Current state of CAR-T therapy for T-cell malignancies

Luo, Liangkui; Zhou, Xuan; Zhou, Lijuan; Lu, Zhao; Yang, Jilong; Tu, Sanfang; Li, Yuhua

doi:10.1177/20406207221143025

Cited by 15 publications

(14 citation statements)

References 125 publications

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“…The qPCR‐based assays are being used extensively to assess CAR‐T‐cellular kinetics, including idecel 19–21,23–25 . Recently, ddPCR has offered advantages over qPCR in accurately determining copy numbers as a measure of CAR‐T cellular kinetics 3,10,31,33 . In general, the sensitivity and accuracy of ddPCR is higher than a qPCR reaction 40–42 …”

Section: Discussionmentioning

confidence: 99%

“…[19][20][21][23][24][25] Recently, ddPCR has offered advantages over qPCR in accurately determining copy numbers as a measure of CAR-T cellular kinetics. 3,10,31,33 In general, the sensitivity and accuracy of ddPCR is higher than a qPCR reaction. [40][41][42] In this work, we provide the comparison of qPCR and ddPCRbased assays used to support clinical development of Idecel.…”

Section: Discussionmentioning

confidence: 99%

“…Chimeric antigen receptor T‐cell (CAR‐T) based therapy is a new modality to treat various forms of cancer 1–4 and autoimmune diseases 5 . Autologous CAR‐T‐cells are generated by genetically modifying the patient's own T‐cells to express antitumor‐targeting proteins (e.g., scFv antibody) on the cell surface, along with transmembrane and cytoplasmic domains.…”

mentioning

confidence: 99%

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Bioanalytical Methods for Characterization of CAR‐T Cellular Kinetics: Comparison of PCR Assays and Matrices

Masilamani

Jawa

Dai

et al. 2023

Clin Pharma and Therapeutics

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Recently, multiple chimeric antigen receptor T‐cell (CAR‐T)‐based therapies have been approved for treating hematological malignancies, targeting CD19 and B‐cell maturation antigen. Unlike protein or antibody therapies, CAR‐T therapies are “living cell” therapies whose pharmacokinetics are characterized by expansion, distribution, contraction, and persistence. Therefore, this unique modality requires a different approach for quantitation compared with conventional ligand binding assays implemented for most biologics. Cellular (flow cytometry) or molecular assays (polymerase chain reaction (PCR)) can be deployed with each having unique advantages and disadvantages. In this article, we describe the molecular assays utilized: quantitative PCR (qPCR), which was the initial platform used to estimate transgene copy numbers and more recently droplet digital PCR (ddPCR) which quantitates the absolute copy numbers of CAR transgene. The comparability of the two methods in patient samples and of each method across different matrices (isolated CD3+ T‐cells or whole blood) was also performed. The results show a good correlation between qPCR and ddPCR for the amplification of same gene in clinical samples from a CAR‐T therapy trial. In addition, our studies show that the qPCR‐based amplification of transgene levels was well‐correlated, independent of DNA sources (either CD3+ T‐cells or whole blood). Our results also highlight that ddPCR can be a better platform for monitoring samples at the early phase of CAR‐T dosing prior to expansion and during long‐term monitoring as they can detect samples with very low copy numbers with high sensitivity, in addition to easier implementation and sample logistics.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Bioanalytical Methods for Characterization of CAR‐T Cellular Kinetics: Comparison of PCR Assays and Matrices

Masilamani

Jawa

Dai

et al. 2023

Clin Pharma and Therapeutics

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“…Some antigens are shared between B and T-cell lymphomas, such as CD37 and CD38, and no significant fratricide has been seen with CAR-T targeting CD37 or CD38 in preclinical experiments ( 172 ). Another hurdle in CAR T development is the risk of contamination by malignant T-cells in autologous products ( 173 ). Further, functional T-cells may be absent in patients with advanced T-NHL, leading to poor autologous T-cell quality ( 174 ).…”

Section: T-cell Lymphomamentioning

confidence: 99%

Novel and multiple targets for chimeric antigen receptor-based therapies in lymphoma

Pang,

Ghosh

2024

Front. Oncol.

