PD-L1 CAR T Therapy May Suppress the Gastric Cancer Tumor Microenvironment

Recent preclinical research suggests that PD-L1-targeted chimeric antigen receptor (CAR) T-cell therapy may improve onefficacy of current CAR T-cell therapies in solid tumors by removing PD-L1-expressing cells in the tumor microenvironment (TME).¹

These data were presented at the American Associated for Cancer Research (AACR) Annual Meeting 2023, held April 14-19 in Orlando, Florida, by Hye-Seong Park, VaxCell Biotherapeutics.

“Heterogeneity and the tumor microenvironment are major obstacles to overcoming incurable advanced gastric cancer (AGC). Although Epstein-Barr virus-positive and microsatellite instability subtypes can be detected early and properly treated, they are rare in AGC. In this regard, recent combinational therapy of immune checkpoint inhibitors such as PD-1/PD-L1 inhibitors and other various therapeutics has been tried, but there are clinically limited doses and drug resistance,” Park and colleagues wrote.¹ “We hypothesized that CAR-T targeting PD-L1, the common tumor-associated antigen (TAA), which expresses in most advanced cancer cells, would make a significant breakthrough in curing a solid tumor.”

Park and colleagues constructed a second-generation PD-L1-targeted, lentiviral, CAR T-cell therapy to have an affinity with PD-L1 in the solid tumor TME. Cd28 was chosen and tested as the secondary signaling motif. Vax-CAR-T, the resulting therapy, was then able to recognize and exhibit in vitro cytotoxic activity against a PD-L1-expressing AGC cell line. Vax-CAR-T cells had higher levels of the CD25 activation marker as well as the Tim3 and LAG3 inhibitory markers compared to untransduced T cells.

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The investigators found that Vax-CAR-T cells significantly suppressed tumor growth in AGC xenograft NSG mouse models both over 95 mm³ and under 50 mm^3. The treated mice experienced no significant adverse events and the CAR T-cell therapy infusion was well-tolerated as of 2 weeks after treatment. The mice also gradually recovered weight gains 5 days after CAR-T cell infusion.¹

“We believe that a new autologous CAR-T targeting PD-L1 could be a promising new tool for removing heterogeneous solid tumors in TME, which would be a significant step forward in improving current conventional and immunotherapeutic strategies,” Park and colleagues concluded.¹

Other cell therapies are being evaluated in clinical trials in the gastric cancer indication, and 1 of these is CARSgen’s CT041 therapy. CT041 is being evaluated in a phase 1 trial (NCT03874897) which last reported data in late 2022. Treated patients with gastric cancer had an overall response rate of 48.6% and a disease control rate of 73.0%. The 6-month duration of response rate was 44.8%. No grade 3 or higher CRS or neurotoxicities, treatment-related deaths or dose-limiting toxicities were reported.²

CARsgen is also pursuing next-generation therapies in the indication, with Hong Ma, senior vice president of clinical development for cancer immunotherapy, telling CGTLive^TM about their new CycloCAR technology “to try to address the challenges we are facing using CAR T targeting solid tumors, namely CAR T persistence.” Ma added that CAR T-cell therapies require “strong preconditioning and a lymphodepletion regimen. With CycloCAR, we arm the CAR T using interleukin-7 CCR 21. Hopefully this improves the T cell persistence, and we have some preclinical data that show in animal models, you may not require lymphodepletion anymore.”

REFERENCES

1. Park HS, Choi EJ, Yu JI, et al. The efficacy and safety of PD-L1-specific CAR-T in advanced gastric cancer. Presented at: AACR Annual Meeting 2023, April 14-19; Orlando, Florida. Abstract #889
2. Ma H. CLDN18.2-targeted CAR T-cell therapy CT041 in subjects with cancers of the digestive system. Presented at: 7th Annual CAR-TCR Summit 2022, September 19-22, Boston, MA.