cause off-target infections in preclinical models, are fully replication-competent and able to contrast the antiviral innate responses they elicit, and prime T cells against tumors.
We developed an ReHV-mediated immunotherapeutic platform (Re-IP) that consists of thymidine kinase-positive cancer cells ex vivo infected with ad hoc designed HER2-tropic ReHV implanted ectopically to immunize mice against cancer without direct tumor treatment.
In a therapeutic-like setting, Re-IP robustly primed anticancer T cells that infiltrated distant untreated tumors and inhibited their growth. Tumor growth inhibition required CD8+ cells. Re-IP vaccinated against both the gnostic TAA (here HER2) employed for ReHV retargeting and a broader repertoire of agnostic tumor antigens, also sensitizing tumors to checkpoint blockade. Ectopically implanted uninfected cancer cells failed to elicit an immune response, highlighting the adjuvant effect of ReHV infection. Re-IP was effective in herpes simplex virus (HSV)-preimmune mice, unlike systemic treatments with oncolytic HSVs, which are blunted by prior antiviral immunity. Re-IP safety rested in the absence of replicating virus in off-target tissues and in tumors whose growth was inhibited.
Ectopically administered Re-IP adjuvants cancer cells' immunogenicity without the need for direct tumor treatment. The induced T-cell immunity inhibits the growth of distant untreated tumors and remains effective in HSV-preimmune mice. In humans, this approach might be applied to elicit anticancer T-cell responses against hard-to-reach, unresectable, or metastatic lesions and to enhance immune cell activation and expansion in adoptive therapies.
癌症免疫疗法包括通过不同方法产生的疫苗，每种方法都有其优缺点。由自体或异体全细胞制成的疫苗不需要预先鉴定抗原，即针对未确定的（不可知的）肿瘤抗原进行免疫。然而，它们通常表现出低佐剂性和适度的抗原性。病毒已成为免疫反应的引发剂和增强剂。溶瘤病毒是正在复制的抗癌剂，最常通过瘤内给药。它们通过不同机制解除免疫抑制性肿瘤微环境的抑制，并且一些病毒可促进抗肿瘤免疫——这一策略被称为溶瘤免疫疗法。我们实验室构建的嗜性重靶向溶瘤单纯疱疹病毒（此处简称ReHVs）特异性靶向一种选定的肿瘤相关抗原（TAA），该抗原作为ReHV进入癌细胞的受体。在临床前模型中，ReHVs不会引起脱靶感染，具有完全的复制能力，并且能够对抗它们引发的抗病毒固有反应，还能启动针对肿瘤的T细胞。
我们开发了一种ReHV介导的免疫治疗平台（Re-IP），该平台由体外感染了专门设计的嗜HER2的ReHV的胸苷激酶阳性癌细胞组成，将其异位植入以在不直接治疗肿瘤的情况下使小鼠对癌症产生免疫。
在类似治疗的环境中，Re-IP有力地启动了抗癌T细胞，这些T细胞浸润远处未治疗的肿瘤并抑制其生长。肿瘤生长抑制需要CD8+细胞。Re-IP针对用于ReHV重靶向的已知TAA（此处为HER2）以及更广泛的未知肿瘤抗原库进行疫苗接种，还使肿瘤对检查点阻断敏感。异位植入的未感染癌细胞未能引发免疫反应，突出了ReHV感染的佐剂作用。与溶瘤性单纯疱疹病毒的全身治疗不同，Re-IP在单纯疱疹病毒（HSV）预免疫的小鼠中有效，溶瘤性单纯疱疹病毒的全身治疗会因先前的抗病毒免疫而减弱。Re-IP的安全性在于脱靶组织和生长受到抑制的肿瘤中不存在复制病毒。
异位给药的Re-IP可增强癌细胞的免疫原性，而无需直接治疗肿瘤。诱导的T细胞免疫抑制远处未治疗肿瘤的生长，并且在HSV预免疫的小鼠中仍然有效。在人类中，这种方法可能适用于引发针对难以触及、无法切除或转移性病变的抗癌T细胞反应，并增强过继性疗法中免疫细胞的激活和扩增。
