Biological processes require specificity and cells are uniquely equipped to execute complex targeted behaviors. One well-understood example involves cells from the immune system that must solve the problem of selective destruction of pathogens and pathogen-infected cells. These mechanisms have been co-opted in oncology to create cell-based medicines designed to target individual molecules expressed in cancer cells. Building on this foundation, research in drug discovery has advanced to the stage where systems for integrating signals derived from multiple antigens have been tested. This strategy offers the prospect of broadening cell therapy to more patients and reducing the toxicities associated with cancer treatment. By analogy with binary computing devices, these approaches are sometimes classified as types of synthetic logic system, where responses are gated by the specific profile of multi-signal inputs. Such elements include cells engineered to integrate signals from two antigens in various ways: (i) OR gates where either of the two antigens activates a response; (ii) AND gates where both antigens must be present to activate; and (iii) NOT gates where one antigen must be present, and the second antigen absent to activate. More complex signal integration is also possible.

In this Research Topic, state-of-the-art multi-signal integration designs are discussed in a series of excellent papers that not only review the subject but also describe advances in this promising area of translational science. By modifying effector cells with variants of natural immune receptors, cell therapies have been created that have remarkable specificity for cancer cells and minimize the collateral damage to normal tissues. The basis for the selectivity is the application of receptor systems that can recognize antigen profiles, rather than single antigens. Recent advances include OR gates with either two activating receptors or a single receptor with dual-binding, AND gates with two receptors that act in concert such that two antigens are required to induce cytotoxicity, and NOT gates that generally incorporate one activating receptor and one inhibitory receptor. A variety of strategies to overcome the technical hurdles associated with these approaches, including CRISPR and synthetic mRNA, are described. Comparison to protein therapeutics-based logic gate approaches, that seek to achieve similar cancer cell specificity through multi-specific large molecule-mediated activation of endogenous immune cells, will also be covered.

We are interested in manuscripts that address any of the following topics:

1. Multi-targeted gene-edited immune cells (e.g., T cells, NK cells, macrophages) designed to react to more than one antigen in a gated fashion
2. Novel concepts for multi-antigen-targeted cell therapy for cancer or inflammation
3. Methods of modification that are transient (e.g., using synthetic mRNA)
4. Comparisons between different multi-targeting modalities: e.g., different effector cell types or cell vs. multi-specific large molecules
5. Comparisons between in vivo and ex vivo methods for multi-antigen-targeted cell therapy
6. Identifying optimal tumor-associated antigen combinations to enable multi-targeted approaches

Manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by robust and relevant validation (clinical cohort or biological validation in vitro or in vivo) are out of scope for this topic.

Submit your idea

Impact

Frontiers in Immunology

Participating Journals

Impact