Late relapse after CAR-T cell therapy for adult patients with hematologic malignancies: A definite evidence from systematic review and meta-analysis on individual data

Zinzi, Alessia; Gaio, Mario; Liguori, Valerio; Cagnotta, Cecilia; Paolino, Donatella; Paolisso, Giuseppe; Castaldo, Giuseppe; Nicoletti, Gianfranco; Rossi, Francesco; Rafaniello, Concetta

doi:10.1016/j.phrs.2023.106742

Cited by 7 publications

(4 citation statements)

References 43 publications

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“…Especially patients refractory towards TKI therapy or after progression to acceleration phase/blast crisis can profit from this novel approach (222). Importantly, Jiang et al have recently shown the preserved functional capacity of CD4 + T cells in CML patients, suggesting that this subgroup could be suitable for the generation of CAR-T cells (223). Additionally, success in implementing novel technologies like streamlined production processes and digital PCR allow for an easier implementation of CAR-T cells into clinical practice.…”

Section: Discussionmentioning

confidence: 99%

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Broadening the horizon: potential applications of CAR-T cells beyond current indications

Karsten,

Matrisch,

Cichutek

et al. 2023

Front. Immunol.

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Engineering immune cells to treat hematological malignancies has been a major focus of research since the first resounding successes of CAR-T-cell therapies in B-ALL. Several diseases can now be treated in highly therapy-refractory or relapsed conditions. Currently, a number of CD19- or BCMA-specific CAR-T-cell therapies are approved for acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), multiple myeloma (MM), and follicular lymphoma (FL). The implementation of these therapies has significantly improved patient outcome and survival even in cases with previously very poor prognosis. In this comprehensive review, we present the current state of research, recent innovations, and the applications of CAR-T-cell therapy in a selected group of hematologic malignancies. We focus on B- and T-cell malignancies, including the entities of cutaneous and peripheral T-cell lymphoma (T-ALL, PTCL, CTCL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), classical Hodgkin-Lymphoma (HL), Burkitt-Lymphoma (BL), hairy cell leukemia (HCL), and Waldenström’s macroglobulinemia (WM). While these diseases are highly heterogenous, we highlight several similarly used approaches (combination with established therapeutics, target depletion on healthy cells), targets used in multiple diseases (CD30, CD38, TRBC1/2), and unique features that require individualized approaches. Furthermore, we focus on current limitations of CAR-T-cell therapy in individual diseases and entities such as immunocompromising tumor microenvironment (TME), risk of on-target-off-tumor effects, and differences in the occurrence of adverse events. Finally, we present an outlook into novel innovations in CAR-T-cell engineering like the use of artificial intelligence and the future role of CAR-T cells in therapy regimens in everyday clinical practice.

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Section: Discussionmentioning

confidence: 99%

“…ibrutinib, acalabrutinib). Due to these available and well-established therapeutics with very high efficacy, research in CAR-T-cell therapy in CLL lacks behind that in other hematological malignancies of comparable clinical relevance ( 225 ).…”

Section: Chronic Lymphocytic Leukemiamentioning

confidence: 99%

Broadening the horizon: potential applications of CAR-T cells beyond current indications

Karsten,

Matrisch,

Cichutek

et al. 2023

Front. Immunol.

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“…Despite these clinical improvements, 40-60% of BCP-ALL patients ultimately relapse after CD19-targeted therapy [57,106,107]. Treatment failure can partly be mediated by the loss of target antigen expression.…”

Section: Immunotherapy and Escape In Bcp-allmentioning

confidence: 99%

The Evolving Landscape of Flowcytometric Minimal Residual Disease Monitoring in B-Cell Precursor Acute Lymphoblastic Leukemia

