肿瘤细胞治疗研究
英文原题：Novel PSCA-Targeting Adapter Molecules for Late-Stage RevCAR-T Cell Therapy in Prostate Cancer.
Novel PSCA-Targeting Adapter Molecules for Late-Stage RevCAR-T Cell Therapy in Prostate Cancer.
这些数据将 PSCA-IgG4 RevTM 定位为 PCa 中分步 RevCAR-T 治疗的有前景候选方案，其中首先使用短寿命的 scFv-RevTM 以确保快速的安全开关，一旦风险特征明确后再使用较大的 IgG4-RevTM。
CAR 疗法正成为有前景的策略，尤其对于转移性去势抵抗性 PCa，因为其可独立于雄激素受体轴发挥作用。适配器 CAR-T 细胞平台，如 RevCAR 系统，通过小型、快速清除的肿瘤特异性适配器提供精准的治疗控制和肿瘤靶向。为了在 PCa 患者中实现更便捷的晚期 RevCAR-T 治疗，并允许非连续输注 RevTM，我们开发了靶向 PSCA 的新型、更大的基于 IgG4 的 RevTM，并将其与先前描述的较小适配器形式进行基准比较。在 RevCAR 系统中，PSCA-IgG4 RevTM 在低效靶比和低 RevTM 浓度下，以严格抗原依赖的方式有效介导 PCa 杀伤。溶瘤活性伴随在广泛 RevTM 浓度范围内促炎细胞因子的快速且显著释放，这对免疫冷型 PCa 尤其有利。最后，在短期小鼠模型中确认了抗肿瘤活性。初步 PET 研究进一步表明，新型 IgG4-RevTM 具有缓慢的血液清除和肿瘤特异性蓄积。总之，这些数据使 PSCA-IgG4 RevTM 成为 PCa 阶梯式 RevCAR-T 治疗的有前景候选者，其中最初使用短寿命 scFv-RevTM 以确保快速安全开关，随后在风险特征明确后使用更大的 IgG4-RevTM。
Chimeric antigen receptor (CAR) therapies are emerging as promising strategies, particularly for metastatic castration-resistant prostate cancer (PCa), as they can act independently of the androgen receptor axis. Adapter CAR-T cell platforms, such as the RevCAR system, offer precise therapeutic control and tumor targeting via small, rapidly eliminated tumor-specific adapters. To enable more convenient late-stage RevCAR-T therapy in PCa patients, allowing for discontinuous reverse target module (RevTM) infusion, we developed novel, larger IgG4-based RevTMs targeting prostate stem cell antigen (PSCA) and benchmarked them against previously described smaller adapter formats. Within the RevCAR system, PSCA-IgG4 RevTMs effectively mediated PCa killing at low effector-to-target ratios and low RevTM concentrations in a strictly antigen-dependent manner. Oncolytic activity was accompanied by a rapid and pronounced release of proinflammatory cytokines across a broad RevTM concentration range, which is particularly advantageous for immunologically cold PCa. Finally, anti-tumor activity was confirmed in a short-term mouse model. Preliminary PET studies further indicate slow blood elimination and tumor-specific accumulation of novel IgG4-RevTMs. Together, these data position PSCA-IgG4 RevTMs as promising candidates for stepwise RevCAR-T treatment in PCa, in which short-lived scFv-RevTMs are initially used to ensure a rapid safety switch, followed by larger IgG4-RevTMs once the risk profile is known.
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