Relapse after CAR-T cell therapy in B-cell malignancies: challenges and future approaches

Gu, Tianning; Zhu, Meng; Huang, He; Hu, Yongxian

doi:10.1631/jzus.b2200256

Cited by 16 publications

(13 citation statements)

References 149 publications

(158 reference statements)

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“…It occurs in approximately 40% to 60% of patients; in R/R ALL, 30% to 60% of patients relapse after CAR-T-cell therapy, of which 10% to 20% are CD19-negative relapses. 74,75 Failure of CAR-T-cell therapy is most often attributed to antigen escape, that is, antigen-negative relapse; however, antigen-positive relapse also occurs frequently, which may be associated with CAR-T-cell intrinsic factors. 76 Thus, the tumor cells themselves, tumor microenvironment (TME) and CAR-T cells may influence relapse.…”

Section: Relapsementioning

confidence: 99%

CAR-T cell therapy: Where are we now, and where are we heading?

Wang,

Wang

2023

Blood Science

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Chimeric antigen receptor (CAR)-T-cell therapies have exhibited remarkable efficacy in the treatment of hematologic malignancies, with 9 CAR-T-cell products currently available. Furthermore, CAR-T cells have shown promising potential for expanding their therapeutic applications to diverse areas, including solid tumors, myocardial fibrosis, and autoimmune and infectious diseases. Despite these advancements, significant challenges pertaining to treatment-related toxic reactions and relapses persist. Consequently, current research efforts are focused on addressing these issues to enhance the safety and efficacy of CAR-T cells and reduce the relapse rate. This article provides a comprehensive overview of the present state of CAR-T-cell therapies, including their achievements, existing challenges, and potential future developments.

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Section: Relapsementioning

confidence: 99%

CAR-T cell therapy: Where are we now, and where are we heading?

Wang,

Wang

2023

Blood Science

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“…Despite outstanding results in the treatment of different CD19+ hematologic cancers, around 30-50% of patients relapse after αCD19-CAR-T infusion (2). CAR-T therapy has shown limited therapeutic efficacy in other hematological malignancies such as chronic lymphocytic leukemia (CLL) (3), and very few reports have shown efficacy on solid tumors (4).…”

Section: Introductionmentioning

confidence: 99%

First-in-classTransactivator-Free, Doxycycline-inducible IL-18-engineered CAR-T cells for relapsed/refractory B-cell lymphomas

Justicia-Lirio,

Tristán-Manzano,

Maldonado-Pérez

et al. 2024

Preprint

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Background: Despite their success treating type B cancers, Chimeric Antigen Receptor (CAR) T cells still showed limited efficacy in certain lymphomas and solid tumors. Reinforcing conventional CAR-T cells to release cytokines can improve their efficacy but also increase safety concerns. Several strategies have been developed to regulate their secretion using minimal promoters that are controlled by chimeric proteins harboring transactivators. However, these chimeric proteins can disrupt the normal physiology of target cells.Methods: Co-transduction with CAR19 and Lent-On-Plus-IL-18 LVs allowed for generating constitutive CAR/Dox-inducible IL-18 CAR-T cells that respond to ultra-low doses of doxycycline (iTRUCK19.18). iTRUCK19.18 were evaluated against an aggressive Burkitt lymphoma model in vitro and in vivo, against primary B-cell tumors and against a CD19-engineered pancreatic tumor model. Patient-derived iTRUCK19.18 cells were also generated.Results: iTRUCK19.18 controlled IL-18 release through a dual mechanism dependent on doxycycline and T cell activation, thereby enhancing the safety profile. IL-18 release increased the activation state/proinflammatory profile of T cells in a doxycycline-dependent manner without altering cellular fitness, which was translated into an increased CAR-T cell antitumor activity against aggressive hematologic and solid tumor models. In a clinically relevant context, we generated patient-derived iTRUCK19.18 cells able to significantly increase elimination of primary B cells tumors under doxycycline. Furthermore, IL-18-releasing iTRUCK19.18 polarized pro-tumoral M2 macrophages towards an antitumoral phenotype (M1), suggesting the ability to modulate the tumor microenvironment.Conclusion: We have generated the first transactivator-free inducible TRUCKs from healthy donors and B-cell neoplasms patients. iTRUCK19-18 exhibit dual safety control mechanisms for IL-18 secretion and improved antitumoral activity against type-B neoplasms. Inducible IL-18 secretion not only enhanced T cell potency but could also change the tumor microenvironment to a more antitumoral state.

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“…To date, the most characteristic mechanism of resistance is the loss of the target antigen (Ag). Several mechanisms have been reported for Ag-negative relapses, including pre-existing Ag-negative tumor cells, gene mutations or alternative splicing, alterations that affect the maturation of target Ag expression, epitope masking, and lineage switch [ 11 , 12 ]. In order to prevent relapse after CAR-T cell therapy, several potential strategies, including research on new CAR targets, sequential therapy, dual/multi-target CARs, combining multiple chemotherapy and immunotherapy, as well as a variety of improved methods such as allo-HSCT, could lead to better disease remission and greater survival benefits in r/r B-ALL patients [ 11 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Unraveling resistance mechanisms in anti-CD19 chimeric antigen receptor-T therapy for B-ALL: a novel in vitro model and insights into target antigen dynamics

Li,

Wang,

Liu

et al. 2024

J Transl Med

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Background Cellular immunotherapy, represented by the chimeric antigen receptor T cell (CAR-T), has exhibited high response rates, durable remission, and safety in vitro and in clinical trials. Unfortunately, anti-CD19 CAR-T (CART-19) treatment alone is prone to relapse and has a particularly poor prognosis in relapsed/refractory (r/r) B-ALL patients. To date, addressing or reducing relapse remains one of the research priorities to achieve broad clinical application. Methods We manufactured second generation CART-19 cells and validated their efficacy and safety in vitro and in vivo. Through co-culture of Nalm-6 cells with short-term cultured CART-19 cells, CD19-negative Nalm-6 cells were detected by flow cytometry, and further investigation of the relapsed cells and their resistance mechanisms was evaluated in vitro. Results In this study, we demonstrated that CART-19 cells had enhanced and specific antileukemic activities, and the survival of B-ALL mouse models after CART-19 treatment was significantly prolonged. We then shortened the culture time and applied the serum-free culture to expand CAR-T cells, followed by co-culturing CART-19 cells with Nalm-6 cells. Surprisingly, we observed the proliferation of CD19-negative Nalm-6 cells around 28 days. Identification of potential resistance mechanisms showed that the relapsed cells express truncated CD19 proteins with decreased levels and, more importantly, CAR expression was detected on the relapsed cell surface, which may ultimately keep them antigen-negative. Furthermore, it was validated that CART-22 and tandem CART-22/19 cells could effectively kill the relapsed cells, but neither could completely eradicate them. Conclusions We successfully generated CART-19 cells and obtained a CD19-negative refractory relapsed B-ALL cell line, providing new insights into the underlying mechanisms of resistance and a new in vitro model for the treatment of r/r B-ALL patients with low antigen density.

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Relapse after CAR-T cell therapy in B-cell malignancies: challenges and future approaches

Cited by 16 publications

References 149 publications

CAR-T cell therapy: Where are we now, and where are we heading?

CAR-T cell therapy: Where are we now, and where are we heading?

First-in-classTransactivator-Free, Doxycycline-inducible IL-18-engineered CAR-T cells for relapsed/refractory B-cell lymphomas

Unraveling resistance mechanisms in anti-CD19 chimeric antigen receptor-T therapy for B-ALL: a novel in vitro model and insights into target antigen dynamics

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