Available online 26 March 2024, 108350

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Chimeric antigen receptor (CAR) T cells are able to recognize specific surface antigens in target cells and carry out a cytotoxic response. Although they own their success and main field of application to cancer, they are potentially able to be designed to attack any pathogenic cell displaying a specific antigen pattern.

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A major limitation of current CAR T therapies is the use of viral vectors for CAR transduction due to the necessity of ex vivo modification and insertional mutagenesis. Several strategies virus-free based are being developed to resolve this issue and to optimize CAR-encoding genetic material delivery into target cells.

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The use of transient-expressed CARs in modified T cells can lower the amount of side effects and widen the range of diseases potentially treated with CAR T cells.

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Continued refinement on targeted non-viral vectors will effectively enable the use of gene therapies in vivo for treatment of a wide range of diseases.

Abstract

The extraordinary success that chimeric antigen receptor (CAR) T cell therapies have shown over the years on fighting hematological malignancies is evidenced by the six FDA-approved products present on the market. CAR T treatments have forever changed the way we understand cellular immunotherapies, as current research in the topic is expanding even outside the field of cancer with very promising results. Until now, virus-based strategies have been used for CAR T cell manufacturing. However, this methodology presents relevant limitations that need to be addressed prior to wide spreading this technology to other pathologies and in order to optimize current cancer treatments. Several approaches are being explored to overcome these challenges such as virus-free alternatives that additionally offer the possibility of developing transient CAR expression or in vivo T cell modification. In this review, we aim to spotlight a pivotal juncture in the history of medicine where a significant change in perspective is occurring. We review the current progress made on viral-based CAR T therapies as well as their limitations and we discuss the future outlook of virus-free CAR T strategies to overcome current challenges and achieve affordable immunotherapies for a wide variety of pathologies, including cancer.

Section snippetsHistory and background of CAR T therapies

Chimeric antigen receptor (CAR) T cell therapies were born in the 1980s (Zhang et al., 2017) as a way to enhance the immune's system response to pathogenic cells when the natural response has failed (Breman et al., 2018). CAR T cells are based on the idea of genetically modified T cells to express engineered receptors, a type of chimeric constructs able to recognize and react towards specific antigens in a major histocompatibility complex (MHC)-independent manner, therefore carrying out a more

Clinical applications of CAR T therapies

The introduction of CAR T therapies in the therapeutic management of cancer has entailed a forward leap in the way tumors are treated and has established cell immunotherapies as a solid third pillar, alongside small chemical and biological molecules in the pharmacological approach of this illness. Consequently, the ability of these modified T cells to recognize specific surface antigens and react towards them in an MHC-independent manner, minimizing systemic off-target effects, sets CAR T cells

Current limitations of CAR T treatments

Although CAR T technology has made huge progress over the years, there are some downsides that are still to overcome. These limitations include limited targeting, prolonged manufacturing time, excessive production costs, “on-target, off-tumor” toxicity, resistance, and adverse reactions to the therapy (e.g., insertional mutagenesis, neurological toxicity, cytokine release syndrome (CRS) and anaphylaxis or allergic processes) (Cappell and Kochenderfer, 2023a). Most of these limitations are

Emerging strategies to overcome CAR T limitations

Potential strategies to mitigate many of the current limitations could involve transforming the manufacturing process into a standardized, readily available approach, akin to an “off-the-shelf” procedure. Being able to shift to an allogeneic cell source would allow to scale-up the production process, diminish the cost and the time needed, but most importantly, take CAR T therapies to the broad public.

One of the primary obstacles encountered in the production of allogeneic CAR T cells revolves

Transient vs. permanent CAR expression

When evaluating the characteristics of cancer as a target disease for CAR T cell treatment the first thing that is clear is that to cure cancer it is imperative to remove all cancerous cells. This may be obvious at first but has critical implications on the nature of the therapy, starting with the stability of the CAR expression in the modified T cells (Aghajanian et al., 2022). In order to eliminate all tumor cells, a stable, long-lasting expression of the CAR within circulating T cells

Non-viral mediated CAR T expression

Even though virus-based vectors have had a leading role in the entering of gene therapies in the clinical frame, it has been in this precise stage were most of their limitations have been exposed. In the specific case of AAVs, the biomass needed for scaling the production process is already a bottleneck. This, linked to their already mentioned limited packaging capacity, low tissue selectivity (despite certain AAVs tropism), liver toxicity and immunogenicity have proven incompatibilities with

Conclusions

Six years have passed since the first CAR T cell therapy appeared on the market for hematological malignancy treatment. It has been a long road since then, and research has shown both the limitations that current products present, as well as the potential progress that biotechnology can offer. Limitations, such as complex manufacturing processes and therefore high costs, have set the reality of these therapies far away from an extended use, limiting them to specific and severe cases. Moreover,

Uncited references

Aghajanian et al., 2022b

Pouya et al., 2022

Zhang and zheng, Wang T, Wang X feng, Zhang Y qing, Song S xia, Ma C qing., 2022

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This work was supported by the Basque Country Government (Consolidated Groups, IT1448-22), and by CIBER-BBN, CB06/01/1028, ISCIII. L.E.R. thanks the Basque Country Government for the granted pre-doctoral fellowship (PRE_2022_1_0042). N.A. and M.M acknowledge the Spanish Ministry of Universities and the European Union-Next Generation EU for the Margarita Salas grant (MARSA21/98 and MARSA21/97, respectively) at the University of the Basque Country (UPV/EHU). I.M. thanks the Spanish Ministry of

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© 2024 Published by Elsevier Inc.