CAR-T cells have shown significant efficacy and safety at treating hematologic malignancies, especially those expressing CD19 on the surface but also BCMA-expressing malignancies. The US Food and Drug Administration (FDA)–approved CAR-T-cell products are autologous T cells genetically engineered by lentiviral or retroviral vectors to express an anti-CD19 CAR. Genome editing is being applied to CAR-T-cell therapies in numerous different ways, but the two most advanced are: (1) to generate off-the-shelf, chemotherapy resistant CAR-T cells and (2) to make CAR-T cells more potent by using targeted integration rather than retroviral or lentiviral semirandom insertion or by knocking out checkpoint inhibitors.

Off-the-Shelf CAR-T Cells

 Autologous CAR-T-cell therapies, although effective, have challenges, including the inability to manufacture a potent cell product from patients who have been exposed to large amounts of prior lympholytic chemotherapy; the inability to manufacture a product in a timely fashion before the patient’s clinical condition deteriorates; and the cost of making personalized cellular products. An “off-the-shelf” allogeneic product would solve many of these problems because they would be manufactured from people with healthy T cells; the products would be ready to go and premade for each patient, and multiple doses (tens to hundreds) could be manufactured at once, thereby decreasing cost. However, allogeneic CAR-T cells would cause graft versus-host disease without modification, but genome editing, in a nuclease-agnostic manner, can create a population of allogeneic CAR-T cells by creating inactivating indels in the T-cell receptor alpha (TRAC) gene.[1] Moreover, genome editing can be used to create an allogeneic product that is resistant to lymphodepletion (e.g., creating anti-CD52 antibody–resistant cells by genome editing the CD52 gene) (Fig. 1).[2] Early clinical trials have demonstrated that genomes edited off-the-shelf do have efficacy but durability seems to be an issue.[3]More patients, as part of different trials, with longer follow-up will be informative. Even if the durability issue is not readily solved, if off-the-shelf CAR-T cells can create significant remissions, it would create the opportunity to build such cells into an HSCT program in which it is known that the efficacy of HSCT is higher when the patients undergo transplant with minimal residual disease.

Fig1. GENOME EDITING TO CREATE CHIMERIC ANTIGEN RECEPTOR (CAR)-T CELLS. GVHD, graft-versus-host disease; HDR, homology-directed repair; NHEJ, nonhomologous end-joining; TRAC, T-cell receptor alpha.

Increasing Potency

The long-term remission rates following CAR-T-cell therapy remain in the 30% to 40% range for the FDA-approved products. Thus a goal is to improve the potency of these therapies to increase the long-term remission rate. Several genome editing approaches have been reported to increase the potency. One approach is to knock the CAR into the TRAC locus such that it is regulated as if it were a T-cell receptor. The proof-of-concept publication demonstrated that the knock-in CAR-T cells had decreased features of exhaustion, including in functional assays.[4] A second approach to improve potency is to use genome editing to knockout out PD-1 to mimic what is achieved pharmacologically by checkpoint blockade using inhibitors of the PD-1 pathway. Preliminary evidence of PD-1 knockout safety has been demonstrated, but the broader safety and efficacy of this genetic manipulation need to be determined.[5]

References

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[1] Osborn MJ, et al. Evaluation of TCR gene editing achieved by TALENs, CRISPR/Cas9, and megaTAL nucleases. Mol Ther. 2016;24(3):570–581.

[2] Poirot L, et al. Multiplex genome-edited T-cell manufacturing platform for “off-the-shelf|” adoptive T-cell immunotherapies. Cancer Res. 2015;75(18):3853–3864.

[3] Qasim W, et al. Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells. Sci Transl Med. 2017;9(374):eaaj2013.

[4] Eyquem J, et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature. 2017;543(7643):113–117.

[5] Stadtmauer EA, et al. CRISPR-engineered T cells in patients with refractory cancer. Science. 2020;367(6481):eaba7365.

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مواضيع ذات صلة

Therapeutic Genome Editing for Hematologic Diseases: β-Thalassemia

Therapeutic Genome Editing for Hematologic Diseases: Sickle Cell Disease

TFIIIA Binding to the Middle of its Gene as Well as to RNA

Biology of 5S RNA Synthesis in Xenopus

Entropy, a Basis for Lambda Repressor Inactivation

Induction from the Lysogenic State

The Need for and the Realization of Hair-Trigger Induction

Site for Cro Repression and CI Activation

Chronology of Becoming a Lysogen

N Protein and Antitermination of Early Gene Transcription

Spontaneous Mutations in bacteria

Mechanisms of Gene Transfer in Bacteria