癌症免疫疗法可以产生完全的治疗反应，然而，在卵巢癌（OC）方面，疗效有限。虽然细胞转移免疫疗法（ACT）已经在OC中进行了评估，但持久效果很少见。治疗效果差可能是多因素的，包括有限的抗原识别、由抑制性肿瘤微环境（TME）引起的不足的肿瘤靶向以及输注T细胞的体内聚集和存在有限。重要的是，宿主T细胞浸润肿瘤，利用内源性肿瘤浸润T细胞的ACT方法可以有效放大治疗反应。通过逆转录病毒转导，我们已经生成了分泌叶酸受体α（FRα）定向双特异性T细胞结合物（FR-B T细胞）的T细胞，该肿瘤抗原在OC和其他肿瘤类型中常常过度表达。使用FRα+癌细胞系、OC患者样本和伴随机械性研究的临床前肿瘤模型评估了FR-B T细胞的抗肿瘤活性和治疗疗效。还评估了T细胞在FR-B T细胞制备过程中的细胞因子刺激（白细胞介素（IL）-2+IL-7 vs IL-2+IL-15）及其对ACT后治疗效果的影响。FR-B T细胞有效溶解FRα+细胞系，靶向FRα+ OC患者肿瘤细胞，并通过分泌T细胞结合物与存在于TME中的患者T细胞发生互动和激活。此外，FR-B T细胞疗法在免疫能力正常的OC体内模型中也具有疗效，反应持续时间取决于内源性T细胞和FR-B T细胞的存在。在ACT之前进行IL-2/IL-15预处理可以产生较不分化的FR-B T细胞，并提高治疗效果，机制研究揭示在腹腔内固体肿瘤的过程中，倾向积累TCF-1+CD39-CD69-干细胞样CD8+ FR B T细胞。这些发现突出了FR-B T细胞在OC中的治疗潜力，并表明FR-B T细胞可以在肿瘤外空间中持续存在并主动指导抗肿瘤免疫。由于固体肿瘤中输注的T细胞的体内聚集能力常常有限，因此，可以有效利用内源性免疫力的分泌结合物T细胞可能具有增强治疗反应率的不同机制优势。(c) 2023作者（或其雇主）。CC BY-NC许可下允许再使用，但不允许商业再使用。由BMJ出版。

Cancer immunotherapies can produce complete therapeutic responses, however, outcomes in ovarian cancer (OC) are modest. While adoptive T-cell transfer (ACT) has been evaluated in OC, durable effects are rare. Poor therapeutic efficacy is likely multifactorial, stemming from limited antigen recognition, insufficient tumor targeting due to a suppressive tumor microenvironment (TME), and limited intratumoral accumulation/persistence of infused T cells. Importantly, host T cells infiltrate tumors, and ACT approaches that leverage endogenous tumor-infiltrating T cells for antitumor immunity could effectively magnify therapeutic responses.Using retroviral transduction, we have generated T cells that secrete a folate receptor alpha (FRα)-directed bispecific T-cell engager (FR-B T cells), a tumor antigen commonly overexpressed in OC and other tumor types. The antitumor activity and therapeutic efficacy of FR-B T cells was assessed using FRα+ cancer cell lines, OC patient samples, and preclinical tumor models with accompanying mechanistic studies. Different cytokine stimulation of T cells (interleukin (IL)-2+IL-7 vs IL-2+IL-15) during FR-B T cell production and the resulting impact on therapeutic outcome following ACT was also assessed.FR-B T cells efficiently lysed FRα+ cell lines, targeted FRα+ OC patient tumor cells, and were found to engage and activate patient T cells present in the TME through secretion of T cell engagers. Additionally, FR-B T cell therapy was effective in an immunocompetent in vivo OC model, with response duration dependent on both endogenous T cells and FR-B T cell persistence. IL-2/IL-15 preconditioning prior to ACT produced less differentiated FR-B T cells and enhanced therapeutic efficacy, with mechanistic studies revealing preferential accumulation of TCF-1+CD39-CD69- stem-like CD8+ FR B T cells in the peritoneal cavity over solid tumors.These findings highlight the therapeutic potential of FR-B T cells in OC and suggest FR-B T cells can persist in extratumoral spaces while actively directing antitumor immunity. As the therapeutic activity of infused T cell therapies in solid tumor indications is often limited by poor intratumoral accumulation of transferred T cells, engager-secreting T cells that can effectively leverage endogenous immunity may have distinct mechanistic advantages for enhancing therapeutic responses rates.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.