Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
Department of Radiation Oncology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
Clin Cancer Res. 2024 Sep 13;30(18):4155-4166. doi: 10.1158/1078-0432.CCR-23-2864.
To overcome the limited efficacy of immune checkpoint blockade, there is a need to find novel cancer immunotherapeutic strategies for the optimal treatment of cancer. The novel anti-4-1BB×PDL1 bispecific antibody-ABL503 (also known as TJ-L14B)-was designed to simultaneously target PDL1 and 4-1BB and demonstrated strong antitumor T-cell responses without considerable toxicity. In this study, we investigated the mechanisms by which the combination of ABL503 and anti-PD1 blockade affected the reinvigoration of exhausted tumor-infiltrating CD8+ T cells (CD8+ TIL) and antitumor efficacy.
Single-cell suspensions of hepatocellular carcinoma and ovarian cancer tissues from treatment-naïve patients were used for immunophenotyping of CD8+ TILs and in vitro functional assays. Humanized hPD1/hPDL1/h4-1BB triple-knock-in mice were used to evaluate the effects of ABL503 and anti-PD1 blockade in vivo.
We observed that ABL503 successfully restored the functions of 4-1BB+ exhausted CD8+ TILs, which were enriched for tumor-specific T cells but unresponsive to anti-PD1 blockade. Importantly, compared with anti-PD1 blockade alone, the combination of ABL503 and anti-PD1 blockade further enhanced the functional restoration of human CD8+ TILs in vitro. Consistently, the combination of ABL503 with anti-PD1 in vivo significantly alleviated tumor growth and induced enhanced infiltration and activation of CD8+ TILs.
ABL503, a PDL1 and 4-1BB dual-targeting bispecific antibody, elicits pronounced additive tumor growth inhibition, with increased infiltration and functionality of exhausted CD8+ T cells, which in turn enhances the anticancer effects of anti-PD1 blockade. These promising findings suggest that ABL503 (TJ-L14B) in combination with PD1 inhibitors will likely further enhance therapeutic benefit in clinical trials. See related commentary by Molero-Glez et al., p. 3971.
为了克服免疫检查点阻断的疗效有限，我们需要寻找新的癌症免疫治疗策略，以实现癌症的最佳治疗效果。新型抗 4-1BB×PDL1 双特异性抗体 ABL503（也称为 TJ-L14B）旨在同时靶向 PDL1 和 4-1BB，并表现出强大的抗肿瘤 T 细胞反应，而没有相当大的毒性。在这项研究中，我们研究了 ABL503 与抗 PD1 阻断联合作用影响衰竭的肿瘤浸润 CD8+T 细胞（CD8+TIL）的再激活和抗肿瘤疗效的机制。
使用治疗初治患者的肝细胞癌和卵巢癌组织的单细胞悬液进行 CD8+TIL 的免疫表型分析和体外功能测定。使用人源化 hPD1/hPDL1/h4-1BB 三重敲入小鼠在体内评估 ABL503 和抗 PD1 阻断的作用。
我们观察到 ABL503 成功地恢复了 4-1BB+衰竭的 CD8+TIL 的功能，这些细胞富含肿瘤特异性 T 细胞，但对抗 PD1 阻断无反应。重要的是，与单独抗 PD1 阻断相比，ABL503 与抗 PD1 阻断的联合应用进一步增强了体外人 CD8+TIL 的功能恢复。一致地，ABL503 与体内抗 PD1 的联合应用显著缓解了肿瘤生长，并诱导了 CD8+TIL 的增强浸润和激活。
ABL503，一种 PDL1 和 4-1BB 双靶向双特异性抗体，引起明显的附加肿瘤生长抑制作用，同时增加了衰竭的 CD8+T 细胞的浸润和功能，从而增强了抗 PD1 阻断的抗癌作用。这些有希望的发现表明，ABL503（TJ-L14B）与 PD1 抑制剂联合使用可能会进一步提高临床试验中的治疗效果。请参阅 Molero-Glez 等人的相关评论，第 3971 页。
