Novel CAR-T Approaches Show Promise Against Solid Tumors in Preclinical Studies

Researchers have made significant progress in developing next-generation CAR-T cell therapies that show promise against solid tumors in preclinical models, addressing a major limitation of current immunotherapies. Two distinct approaches—one using an in vivo gene editing system and another employing highly sensitive HLA-independent T cell receptors—have demonstrated the ability to clear various solid tumors in mice, potentially expanding the reach of cell therapies beyond blood cancers.

A study published in Nature Magazine by Azalea Therapeutics proves that an in vivo CAR-T approach can generate CAR-T cells directly in the body and clear both blood and solid tumors in mice. By using a precise, multi-step gene editing system, the team was able to target the right cells and the right location in the genome, addressing one of the biggest safety challenges in the field. If successful in humans, this approach could simplify manufacturing, expand access, and unlock broader use of CAR-T therapies.

Separately, researchers have developed a novel CAR T cell therapy using HLA-independent T cell (HIT) receptors that can effectively eliminate different tumor types, as described in a recent article in Science. The team identified CD70 as an optimal therapeutic target due to its restricted expression on tumors across different tumor types. While CD70 was thought to not be consistently expressed throughout entire solid tumors, the researchers suspected conventional CD70 might be expressed on all tumor cells but under the threshold of sensitivity for detection.

The HIT engineered cells are a more sensitive CAR T cell design that effectively eradicated solid tumors in preclinical models. Researchers generated mice that grew human tumors with varying CD70 expression, including kidney, ovarian, and pancreatic cancer—all clinically hard-to-treat tumors. In comparison studies, the HIT cells effectively targeted CD70 and completely eradicated all three tumor types, while conventional CAR T cell therapy showed limited efficacy. This discovery demonstrates that CD70 is expressed on all tumor cells but at varying levels, providing an effective approach to combat heterogeneous tumors, which has been a major obstacle to cancer treatment.

Researchers confirmed that cancer cells that appeared CD70-negative actually retained CD70 expression. Computational analysis of patient tumors revealed low-level expression at the DNA level, previously undetectable due to a biological mechanism that silences gene expression. This work is groundbreaking as the first to report CD70 expression throughout entire tumors initially thought to be CD70-heterogeneous.

Another innovative approach involves lipid nanoparticle-mediated in vivo generation of panCAR immune cells for solid tumor immunotherapy. Researchers have introduced an immune cell-tropic lipid nanoparticle platform that enables systemic delivery of CAR-encoding mRNA for the in vivo generation of panCAR immune cells. A single intravenous injection of this LNP system efficiently and transiently engineers T cells, macrophages, dendritic cells, and NK cells across the spleen, bone marrow, and peripheral blood, yielding a synergistic, multilineage antitumor response.

Using human epidermal growth factor receptor 2 (HER2) as a CAR target, repeated administration of LNP formulated with HER2-CAR mRNA effectively inhibits tumor growth and prolongs overall survival in three murine syngeneic xenograft tumor models, without causing obvious side effects. Immune profiling of treated tumors reveals a remodeled tumor microenvironment with a shift toward an immunostimulatory phenotype, characterized by reduced M2-like macrophages and an increased presence of effector T cell subsets. This establishes LNP-panCAR as a broadly applicable, off-the-shelf in vivo CAR cell therapy platform for solid tumor immunotherapy.