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Engineering the next generation of cell-based therapeutics

Nature Reviews Drug Discovery volume 21, pages 655–675 (2022)Cite this article

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Abstract

Cell-based therapeutics are an emerging modality with the potential to treat many currently intractable diseases through uniquely powerful modes of action. Despite notable recent clinical and commercial successes, cell-based therapies continue to face numerous challenges that limit their widespread translation and commercialization, including identification of the appropriate cell source, generation of a sufficiently viable, potent and safe product that meets patient- and disease-specific needs, and the development of scalable manufacturing processes. These hurdles are being addressed through the use of cutting-edge basic research driven by next-generation engineering approaches, including genome and epigenome editing, synthetic biology and the use of biomaterials.

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Fig. 1: A cellular therapy process flow.
Fig. 2: Leveraging CRISPR–Cas-mediated genome and epigenome editing for improved cell-based therapeutics.
Fig. 3: Using synthetic biology approaches to endow therapeutic cells with enhanced functional properties.
Fig. 4: Using synthetic circuits to enhance therapeutic function.
Fig. 5: Strategies to overcome immune rejection for allogeneic cell therapy.

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Acknowledgements

The authors acknowledge editorial assistance of J. Veljkovic Garafalo, an employee of Sigilon Therapeutics (Cambridge, MA). Work in the authors’ laboratories was supported by the JDRF grant JDRF 3-SRA-2021-1023-S-B (O.V.), the US NIH, grants R01DK120459 (O.V.), R35GM143532 (I.B.H.), R21EB030772 (I.B.H.) and R01EB032272 (C.J.B.), ONR N00014-21-1-4006 (C.J.B.) the Cancer Prevention & Research Institute of Texas (CPRIT) grants RR170030 (I.B.H.) and RP210205 (O.V.).

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Author notes

  1. Hozefa Bandukwala

    Present address: Flagship Pioneering, Cambridge, MA, USA

  2. Devyn M. Smith

    Present address: Arbor Biotechnologies, Cambridge, MA, USA

Authors and Affiliations

  1. Department of Bioengineering, Rice University, Houston, TX, USA

    Caleb J. Bashor, Isaac B. Hilton & Omid Veiseh

  2. Department of Biosciences, Rice University, Houston, TX, USA

    Caleb J. Bashor & Isaac B. Hilton

  3. Sigilon Therapeutics, Cambridge, MA, USA

    Hozefa Bandukwala & Devyn M. Smith

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Contributions

All authors performed literature reviews and participated in the writing of the manuscript. C.J.B., I.B.H. and O.V. share corresponding author responsibilities.

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Correspondence to Caleb J. Bashor, Isaac B. Hilton or Omid Veiseh.

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Competing interests

All authors are inventors on several patents in the field of cell-based therapeutics, biomaterials, genome editing and genetic engineering that are owned by their current or former employers. D.M.S. holds equity in Sigilon Therapeutics and is currently an employee and shareholder of Arbor Bio. H.B. holds equity in Sigilon Therapeutics and is currently an employee and shareholder of Flagship Pioneering. O.V. is co-founder, holds equity in and receives consulting payments from Sigilon Therapeutics, Pana Bio, Avenge Bio and Curada Bio. O.V. has received compensation for consulting from Establishment Labs and Auregen Bio Therapeutics SA. The views presented here should not be considered as endorsements of any specific product or company.

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Glossary

Adoptive cell transfer

The transfer of cells into a recipient patient.

Gene therapy

A therapy whereby vectors are administered to modify a person’s genes to treat or cure a disease.

Chimeric antigen receptors

Receptors that have been engineered to direct immune cell response to cells expressing specific antigens.

Cell therapy

A form of treatment in which viable cells are administered to a patient to elicit a medicinal effect.

Epigenome editing

Genetic engineering approach in which the epigenome is modified at specific genomic sites using engineered molecules.

Allogeneic cell therapies

Cell therapy interventions that rely on a single donor source to treat many patients.

Pluripotent stem cells

Cells that have the capacity to self-renew by dividing and to differentiate into various phenotypes.

Universal cells

Cells that have been genetically manipulated to remove required components for immune recognition to create a universal donor.

Non-homologous end joining

(NHEJ). An error-prone mechanism in which broken ends of DNA are joined together.

Homology-directed repair

(HDR). A precise repair mechanism that uses homologous donor DNA to repair DNA damage.

Base editing

CRISPR–Cas9-based genome editing technology that allows the introduction of point mutations in the DNA without generating double-stranded breaks.

Safety kill switch

Engineered gene into therapeutic cells that can be activated using small molecules to induce apoptosis to enhance the safety of cell therapy.

Switch-like activation

When system activates abruptly at a specific threshold of input.

Boolean AND-gate

A system that performs a computation whereby an output occurs only when all the inputs are present.

Hypoimmunogenic

Describes genetically manipulated cells designed to avoid adaptive and innate immune surveillance.

Autologous cell therapy

Cell therapy intervention that uses an individual’s own cells.

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Bashor, C.J., Hilton, I.B., Bandukwala, H. et al. Engineering the next generation of cell-based therapeutics. Nat Rev Drug Discov 21, 655–675 (2022). https://doi.org/10.1038/s41573-022-00476-6

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