CAR-T Cell Advances Target Solid Tumors and Blood Cancers with New Strategies

Researchers have developed ultra-sensitive CAR-T cells capable of detecting very low levels of the CD70 protein, successfully eradicating kidney, ovarian, and pancreatic tumors in preclinical models. The study, published in the journal Science, addresses a key limitation of CAR-T cell therapy: while effective against certain blood cancers, these treatments have not worked well in solid tumors due to the lack of a common target on the surface of cells.

The study introduces an important conceptual shift in the current CAR-T paradigm for solid tumors, suggesting that the problem is not necessarily that the target tumor antigen is absent, but rather that the receptor is not sufficiently sensitive. The ultra-sensitive CAR-T cells feature a HIT receptor with CD80/4-1BBL costimulation, compared to conventional CAR designs.

In a separate development, researchers have successfully developed CAR-T cells targeting the KRASG12V/HLA-A*02:01 complex for solid tumor treatment. KRAS is frequently mutated in tumors of three major cancers: lung adenocarcinomas (30%), colorectal cancer (40%), and pancreatic ductal adenocarcinoma (more than 90%). Primary mutations in KRAS, particularly G12D and G12V, are present in 60 to 70% of pancreatic cancer and 20 to 30% of colorectal cancer.

The KRASG12V/HLA-A02:01-targeting approach addresses a broader patient population than previous strategies. HLA-A02:01 is present in approximately 10 to 20% of Asian populations and dominates in European and American populations at 30 to 50%, compared to HLA-A*11:01 which is relatively frequent only in Asian populations at 15 to 30%. Currently, no targeted therapy is available for the KRAS G12V mutation due to structural challenges for drug development.

Researchers used phage antibody display technology to screen antibodies capable of specific, high-avidity interactions with KRASG12V peptides presented by HLA-A02:01 from single-chain variable fragment libraries. These antibodies were combined with the CAR intracellular domains 4-1BB and CD3ζ to construct chimeric antigen receptors that can selectively target KRASG12V/HLA-A02:01-expressing cells. An RQR8 tag was added to enhance safety in clinical settings.

The KRASG12V/HLA-A*02:01-targeting CAR-T cells demonstrated antitumor activity both in vitro and in vivo. While CAR-T cell therapy targeting CD19 and B-cell maturation antigen has made marked breakthroughs in the treatment of hematological tumors, therapeutic advancements for solid tumors have remained limited, with persistent barriers to achieving durable clinical responses.

The CD70-targeting work implies a possible expansion of the universe of targets in solid tumors, a change in patient selection criteria, greater regulatory complexity, and a potential risk of toxicity if sensitivity is excessive. Both approaches represent efforts to overcome the substantial obstacles CAR-T cell therapy encounters in solid tumor treatment, where target selection represents a pivotal challenge.