CRISPR Takes the Front Seat in CART-Cell Development

Manriquez-Roman, Claudia; Siegler, Elizabeth L.; Kenderian, Saad S.

doi:10.1007/s40259-021-00473-y

Cited by 10 publications

(17 citation statements)

References 112 publications

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“…There was no clinical correlation associated with the kinetic patterns observed, nor was there a relationship to the vector integration site [24] . However, single cell RNA-sequencing revealed gene expression patterns associated with cytotoxicity and proliferation and enrichment of the AP-1 family, CD69, and glycolysis [24] . This suggested preferential expansion of T cell clones with this gene expression signature.…”

Section: T Cell Molecular State To Uncover Mechanisms Of Resistancementioning

confidence: 76%

“…This tool could lead to more precise CART cell therapies targeting a specific subtype of DLBCL. In another strategy to understand the molecular state of CART cell therapy, T cell receptor beta (TCRB) sequencing, lentiviral integration sites analysis, and RNA sequencing on patient samples were simultaneously performed [24] . The investigators compared the infused CART cells to the expanded CART cells at 1-2 weeks and 26-30 days post infusion.…”

Section: T Cell Molecular State To Uncover Mechanisms Of Resistancementioning

confidence: 99%

“…The investigators compared the infused CART cells to the expanded CART cells at 1-2 weeks and 26-30 days post infusion. TCRB sequencing revealed that while CART cells remain polyclonal, there is a decrease in clonal diversity over time [24] , suggesting that specific clones may preferentially expand over time. Three patterns were observed: (1) steady proliferation;…”

Section: T Cell Molecular State To Uncover Mechanisms Of Resistancementioning

confidence: 99%

Section: T Cell Molecular State To Uncover Mechanisms Of Resistancementioning

confidence: 99%

“…(2) immediate increase followed by a decrease; or (3) steady decline in number [24] . There was no clinical correlation associated with the kinetic patterns observed, nor was there a relationship to the vector integration site [24] . However, single cell RNA-sequencing revealed gene expression patterns associated with cytotoxicity and proliferation and enrichment of the AP-1 family, CD69, and glycolysis [24] .…”

Section: T Cell Molecular State To Uncover Mechanisms Of Resistancementioning

confidence: 99%

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Omics analyses provide insights to CART cell therapy resistance

Cox¹,

Kenderian²

2021

JTGG

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Chimeric antigen receptor T (CART) cell therapy has revolutionized the treatment of relapsed/refractory B cell malignancies in recent years. Despite high initial response rates, durable response rates are low, and CART cell efficacy in solid tumors is very modest. Additionally, the overall success of CART cell therapy is limited by toxicities such as cytokine release syndrome and neurotoxicity. Decades of advancement in genome sequencing technology and bioinformatics have given us a better understanding of how cancer develops and evolves following treatments. This has resulted in a better understanding of patient response to cancer treatment on a molecular level. Resistance to CART cell therapy can be mediated by the cancer cells, the tumor microenvironment, or the patient's T cells. In this review, we will outline lessons learned from multi-omics studies (1) to identify biomarkers of response or toxicity to CART cell therapy or (2) to develop biomarker-guided therapeutic interventions to overcome these limitations.

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Section: T Cell Molecular State To Uncover Mechanisms Of Resistancementioning

confidence: 76%

Section: T Cell Molecular State To Uncover Mechanisms Of Resistancementioning

confidence: 99%

Section: T Cell Molecular State To Uncover Mechanisms Of Resistancementioning

confidence: 99%

Section: T Cell Molecular State To Uncover Mechanisms Of Resistancementioning

confidence: 99%

Section: T Cell Molecular State To Uncover Mechanisms Of Resistancementioning

confidence: 99%

See 3 more Smart Citations

Omics analyses provide insights to CART cell therapy resistance

Cox¹,

Kenderian²

2021

JTGG

Self Cite

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Clinical Pharmacology and Translational Considerations in the Development of CRISPR‐Based Therapies

Abdelhady

Phillips

et al. 2023

Clin Pharma and Therapeutics

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Genome editing holds the potential for curative treatments of human disease, however, clinical realization has proven to be a challenging journey with incremental progress made up until recently. Over the last decade, advances in clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR‐associated protein (Cas) systems have provided the necessary breakthrough for genome editing in the clinic. The progress of investigational CRISPR therapies from bench to bedside reflects the culmination of multiple advances occurring in parallel, several of which intersect with clinical pharmacology and translation. Directing the CRISPR therapy to the intended site of action has necessitated novel delivery platforms, and this has resulted in special considerations for the complete characterization of distribution, metabolism, and excretion, as well as immunogenicity. Once at the site of action, CRISPR therapies aim to make permanent alterations to the genome and achieve therapeutically relevant effects with a single dose. This fundamental aspect of the mechanism of action for CRISPR therapies results in new considerations for clinical translation and dose selection. Early advances in model‐informed development of CRISPR therapies have incorporated key facets of the mechanism of action and have captured hallmark features of clinical pharmacokinetics and pharmacodynamics from phase I investigations. Given the recent emergence of CRISPR therapies in clinical development, the landscape continues to evolve rapidly with ample opportunity for continued innovation. Here, we provide a snapshot of selected topics in clinical pharmacology and translation that has supported the advance of systemically administered in vivo and ex vivo CRISPR‐based investigational therapies in the clinic.

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Allogeneic Chimeric Antigen Receptor Therapy in Lymphoma

Khurana

Lin

2022

Curr. Treat. Options in Oncol.

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Opinion statementThe therapeutic armamentarium has significantly expanded since the approval of various CD19-targeting chimeric antigen receptor T cell (CAR-T) therapies in non-Hodgkin lymphoma (NHL). These CAR-Ts are patient-specific and require a complex, resource, and time-consuming process. While this appears promising, autologous CAR-Ts are limited due to the lack of accessibility, manufacturing delays, and variable product quality. To overcome these, allogeneic (allo) CARs from healthy donors appear appealing. These can be immediately available as “off the shelf” ready-to-use products of standardized and superior quality exempt from the effects of an immunosuppressive tumor microenvironment and prior treatments, and potentially with lower healthcare utilization using industrialized scale production. Allogeneic CARs, however, are not devoid of complications and require genomic editing, especially with αβ T cells to avoid graft versus host disease (GvHD) and allo-rejection by the recipient’s immune system. Tools for genomic editing such as TALEN and CRISPR provide promise to develop truly “off the shelf” universal CARs and further advance the field of cellular immunotherapy. Several allogeneic CARs are currently in early phase clinical trials, and preliminary data is encouraging. Longer follow-up is required to truly assess the feasibility and safety of these techniques in the patients. This review focuses on the strategies for developing allogeneic CARs along with cell sources and clinical experience thus far in lymphoma.

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CRISPR Takes the Front Seat in CART-Cell Development

Cited by 10 publications

References 112 publications

Omics analyses provide insights to CART cell therapy resistance

Omics analyses provide insights to CART cell therapy resistance

Clinical Pharmacology and Translational Considerations in the Development of CRISPR‐Based Therapies

Allogeneic Chimeric Antigen Receptor Therapy in Lymphoma

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