Over the past decade, substantial progress has been made in modern immunotherapy, driven by targeted therapies that inhibit tumor angiogenesis and intrinsic drivers of cancer-cell growth. While current targeted therapies—such as genetically engineered immune cells expressing chimeric antigen receptors (CARs)—rely on identifying ‘specific targets,’ the adaptive immune system relies on a broad and diversified repertoire of antibodies to recognize antigens.

New research reports the development and applicability of libraries of immune cells displaying diverse repertoires of CARs that can recognize non-self antigens and display antigen-dependent clonal expansion, with the expanded population of tumor-specific effector cells leading to long-lasting antitumor responses in mouse models of epithelial tumors. These results demonstrate that synthetic CAR libraries are a compelling technology for screening functional CAR binders to be further characterized preclinically or directly used for clinical translation.

The findings are published in Nature Biomedical Engineering in a paper titled “Synthetic libraries of immune cells displaying a diverse repertoire of chimaeric antigen receptors as a potent cancer immunotherapy.”

In humans, hundreds of millions of different antibodies (or immunoglobulin-like proteins) are created by the immune system so that host immune cells can, among other functions, recognize and destroy nascent malignancies. However, tumors can arise at more frequent intervals than detected, evidenced by the link of immune incompetence with an increased incidence of cancers. Tumor-associated antigens (TAAs), which are mutated self-proteins expressed by some tumors, can elicit a tumor-specific immune response, and the failure of the immune system to recognize TAAs may lead to the evolution of the manifested cancerous disease.

Since the immune system can shape tumor immunogenicity, cancer immunotherapies may require large numbers of high-quality effectors capable of eliminating tumors and tumor-induced immune suppressors to be effective. Antibody libraries can be constructed based on immunized animals, naturally immunized or infected humans, naïve immune systems, or synthetic sources. With sufficiently high diversity, antibody libraries can generate antibodies against different antigens, including self non-immunogenic and toxic antigens. For this reason, these libraries are now extensively used in industry and academia.

Assistant Professor from the Naval Medical University in Shanghai, China, Shi Hu, MD, PhD, and colleagues hypothesized that the synthetic immune cell repertoire could recognize a variety of non-self antigens and be used as a tool for antibody/target identification or as therapeutic agents. The research article reports the development of small-scale to large-scale synthetic cell libraries of immune cells displaying diverse repertoires of CARs that can recognize non-self antigens and display antigen-dependent clonal expansion characterized for antitumor effects in vitro and in vivo.

The expanded population of tumor-specific effector cells led to long-lasting antitumor responses in mouse models of epithelial tumors. The intravenous injection of synthetic libraries of murine CAR-T cells led to robust immunological memory and the recognition of mutated or evolved tumors, owing to the maintenance of CAR diversity. Off-the-shelf libraries of 106 murine or human CAR clones displayed on genetically modified human NK-92 cancer cells eliminated established tumors in mice with murine xenografts and patient-derived xenografts.

“We have shown that combining a mammalian-cell antibody display library with CAR technology builds a ‘molecular evolution machine’ that can function in vivo, acting in ways similar to TCR and B-cell receptor repertoire-based adoptive cellular immunity but in a synthetic fashion,” wrote the researchers.

This technology would allow: (1) the creation of polyclonal yet defined candidate constructs targeting tumors, (2) the generation of individual tumor-specific antibodies, and (3) the identification of tumor-specific neoantigens. Therefore, the synthetic cell library can extend the scope of both adoptive cell therapy and antibody-display and screening technologies. Considering the evolutionary enrichment properties, the synthetic cell library could be particularly well suited to tumor-xenograft settings and can be extended to other disease models, such as endometriosis and organ fibrosis. This system could be a compelling technology to screen for functional CAR binders and discover drug candidates and targets.

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