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‘Off-the-shelf’ allogeneic CAR T cells: development and challenges

Abstract

Autologous chimeric antigen receptor (CAR) T cells have changed the therapeutic landscape in haematological malignancies. Nevertheless, the use of allogeneic CAR T cells from donors has many potential advantages over autologous approaches, such as the immediate availability of cryopreserved batches for patient treatment, possible standardization of the CAR-T cell product, time for multiple cell modifications, redosing or combination of CAR T cells directed against different targets, and decreased cost using an industrialized process. However, allogeneic CAR T cells may cause life-threatening graft-versus-host disease and may be rapidly eliminated by the host immune system. The development of next-generation allogeneic CAR T cells to address these issues is an active area of research. In this Review, we analyse the different sources of T cells for optimal allogeneic CAR-T cell therapy and describe the different technological approaches, mainly based on gene editing, to produce allogeneic CAR T cells with limited potential for graft-versus-host disease. These improved allogeneic CAR-T cell products will pave the way for further breakthroughs in the treatment of cancer.

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Fig. 1: Manufacturing of allogeneic CAR T cells.
Fig. 2: Persistence of CAR T cells and tumour evolution.
Fig. 3: Examples of gene editing strategies to optimize CAR-T cell functions.

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Acknowledgements

The authors thank C. Delenda (Cellectis) and V. Alcazer (Centre Léon Bérard) for their help in preparing tables and figures and D. Sourdive (Cellectis) for his critical comments on process and manufacturing and his help in establishing Fig. 1.

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S.D. contributed to all aspects of the article. P.D and L.P. researched data, provided substantial contribution to the content and wrote the article. S.A.G. contributed substantially to discussion of the content, wrote the article and edited and reviewed the manuscript before submission. G.M. and S.D. edited and reviewed the article before submission.

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Correspondence to S. Depil.

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S.D. has been an employee of Cellectis and has served as a consultant for or on the scientific advisory boards of Servier, Celyad, PDC*line Pharma, Erytech, AstraZeneca, Elsalys and Netris Pharma. L.P. and P.D. are employees of Cellectis. S.A.G. has received research and/or clinical trial support from Novartis, Servier and Kite and has served as a consultant for or on study steering committees or scientific advisory boards of Novartis, Cellectis, Adaptimmune, Eureka, TCR2, Juno, GlaxoSmithKline, Vertex, Cure Genetics, Humanigen and Roche.

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Glossary

Leukapheresis

Procedure through which white blood cells are separated and collected from the blood with an advanced centrifuge while red blood cells and other blood components are returned into the circulation.

HLA disparities

Human leukocyte antigen (HLA) incompatibility between the donor and the recipient. HLA disparities are associated with higher risk of graft failure, delayed immune reconstitution and graft-versus-host disease. New protocols allow donors mismatched for up to six alleles (haploidentical donors) to be used in haematopoietic stem cell transplantation without detrimental graft-versus-host disease.

Antigen-naive

Not previously exposed to foreign antigens.

Extravillous cytotrophoblast cells

The cells of the outermost layer of the fetal component of the placenta.

Syncytiotrophoblast

The epithelial covering of the vascular embryonic placental villi, which invades the wall of the uterus to establish nutrient circulation between the embryo and the mother.

Alloimmunization

Formation of antibodies against non-self antigens (here human leukocyte antigen molecules of the donor).

Stem cell transplantation

(SCT). For allogeneic SCT, haematopoietic stem cells are taken from the bone marrow, peripheral blood or umbilical cord blood of a healthy donor matched for human leukocyte antigen alleles. For haploidentical transplant, a healthy first-degree relative — a parent, sibling or child — serves as a donor, who needs to be only a 50% match to the recipient.

Spectratyping

Technique that measures T cell receptor repertoire diversity.

Multiplex gene editing

Gene editing technology that targets multiple regions in a genome.

Non-myeloablative and lymphodepletive chemotherapy

A chemotherapy regimen that does not destroy all the cells of the bone marrow but specifically induces destruction of the lymphocytes.

Killer cell immunoglobulin-like receptors

(KIRs). These receptors on natural killer (NK) cells recognize groups of for human leukocyte antigen class I alleles. The interaction between a KIR and a class I allele inhibits reactivity of the NK cell. The absence of recognition of the appropriate KIR ligand on  a mismatched cell triggers NK cell reactivity.

Immunomagnetic separation

A technique for separating cells by means of their antigens bound to antibodies coating microscopic paramagnetic beads, which can then be separated by magnetic attraction.

PiggyBac transposition

The piggyBac transposon is a movable genetic element that efficiently transposes between vectors and chromosomes through a ‘cut-and-paste’ mechanism.

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Depil, S., Duchateau, P., Grupp, S.A. et al. ‘Off-the-shelf’ allogeneic CAR T cells: development and challenges. Nat Rev Drug Discov 19, 185–199 (2020). https://doi.org/10.1038/s41573-019-0051-2

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