Data from Anti–4-1BB×PDL1 Bispecific Antibody Reinvigorates Tumor-Specific Exhausted CD8⁺ T Cells and Enhances the Efficacy of Anti-PD1 Blockade

• DOI: 10.1158/1078-0432.c.7447741.v1
• Publication Date: 2024-09-13T07:31:52Z
• Authors: 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
• Keywords: Bispecific antibody

<div>AbstractPurpose:<p>To overcome the limited efficacy of immune checkpoint blockade, there is a need to find novel cancer immunotherapeutic strategies for optimal treatment cancer. The anti–4-1BB×PDL1 bispecific antibody—ABL503 (also known as TJ-L14B)—was designed simultaneously target PDL1 and 4-1BB demonstrated strong antitumor T-cell responses without considerable toxicity. In this study, we investigated mechanisms by which combination ABL503 anti-PD1 blockade affected reinvigoration exhausted tumor-infiltrating CD8<sup>+</sup> T cells (CD8<sup>+</sup> TIL) efficacy.</p>Experimental Design:<p>Single-cell suspensions hepatocellular carcinoma ovarian tissues from treatment-naïve patients were used immunophenotyping TILs <i>in vitro</i> functional assays. Humanized hPD1/hPDL1/h4-1BB triple–knock-in mice evaluate effects vivo</i>.</p>Results:<p>We observed that successfully restored functions 4-1BB<sup>+</sup> TILs, enriched tumor-specific but unresponsive blockade. Importantly, compared with alone, further enhanced restoration human vitro</i>. Consistently, vivo</i> significantly alleviated tumor growth induced infiltration activation TILs.</p>Conclusions:<p>ABL503, dual-targeting antibody, elicits pronounced additive inhibition, increased functionality cells, in turn enhances anticancer These promising findings suggest (TJ-L14B) PD1 inhibitors will likely enhance therapeutic benefit 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 Molero-Glez et al., p. 3971</a></i></p></div>