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Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 in B-cell non-Hodgkin lymphoma (NHL) validates the utility of CAR-based therapy for lymphomatous malignancies. Despite the success, treatment failure due to CD19 antigen loss, mutation, or down-regulation remains the main obstacle to cure. On-target, off-tumor effect of CD19-CAR T leads to side effects such as prolonged B-cell aplasia, limiting the application of therapy in indolent diseases such as chronic lymphocytic leukemia (CLL). Alternative CAR targets and multi-specific CAR are potential solutions to improving cellular therapy outcomes in B-NHL. For Hodgkin lymphoma and T-cell lymphoma, several cell surface antigens have been studied as CAR targets, some of which already showed promising results in clinical trials. Some antigens are expressed by different lymphomas and could be used for designing tumor-agnostic CAR. Here, we reviewed the antigens that have been studied for novel CAR-based therapies, as well as CARs designed to target two or more antigens in the treatment of lymphoma.

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“…Another problem intrinsic to the use of this therapeutic modality in T-cell malignancies refers to the potential contamination of the product collected for the construction of CAR-T with clonal T-cells, however, the use of allogeneic CAR-T products or CAR-NK-cells are possible strategies with ability to mitigate this contamination. Currently, data about the use of CAR-T therapy in PTCL, particularly for AITL are very scarce, although it may constitute an interesting therapeutic option for R/R disease in the next future ( 153 ). Figure 5 summarizes the proposal for a therapeutic algorithm to approach patients with AITL in first line and in the context of R/R disease.…”

Section: Treatmentmentioning

confidence: 99%

Angioimmunoblastic T-cell lymphoma and correlated neoplasms with T-cell follicular helper phenotype: from molecular mechanisms to therapeutic advances

et al. 2023

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Angioimmunoblastic T-cell lymphoma (AITL) is the second most frequent subtype of mature T-cell lymphoma (MTCL) in the Western world. It derives from the monoclonal proliferation of T-follicular helper (TFH) cells and is characterized by an exacerbated inflammatory response and immune dysregulation, with predisposition to autoimmunity phenomena and recurrent infections. Its genesis is based on a multistep integrative model, where age-related and initiator mutations involve epigenetic regulatory genes, such as TET-2 and DNMT3A. Subsequently, driver-mutations, such as RhoA G17V and IDH-2 R172K/S promote the expansion of clonal TFH-cells (“second-hit”), that finally begin to secrete cytokines and chemokines, such as IL-6, IL-21, CXCL-13 and VEGF, modulating a network of complex relationships between TFH-cells and a defective tumor microenvironment (TME), characterized by expansion of follicular dendritic cells (FDC), vessels and EBV-positive immunoblasts. This unique pathogenesis leads to peculiar clinical manifestations, generating the so-called “immunodysplastic syndrome”, typical of AITL. Its differential diagnosis is broad, involving viral infections, collagenosis and adverse drug reactions, which led many authors to use the term “many-faced lymphoma” when referring to AITL. Although great advances in its biological knowledge have been obtained in the last two decades, its treatment is still an unmet medical need, with highly reserved clinical outcomes. Outside the setting of clinical trials, AITL patients are still treated with multidrug therapy based on anthracyclines (CHOP-like), followed by up-front consolidation with autologous stem cell transplantation (ASCT). In this setting, the estimated 5-year overall survival (OS) is around 30-40%. New drugs, such as hypomethylating agents (HMAs) and histone deacetylase inhibitors (HDAi), have been used for relapsed/refractory (R/R) disease with promising results. Such agents have their use based on a biological rationale, have significant potential to improve the outcomes of patients with AITL and may represent a paradigm shift in the therapeutic approach to this lymphoma in the near future.

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Current state of CAR-T therapy for T-cell malignancies

Cited by 15 publications

References 125 publications

Bioanalytical Methods for Characterization of CAR‐T Cellular Kinetics: Comparison of PCR Assays and Matrices

Bioanalytical Methods for Characterization of CAR‐T Cellular Kinetics: Comparison of PCR Assays and Matrices

Novel and multiple targets for chimeric antigen receptor-based therapies in lymphoma

Angioimmunoblastic T-cell lymphoma and correlated neoplasms with T-cell follicular helper phenotype: from molecular mechanisms to therapeutic advances

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