Implementing Logic Gates in Adoptive Cell Therapy

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Background

In various approaches for adoptive cell therapy (ACT) of cancer, T cells are genetically redirected to recognize shared, non-mutated tumor-associated antigens (TAAs). However, almost all these TAAs are also expressed by ‘normal’, essential cells and - with no counteracting measures - their targeting can lead to life-threatening toxicity. Strict specificity is also mandatory when regulatory T cells (Tregs) are redirected to suppress inflammation, as the enforcement of immune tolerance in related healthy tissue can severely impair the ability of the immune system to control infection or cancer.

The implementation of logic gates offers a powerful tool for obviating these risks and securing the intended specificity of engineered T cells. Genetic and immunological methodologies for creating AND and AND-NOT gates could capitalize on combinations of presence or absence of selected antigens. It could also translate the activation status of distinct promoters, the unique cellular composition of the target tissue, environmental cues such as hypoxia or acidity and the local level of metabolites, enzymes or cytokines, into designated logic gate inputs.

This Research Topic addresses two critical challenges: what cues can be translated into clinically useful inputs in all possible applications of ACT, and how can this be achieved.

This Research Topic has two goals:
1. To extend our knowledge on the landscape of antigenic and environmental cues, which can be exploited for increasing T cell specificity in ACT. For example, the recent demonstration in ‘Cell Systems’ of “the discriminatory power of combinatorial antigen recognition in cancer T cell therapies”, or the realization that many tumors lose a significant portion of their genetic material already at the premalignant stage. Such progress paves the way for novel methods of differentiating between tumor and normal tissues through the concomitant use of activating and inhibitory receptors.
2. To communicate new tools for translating the increasing knowledge on the unique antigenic and environmental signature characteristic of different clinical conditions into highly selective and hence, safe cell-based therapies. A growing number of immunological and genetic strategies are being devised for implementing logic gates with clever receptors, gene circuits, antibodies or other recognition moieties and their combinations (see SUPRA CARs, Co-LOCKR and others). Recent advances also include genetic switches, which turn on the synthesis of a therapeutic cargo under predefined stimuli that can only be received at the target tissue (e.g. TRUCKs) or hypoxia-sensitive promoters or proteins, which confine the activation of redirected T cells to hypoxic niches.

We invite authors to contribute Original Research, Review, Methods, Mini review, Hypothesis and Theory, Perspective, Clinical Trial, Brief Research Report and Opinion articles addressing both goals of the Research Topic, as defined above.
The first goal calls for scientific articles of a more basic nature focusing on the discovery of antigenic, genetic and environmental constituents of tumors, infected or inflamed tissues and their microenvironment, which could possibly be translated into new targetable entities in ACT.
The second goal calls for articles of a more applicative nature, describing novel technologies or concepts. These will contribute to translating the accumulating knowledge on these unique, composite signatures into safe cell therapies.

Dr. Gidi Gross is a co-founder of ImmPACT Bio and is a co-inventor on patent applications related to cell therapies to treat cancer. Dr. Hinrich Abken is a co-inventor on patent applications related to CAR T Cell therapy. The other Topic Editors declare no potential competing interests in relation this topic.

Keywords: adoptive T cell therapy, synthetic biology, boolean logic gates, combinatorial antigen recognition, genetic switches, CAR-T cells, tumor microenvironment

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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