Verbeek,

van der Velden

2024

IJMS

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Detection of minimal residual disease (MRD) is a major independent prognostic marker in the clinical management of pediatric and adult B-cell precursor Acute Lymphoblastic Leukemia (BCP-ALL), and risk stratification nowadays heavily relies on MRD diagnostics. MRD can be detected using flow cytometry based on aberrant expression of markers (antigens) during malignant B-cell maturation. Recent advances highlight the significance of novel markers (e.g., CD58, CD81, CD304, CD73, CD66c, and CD123), improving MRD identification. Second and next-generation flow cytometry, such as the EuroFlow consortium’s eight-color protocol, can achieve sensitivities down to 10−5 (comparable with the PCR-based method) if sufficient cells are acquired. The introduction of targeted therapies (especially those targeting CD19, such as blinatumomab or CAR-T19) introduces several challenges for flow cytometric MRD analysis, such as the occurrence of CD19-negative relapses. Therefore, innovative flow cytometry panels, including alternative B-cell markers (e.g., CD22 and CD24), have been designed. (Semi-)automated MRD assessment, employing machine learning algorithms and clustering tools, shows promise but does not yet allow robust and sensitive automated analysis of MRD. Future directions involve integrating artificial intelligence, further automation, and exploring multicolor spectral flow cytometry to standardize MRD assessment and enhance diagnostic and prognostic robustness of MRD diagnostics in BCP-ALL.

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“…A few previous studies assessed the efficacy of CAR T-cell therapy in CNSL patients, but they did not evaluate the duration response to this therapy ( Cook et al, 2023 ; Zinzi et al, 2023 ). Herein, we conducted a systematic review and meta-analysis to evaluate the DoR of CAR T-cell therapy in CNSL patients and the associated factors.…”

Section: Introductionmentioning

confidence: 99%

Sustained efficacy of chimeric antigen receptor T-cell therapy in central nervous system lymphoma: a systematic review and meta-analysis of individual data

Zhou,

Wang,

Wang

et al. 2024

Front. Pharmacol.

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Background: Central nervous system lymphoma (CNSL) is considered an aggressive lymphoma with a poor prognosis. Studies investigating CNSL have shown that chimeric antigen receptor (CAR) T-cell therapy has demonstrated an effective response in limited sample sizes. Therefore, we conducted this systematic review and meta-analysis to clarify the sustained efficacy and factors associated with the sustained efficacy of CAR T-cell therapy in the treatment of CNSL.Methods: We searched studies from PubMed, Embase, Medline, and the Cochrane Center Register of Controlled Trials up to July 2023. Studies that included individual data on the duration of response (DoR) after receiving CAR T-cell therapy were enrolled. Pooled response rates were calculated using fixed-effects or random-effects models. Subgroup analysis was performed to analyze the heterogeneity, and a Cox regression model was performed to identify the factors associated with sustained efficacy.Results: In total, 12 studies including 69 patients were identified and included in this meta-analysis. The pooled relapse rate was 45% [95% CI 35, 56]. Subgroup analyses of relapse rates revealed that CAR T-cells using the CD28/4-1BB domain (CD28/4-1BB vs. CD28 vs. 4-1BB, p = 0.0151), parenchymal or leptomeningeal involvement (parenchymal or leptomeningeal vs. both parenchymal and leptomeningeal, p < 0.0001), and combined treatment with CAR T-cell therapy [Autologous stem cell transplantation (ASCT) plus CAR T-cell therapy vs. CAR T cells with maintenance therapy vs. CAR T-cell therapy alone, p = 0.003] were associated with lower relapse rates in patients. Time-to-event endpoints were assessed using reconstructed individual patient survival data to explore key modulators of DoR. Partial response status at CAR-T infusion and the use of ASCT plus CAR T-cell therapy were associated with longer DoR at the multivariate level, with hazard ratios of 0.25 and 0.26, respectively.Conclusion: CAR T-cell therapy shows promising and sustained efficacy in CNSL patients. However, further prospective large-scale studies are needed to assess these effect modifiers to optimize patient selection and improve the sustained efficacy of CAR T-cell therapy in the treatment of CNSL.Systematic review registration:https://clinicaltrials.gov/, identifier PROSPERO CRD42023451856.

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Late relapse after CAR-T cell therapy for adult patients with hematologic malignancies: A definite evidence from systematic review and meta-analysis on individual data

Cited by 7 publications

References 43 publications

Broadening the horizon: potential applications of CAR-T cells beyond current indications

Broadening the horizon: potential applications of CAR-T cells beyond current indications

The Evolving Landscape of Flowcytometric Minimal Residual Disease Monitoring in B-Cell Precursor Acute Lymphoblastic Leukemia

Sustained efficacy of chimeric antigen receptor T-cell therapy in central nervous system lymphoma: a systematic review and meta-analysis of individual data

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