封锁
双特异性抗体
癌症研究
抗体
细胞毒性T细胞
化学
医学
免疫学
内科学
单克隆抗体
生物化学
受体
体外
作者
Seung Hyuck Jeon,Gihoon You,Junsik Park,Youseung Chung,Kyungjin Park,Hyunjoo Kim,Jaehyoung Jeon,Youngkwang Kim,Woo‐Chan Son,Da Som Jeong,Eui‐Cheol Shin,Jung‐Yun Lee,Dai Hoon Han,Jaeho Jung,Su‐Hyung Park
标识
DOI:10.1158/1078-0432.c.7447741.v1
摘要
<div>AbstractPurpose:<p>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<sup>+</sup> T cells (CD8<sup>+</sup> TIL) and antitumor efficacy.</p>Experimental Design:<p>Single-cell suspensions of hepatocellular carcinoma and ovarian cancer tissues from treatment-naïve patients were used for immunophenotyping of CD8<sup>+</sup> TILs and <i>in vitro</i> functional assays. Humanized hPD1/hPDL1/h4-1BB triple–knock-in mice were used to evaluate the effects of ABL503 and anti-PD1 blockade <i>in vivo</i>.</p>Results:<p>We observed that ABL503 successfully restored the functions of 4-1BB<sup>+</sup> exhausted CD8<sup>+</sup> 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<sup>+</sup> TILs <i>in vitro</i>. Consistently, the combination of ABL503 with anti-PD1 <i>in vivo</i> significantly alleviated tumor growth and induced enhanced infiltration and activation of CD8<sup>+</sup> TILs.</p>Conclusions:<p>ABL503, a PDL1 and 4-1BB dual-targeting bispecific antibody, elicits pronounced additive tumor growth inhibition, with increased infiltration and functionality of exhausted CD8<sup>+</sup> 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.</p><p><i><a href="https://aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-24-1568" target="_blank">See related commentary by Molero-Glez et al., p. 3971</a></i></p></div>
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