A carcinoembryonic antigen-specific cell therapy selectively targets tumor cells with HLA loss of heterozygosity in vitro and in vivo

Abstract

The CEACAM5 gene product [carcinoembryonic antigen (CEA)] is an attractive target for colorectal cancer because of its high expression in virtually all colorectal tumors and limited expression in most healthy adult tissues. However, highly active CEA-directed investigational therapeutics have been reported to be toxic, causing severe colitis because CEA is expressed on normal gut epithelial cells. Here, we developed a strategy to address this toxicity problem: the Tmod dual-signal integrator. CEA Tmod cells use two receptors: a chimeric antigen receptor (CAR) activated by CEA and a leukocyte Ig-like receptor 1 (LIR-1)–based inhibitory receptor triggered by human leukocyte antigen (HLA)-A*02. CEA Tmod cells exploit instances of HLA heterozygous gene loss in tumors to protect the patient from on-target, off-tumor toxicity. CEA Tmod cells potently killed CEA-expressing tumor cells in vitro and in vivo. But in contrast to a traditional CEA-specific T cell receptor transgenic T cell, Tmod cells were highly selective for tumor cells even when mixed with HLA-A*02–expressing cells. These data support further development of the CEA Tmod construct as a therapeutic candidate for colorectal cancer.

Robust In Vitro Pharmacology of Tmod, a Synthetic Dual-Signal Integrator for Cancer Cell Therapy

“…In previous work we noted a general correlation between activator and blocker receptor function in Jurkat and primary T cells ( 5 , 11 , 13 , 15 ). We next attempted to confirm our findings from Jurkat effector cells in primary T cells, focusing on the MSLN CAR/A*02 blocker pair.…”

“…It directs engineered T cells to kill tumor cells with great specificity, even in co-culture with a 10-fold excess of normal cells. Finally, it can achieve absolute potency and selectivity levels that rival the adaptive immune response ( 11 , 13 ). Here we explore the pharmacology of Tmod in vitro by systematic variation of Ag and/or receptor inputs.…”

Tumor buster - where will the CAR-T cell therapy ‘missile’ go?

“…However, CEA CAR-T cells have been reported to induce transient colitis because CEA is expressed on normal gut epithelial cells [ 242 ]. To address this issue, Mark et al designed CEA Tmod cells using a CAR activated by CEA and an LIR-1-based inhibitory receptor triggered by HLA-A*02 [ 243 ]. These cells could harness the loss of HLA heterozygous genes in tumors to safely and effectively kill tumor cells.…”

“…These cells could harness the loss of HLA heterozygous genes in tumors to safely and effectively kill tumor cells. However, unlike CEA CAR-T cells, Tmod cells still could specifically target tumor cells in the presence of cells expressing HLA-A*02 [ 243 ]. However, there are no clinical trials of Tmod cells.…”

Current State of Cell Therapies for Gastrointestinal Cancers

“…In one such study, CAR T cells targeting carbonic anhydrase IX for metastatic renal cell cancer caused biliary adverse effects (AEs) due to physiologic expression within the biliary duct cells, which was attenuated with pretreatment of carbonic anhydrase IX antibody 40 . Sandberg et al 41 developed a CAR T cell therapy with a CEA ligand and an inhibitory molecule targeting HLA A*2, found in some patients with CRC. The blocker was inactivated for patients with an HLA-A2 loss of heterozygosity, often seen in tumor cells, leading to a robust antitumor response.…”