Time 2EVOLVE: predicting efficacy of engineered T-cells – how far is the bench from the bedside?

Guedan, Sonia; Luu, Maik; Ammar, Delphine; Barbao, Paula; Bonini, Chiara; Bousso, Philippe; Buchholz, Christian J.; Casucci, Monica; Angelis, Biagio De; Donnadieu, Emmanuel; Espie, David; Greco, Béatrice; Groen, Richard W.J.; Huppa, Johannes B.; Kantari‐Mimoun, Chahrazade; Laugel, Bruno; Mantock, Mary; Markman, Janet L.; Morris, Emma; Quintarelli, Concetta; Rade, Michael; Reiche, Kristin; Rodríguez-García, Alba; Rodríguez-Madoz, Juan R.; Ruggiero, Eliana; Themeli, Maria; Hudecek, Michael; Marchiq, Ibtissam

doi:10.1136/jitc-2021-003487

Cited by 19 publications

(20 citation statements)

References 135 publications

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“…Administration of TCR-T cells in engineered mouse models is a prerequisite to validate TCR-T cell viability, functionality, and persistence in vivo (tumor cell infiltration and formation of a memory compartment). A detailed review of all the models and options available to evaluate efficacy and safety has been made in two publications of the T 2 EVOLVE consortium ( 79 , 80 ).…”

Section: Tcr Identification and Optimizationmentioning

confidence: 99%

TCR-engineered T cell therapy in solid tumors: State of the art and perspectives

Baulu

Gardet

Chuvin³

et al. 2023

Sci. Adv.

112

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T cell engineering has changed the landscape of cancer immunotherapy. Chimeric antigen receptor T cells have demonstrated a remarkable efficacy in the treatment of B cell malignancies in hematology. However, their clinical impact on solid tumors has been modest so far. T cells expressing an engineered T cell receptor (TCR-T cells) represent a promising therapeutic alternative. The target repertoire is not limited to membrane proteins, and intrinsic features of TCRs such as high antigen sensitivity and near-to-physiological signaling may improve tumor cell detection and killing while improving T cell persistence. In this review, we present the clinical results obtained with TCR-T cells targeting different tumor antigen families. We detail the different methods that have been developed to identify and optimize a TCR candidate. We also discuss the challenges of TCR-T cell therapies, including toxicity assessment and resistance mechanisms. Last, we share some perspectives and highlight future directions in the field.

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Section: Tcr Identification and Optimizationmentioning

confidence: 99%

TCR-engineered T cell therapy in solid tumors: State of the art and perspectives

Baulu

Gardet

Chuvin³

et al. 2023

Sci. Adv.

112

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“…Several in vitro and preclinical in vivo models exist for the prediction of clinical efficacy and toxicity of CAR‐T cell therapy 61,62 . In vitro cell killing assays are most frequently used to assess antitumor activity, however, their translation into in vivo expansion, persistence, and efficacy potential is far from optimal 33,38,62 .…”

Section: Drug Developmentmentioning

confidence: 99%

“…In addition, the model‐informed analysis of CAR‐T cell proliferation and exhaustion using real‐time in vitro killing assay data could help to characterize the relationship between target cell‐related features (e.g., tumor growth rate and level of antigen expression) and the properties (e.g., proliferation rate, exhaustion rate, and killing rate) of a new CAR‐T cell construct 64 . Mathematical models may moreover help to predict the risk for tonic signaling based on the CAR design during the drug discovery stage, thereby reducing the risk of aborting development at the transition from the in vitro to the preclinical in vivo stage 62 …”

Section: Drug Developmentmentioning

confidence: 99%

“…Both immune‐compromised and immune‐competent mice are used, each with their own advantages and disadvantages. Immune‐compromised mice, such as NSG mouse models, lack cells crucial for the function of both the innate and the adaptive immune system, and therefore allow the implantation of patient‐derived xenografts 62 . Studying the interplay of CAR‐T cell candidates with original human tumors is imperative to understanding their behavior in a living organism.…”

