The latest trends in improving CAR-T cell therapy: from leukemia to solid malignant tumors

Ершов, А. В.; Демьянов, Г. В.; Насруллаева, Д. А.; Радкевич, Е. Р.; Долгих, В. Т.; Сидорова, Н. В.; Валиев, Т. Т.; Efimova, M M; Мачнева, Е. Б.; Киргизов, К. И.; Киселевский, М. В.; Манасова, З. Ш.

doi:10.21682/2311-1267-2021-8-2-84-95

Cited by 3 publications

(1 citation statement)

References 66 publications

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“…Moreover, electroporation is cheaper and does not require such complex preparation or dedicated facilities as viral transduction [ 60 ]. In our opinion, this approach may help to lower safety problems arising from on-target off-tumor CAR-lymphocyte reactions [ 69 ]. Unstable CAR expression is even desirable in a case when such dangerous anti-HER2 reactions against benign tissues are inevitable.…”

Section: Discussionmentioning

confidence: 99%

Anti-Cancer Potential of Transiently Transfected HER2-Specific Human Mixed CAR-T and NK Cell Populations in Experimental Models: Initial Studies on Fucosylated Chondroitin Sulfate Usage for Safer Treatment

Chikileva,

Bruter,

Persiyantseva

et al. 2023

Biomedicines

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Human epidermal growth factor receptor 2 (HER2) is overexpressed in numerous cancer cell types. Therapeutic antibodies and chimeric antigen receptors (CARs) against HER2 were developed to treat human tumors. The major limitation of anti-HER2 CAR-T lymphocyte therapy is attributable to the low HER2 expression in a wide range of normal tissues. Thus, side effects are caused by CAR lymphocyte “on-target off-tumor” reactions. We aimed to develop safer HER2-targeting CAR-based therapy. CAR constructs against HER2 tumor-associated antigen (TAA) for transient expression were delivered into target T and natural killer (NK) cells by an effective and safe non-viral transfection method via nucleofection, excluding the risk of mutations associated with viral transduction. Different in vitro end-point and real-time assays of the CAR lymphocyte antitumor cytotoxicity and in vivo human HER2-positive tumor xenograft mice model proved potent cytotoxic activity of the generated CAR-T-NK cells. Our data suggest transient expression of anti-HER2 CARs in plasmid vectors by human lymphocytes as a safer treatment for HER2-positive human cancers. We also conducted preliminary investigations to elucidate if fucosylated chondroitin sulfate may be used as a possible agent to decrease excessive cytokine production without negative impact on the CAR lymphocyte antitumor effect.

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Section: Discussionmentioning

confidence: 99%

Anti-Cancer Potential of Transiently Transfected HER2-Specific Human Mixed CAR-T and NK Cell Populations in Experimental Models: Initial Studies on Fucosylated Chondroitin Sulfate Usage for Safer Treatment

Chikileva,

Bruter,

Persiyantseva

et al. 2023

Biomedicines

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Pharmacoeconomic Analysis of CAR-T Cell Therapy in Diffuse Large B-Cell Lymphoma and B-Lineage Acute Lymphoblastic Leukemias

Gribkova

Завьялов

2022

Клиническая онкогематология

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Genetically modified Т-lymphocytes with chimeric antigen receptors (CAR-T cells) represent a new treatment strategy in relapsed/refractory B-cell malignant neoplasms. In 20172018 two CAR-T cell drugs, tisagenlecleucel and axicabtagene ciloleucel, were approved by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) for clinical use in patients with refractory acute lymphoblastic leukemia and relapsed/refractory B-cell lymphomas. Due to its high efficacy, CAR-T cell therapy is increasingly becoming an integral part of clinical practice. However, this method of chemotherapy is very expensive. The mean cost of tisagenlecleucel is $475,000 and that of axicabtagene ciloleucel is $373,000. It is worth noting that these are only the drug prices which exclude other therapy-related costs. In the studies of 2018-2020 groups of researchers attempted to estimate the CAR-T cell therapy-associated costs. The aim of the present review is to analyze these studies and to assess the total treatment cost and expense structure, as well as to discuss the factors underlying the increasing costs and to explore opportunities to improve availability of the CAR-T technology, on the whole. The results showed that the mean cost of tisagenlecleucel therapy in B-cell lymphoma was $515,150 and that of axicabtagene ciloleucel therapy was $503,955. The treatment cost in acute lymphoblastic leukemia was $580,459. The major factors affecting the total therapy cost were CAR-T cell drug prices, severity of adverse events, and high tumor load prior to CAR-T cell drug infusion. It is agreed that the main opportunities to rise affordability of the CAR-T cell therapy lie in reducing the drug prices (for example, by means of medical facility-based production at its own expense), further therapy improvement aimed at less toxicity, and its implementation at earlier stages of tumor disease.

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Methodological Approaches to Risk Management of Advanced Therapy Medicinal Products

Taube,

Velts

2023

Razrabotka i registraciâ lekarstvennyh sredstv

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Introduction. Advanced therapy medicinal products (ATMPs) rely on recent advances in medical science, but alongside with potential benefits they may also bring safety concerns for patients. The inherent complexity of the ATMP production and use calls for special approaches to risk management throughout their lifecycle, from obtaining the raw materials to administration to the patient.Aim. The aim of the present study was to develop approaches to risk management for ATMPs, using the example of CAR T-cell therapy.Materials and methods. The study analysed the relevant regulatory frameworks currently in force in the European Union and the United States of America, namely the regulations and guidelines adopted by the Center for Biologics Evaluation and Research of the U.S. Food and Drug Administration and the Committee for Medicinal Products for Human Use of the European Medicines Agency.Results and discussion. The paper provides a classification of patient risks, which was developed based on the European risk-based approach. It formulates the principles of risk management for each of the risks, depending on the stage of the product life cycle. Each type of risk was considered separately. The following risk minimization strategies were determined: compliance with the good practices, ensuring the necessary qualifications or expertise of all parties involved in the product life cycle. The main element of risk control is the detailed description of the medicinal product use in the summary of product characteristics and patient information leaflet.Conclusion. The study identified the main stages at which ATMP risks may occur, and each type of risk was considered separately. The following requirements should be put in place in order to manage the ATMP risks: requirements for distributors on how to perform the product transportation and storage and to keep records for the marketing authorisation holder; requirements for healthcare facilities on how to perform the product storage, its preparation for use, advising and informing the patients on the treatment risks, symptoms of adverse events, preparatory and follow-up medical procedures, and on how to keep records for the marketing authorisation holder; requirements for the qualifications of healthcare professionals who are in charge of the product storage, its preparation for use, treatment procedures, advising and informing the patients on the treatment risks, symptoms of adverse events, and follow-up medical procedures. The data obtained will be used in the preparation of recommendations for ATMP developers.

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The latest trends in improving CAR-T cell therapy: from leukemia to solid malignant tumors

Cited by 3 publications

References 66 publications

Anti-Cancer Potential of Transiently Transfected HER2-Specific Human Mixed CAR-T and NK Cell Populations in Experimental Models: Initial Studies on Fucosylated Chondroitin Sulfate Usage for Safer Treatment

Anti-Cancer Potential of Transiently Transfected HER2-Specific Human Mixed CAR-T and NK Cell Populations in Experimental Models: Initial Studies on Fucosylated Chondroitin Sulfate Usage for Safer Treatment

Pharmacoeconomic Analysis of CAR-T Cell Therapy in Diffuse Large B-Cell Lymphoma and B-Lineage Acute Lymphoblastic Leukemias

Methodological Approaches to Risk Management of Advanced Therapy Medicinal Products

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