Immunogenicity of CAR T cells in cancer therapy

Wagner, Dimitrios L.; Fritsche, Enrico; Pulsipher, Michael A.; Ahmed, Nabil; Hamieh, Mohamad; Hegde, Meenakshi; Ruella, Marco; Savoldo, Barbara; Shah, Nirali N.; Turtle, Cameron J.; Wayne, Alan S.; Abou‐El‐Enein, Mohamed

doi:10.1038/s41571-021-00476-2

Cited by 184 publications

(148 citation statements)

References 155 publications

(232 reference statements)

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“…Despite these advantages, allogeneic CAR T cells face formidable challenges. Foremost among these is controlling the risk of allo-rejection of infused cells by the recipient immune system and, to a lesser extent, the development of graft-versus-host disease (87). To overcome these issues, gene-editing methods such as CRISPR-Cas9, transcription activator-like effector nucleases (TALEN), or zinc finger nucleases (ZFN) have been used to disrupt the expression of endogenous T-cell receptors and/or MHC on the allogeneic T cells (refs.…”

Section: Moving From Autologous To Allogeneic Productsmentioning

confidence: 99%

“…3). While these promising approaches mitigate immunogenic recognition of MHC-deficient CAR T cells by host CD8 T cells, the infused cells become more prone to natural killer-cell killing (87). In addition, the tolerable number of potentially alloreactive CAR T cells infused into the recipient has yet to be established (87).…”

Section: Moving From Autologous To Allogeneic Productsmentioning

confidence: 99%

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Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy

Abou‐El‐Enein

Elsallab

Feldman³

et al. 2021

Blood Cancer Discovery

Self Cite

144

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As of April 2021, there are five commercially available chimeric antigen receptor (CAR) T cell therapies for hematologic malignancies. With the current transition of CAR T cell manufacturing from academia to industry, there is a shift toward Good Manufacturing Practice (GMP)-compliant closed and automated systems to ensure reproducibility and to meet the increased demand for patients with cancer. In this review, we describe current CAR T cell clinical manufacturing models and discuss emerging technologic advances that embrace scaling and production optimization. We summarize measures being used to shorten CAR T cell manufacturing times and highlight regulatory challenges to scaling production for clinical use. Significance:As the demand for CAR T cell cancer therapy increases, several closed and automated production platforms are being deployed, and others are in development. This review provides a critical appraisal of these technologies, which can be leveraged to scale and optimize the production of nextgeneration CAR T cells. iNtRODUctiONChimeric antigen receptor (CAR)-modified T cells have emerged as an efficacious treatment for patients with certain hematologic malignancies (1). Currently, five CAR T cell products are approved for commercial use and available on the U.S. market: three for B-cell leukemia and lymphoma (tisagenlecleucel, axicabtagene ciloleucel, lisocabtagene maraleucel), one for mantle cell lymphoma (brexucabtagene autoleucel), and one for multiple myeloma (idecabtagene vicleucel; refs. 2-8). These therapies involve genetically modifying patient-derived (autologous) peripheral blood T cells to express a CAR directed against antigens present on the surface of targeted tumor cells, such as the CD19 molecule, or, in the case of idecabtagene vicleucel, B-cell maturation antigen (BCMA;. After antigen recognition, the intracellular signaling domains activate the immune effector and memory functions of the CAR T cells. Once activated, these T cells proliferate, infiltrate tumor sites, secrete cytokines, and release cytolytic granules to eliminate targeted cells in an antigen-dependent manner (1). All approved CAR T cell products are second-generation CARs that incorporate CD28 or CD137 (4-1BB) costimulatory signals, which are essential for eliciting a clinically relevant immune response (9-15). These CAR T cells were able to elicit complete responses (CR) in 32% to 67% of patients with lymphoma and showed better CR rates in patients with leukemia (16)(17)(18)(19).The increasing success of CAR T immunotherapies in relapsed/refractory hematologic malignancies sparked the interest of pharmaceutical companies, and several products targeting a variety of cancers are currently in the pipeline (20). However, many limitations to current CAR T cell manufacturing must be overcome before this modality can be fully integrated into routine clinical practice. First, most CAR T cell trials to date have used autologous peripheral blood and apheresis as the main cell sources for manufacturing