Section: Drug Developmentmentioning

confidence: 99%

“…Moreover, immunomodulatory effects of lymphodepletion 68 and combination regimens with other immune‐targeting agents 69 can be investigated. Available immune‐competent mouse models include syngeneic mice with implanted histocompatible tumors, genetically engineered mice, and humanized mice with a partially reconstituted human immune system 61,62 . A detailed description and comparison of the advantages and disadvantages of the different types of immune‐competent mouse models is provided elsewhere, 61,62 however, it should be noted here, that there is currently no optimal preclinical in vivo model and, at best, a qualified approximation will be made that will in part be dependent on the specific research question, availability of materials (e.g., human tumor tissue), funding resources, and understanding of potential shortcomings of a given model.…”

Section: Drug Developmentmentioning

confidence: 99%

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Model‐informed drug development of autologous CAR‐T cell therapy: Strategies to optimize CAR‐T cell exposure leveraging cell kinetic/dynamic modeling

Laughlin¹,

Milligan²,

Yee

et al. 2023

CPT Pharmacom & Syst Pharma

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Autologous Chimeric antigen receptor (CAR‐T) cell therapy has been highly successful in the treatment of aggressive hematological malignancies and is also being evaluated for the treatment of solid tumors as well as other therapeutic areas. A challenge, however, is that up to 60% of patients do not sustain a long‐term response. Low CAR‐T cell exposure has been suggested as an underlying factor for a poor prognosis. CAR‐T cell therapy is a novel therapeutic modality with unique kinetic and dynamic properties. Importantly, “clear” dose‐exposure relationships do not seem to exist for any of the currently approved CAR‐T cell products. In other words, dose increases have not led to a commensurate increase in the measurable in vivo frequency of transferred CAR‐T cells. Therefore, alternative approaches beyond dose titration are needed to optimize CAR‐T cell exposure. In this paper, we provide examples of actionable variables – design elements in CAR‐T cell discovery, development, and clinical practice, which can be modified to optimize autologous CAR‐T cell exposure. Most of these actionable variables can be assessed throughout the various stages of discovery and development as part of a well‐informed research and development program. Model‐informed drug development approaches can enable such study and program design choices from discovery through to clinical practice and can be an important contributor to cell therapy effectiveness and efficiency.

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Optimization and validation of in vivo flow cytometry chimeric antigen receptor T cell detection method using CD19his indirect staining

Zaninelli,

Meli,

Borleri

et al. 2023

Cytometry Pt A

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CD19‐targeted Chimeric Antigen Receptor T (CAR‐T) cell therapy has shown unprecedented results in patients with B cell relapsed/refractory acute lymphoblastic leukemia (R/R‐ALL) and B cell non‐Hodgkin lymphomas where no other curative options are available. In vivo monitoring of CAR‐T cell kinetics is fundamental to understand the correlation between CAR‐T cells expansion and persistence with treatment response and toxicity development. The aim of this study was to define a robust, sensitive, and universal method for CAR‐T cell detection using flow cytometry. We set‐up and compared with each other three assays for CD19 CAR‐T cell detection, all based on commercially available reagents. All methods used a recombinant human CD19 protein fragment recognized by the single chain variable fragment of the CAR construct. The two indirect staining assays (CD19his + APC‐conjugated anti‐histidine antibody and CD19bio + APC‐conjugated anti‐biotin antibody) showed better sensitivity and specificity compared to the direct staining with CD19‐FITC, and CD19his had a better cost‐effective profile. We validated CAR detection with CD19his with parallel quantitative real time PCR data and we could demonstrate a strong positive correlation. We also showed that CD19his staining can be easily included in a multicolor flow cytometry panel to achieve additional information about the cell phenotype of CAR‐T cell positive subpopulations. Finally, this method can be used for different anti‐CD19 CAR‐T cell products and for different sample sources. These data demonstrate that detection of CAR‐T cells by CD19his flow cytometry staining is a reliable, robust, and broadly applicable tool for in vivo monitoring of CAR‐T cells.This article is protected by copyright. All rights reserved.

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Time 2EVOLVE: predicting efficacy of engineered T-cells – how far is the bench from the bedside?

Cited by 19 publications

References 135 publications

TCR-engineered T cell therapy in solid tumors: State of the art and perspectives

TCR-engineered T cell therapy in solid tumors: State of the art and perspectives

Model‐informed drug development of autologous CAR‐T cell therapy: Strategies to optimize CAR‐T cell exposure leveraging cell kinetic/dynamic modeling

Optimization and validation of in vivo flow cytometry chimeric antigen receptor T cell detection method using CD19his indirect staining

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