531P - Enhanced antitumor efficacy and safety through a novel CAR-T strategy targeting MSLN and CLDN18.2

Background

High levels of Claudin18.2(CLDN18.2) and MSLN expression are common in pancreatic cancer and gastric cancer, both with limited treatment options and poor prognoses. While targeting CLDN18.2 shows promise as a therapeutic approach, its direct application in chimeric antigen receptor T cell (CAR-T) may pose the risk of gastrointestinal (GI) toxicities, including Grade 4 GI hemorrhage, due to on-target off-tumor adverse effects.

Methods

To tackle the challenges of on-target toxicities and enable the administration of higher dose of CAR-T cells, we developed OriC613, a dual-targeting CAR-T cell. OriC613 incorporates highly specific and well-tuned MSLN nanobody and CLDN18.2 scFv using logic-gating technology, ensuring CAR-T functionality in tumors expressing both antigens, sparing normal GI tissue expressing only CLDN18.2.

Results

While CLDN18.2 CAR-T and MSLN CAR-T displayed substantial cytotoxicity against CLDN18.2- and MSLN-expressing cells, respectively, OriC613 demonstrated no cytotoxicity towards cells expressing CLDN18.2 alone. Notably, OriC613 exhibited enhanced CAR-T expansion and MSLN targeting efficacy, even in the presence of very low levels of MSLN expression, in a CLDN18.2-dependent manner, both in vitro and in vivo, using gastric (NUGC-4 and derived cell lines) and pancreatic (AsPC-1 and derived cell lines) cancer cells. Moreover, OriC613 showed potent antitumor efficacy from relatively small (119 mm³) to relatively large (976 mm³) tumor sizes, when administered at a dose of 3e6 CAR-T cells, indicating its potential effectiveness in patients with high tumor burden. Importantly, unlike CLDN18.2 CAR-T, OriC613 did not induce significant weight loss and gastrointestinal toxicity in vivo, suggesting a favorable safety profile for OriC613. Furthermore, OriC613 extended the duration of antitumor efficacy through tumor rechallenge experiments, lasting for over 100 days. These findings underscore the potential clinical durability and antitumor efficacy of OriC613.

Conclusions

OriC613 exhibits strong antitumor efficacy and a promising safety profile. These results warrant further clinical trials of OriC613 in patients with pancreatic cancer and gastric cancer.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.