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Section: Moving From Autologous To Allogeneic Productsmentioning

confidence: 99%

Section: Moving From Autologous To Allogeneic Productsmentioning

confidence: 99%

Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy

Abou‐El‐Enein

Elsallab

Feldman³

et al. 2021

Blood Cancer Discovery

Self Cite

144

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“…235 CAR T cell therapy has even induced anaphylaxis, an event thought to reflect the induction of an IgE response against murine scFv epitopes. 236 Methods to reduce CAR immunogenicity have been extensively reviewed by Wagner et al 237 and encompasses the removal of immunogenic CAR components, exchange of mouse-derived scFvs with humanised/ human scFvs, 238 eliminating immunogenic linkers through the use of heavy chain only CARs including nanobodies 239 and replacement of scFvs with receptorligand binding moieties. [240][241][242]…”

Section: Enhancing Car T Cell Efficacy By Refining Immunogenicity Of Target Bindersmentioning

confidence: 99%

How Can We Engineer CAR T Cells to Overcome Resistance?

Glover¹,

Avraamides²,

Maher³

2021

BTT

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Chimeric antigen receptor (CAR) T cell therapy has achieved unrivalled success in the treatment of B cell and plasma cell malignancies, with five CAR T cell products now approved by the US Food and Drug Administration (FDA). However, CAR T cell therapies for solid tumours have not been nearly as successful, owing to several additional challenges. Here, we discuss mechanisms of tumour resistance in CAR T cell therapy and the emerging strategies that are under development to engineer CAR T cells to overcome resistance.

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“…Moreover, use of these technologies is likely to complement and enhance patient responsiveness and/or serve as an alternative to monoclonal antibody treatment that targets immune checkpoint inhibitors (ICIs), such as PD-1 or CTLA-4, which have been effective in only a subset of cancers. [117][118][119] Aside from the suitable safety documented in the above CRISPR-Cas9-based anti-tumor immunotherapy clinical trials, the small sample sizes and high variability in survival of individual patients limit definitive conclusions on the efficacy of these treatments. However, with a number of current CRISPR-based trials targeted toward boosting the immune response via manipulation of immune-related genes (Table 2), more conclusive results are likely to be seen during the coming months.…”

Section: Pd-1 Knockout T Cellsmentioning

confidence: 99%

“…Principally, in the context of cancer immunotherapy where potent immune activation is the goal, the extent of anti-Cas antibodies and/or T cells that may interfere with CRISPR-based treatment needs to be elucidated. 119,162 Recently, three studies have shown that both antibodies and T cells against Streptococcus pyogenes Cas9 (SpCas9) and Staphylococcus aureus Cas9 (SaCas9) are indeed present in many individuals, supporting that further investigation is required. First, Simhadri et al 163 highlighted that approximately 2.5% and 10% of donors (a predominantly white cohort from the United States) tested positive for anti-SpCas9 and anti-SaCas9 antibodies in human sera, respectively, by enzyme-linked immunosorbent assay (ELISA).…”

Section: Pre-existing Crispr Immunitymentioning

confidence: 99%

Reprogramming the anti-tumor immune response via CRISPR genetic and epigenetic editing

Alves

Taifour

Dolcetti

et al. 2021

Molecular Therapy - Methods & Clinical Development

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Precise clustered regularly interspaced short palindromic repeats (CRISPR)-mediated genetic and epigenetic manipulation of the immune response has become a promising immunotherapeutic approach toward combating tumorigenesis and tumor progression. CRISPR-based immunologic reprograming in cancer therapy comprises the locus-specific enhancement of host immunity, the improvement of tumor immunogenicity, and the suppression of tumor immunoevasion. To date, the ex vivo re-engineering of immune cells directed to inhibit the expression of immune checkpoints or to express synthetic immune receptors (chimeric antigen receptor therapy) has shown success in some settings, such as in the treatment of melanoma, lymphoma, liver, and lung cancer. However, advancements in nuclease-deactivated CRISPR-associated nuclease-9 (dCas9)-mediated transcriptional activation or repression and Cas13-directed gene suppression present novel avenues for the development of tumor immunotherapies. In this review, the basis for development, mechanism of action, and outcomes from recently published Cas9-based clinical trial (genetic editing) and dCas9/Cas13-based pre-clinical (epigenetic editing) data are discussed. Lastly, we review cancer immunotherapy-specific considerations and barriers surrounding use of these approaches in the clinic.

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Immunogenicity of CAR T cells in cancer therapy

Cited by 184 publications

References 155 publications

Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy

Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy

How Can We Engineer CAR T Cells to Overcome Resistance?

Reprogramming the anti-tumor immune response via CRISPR genetic and epigenetic editing

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