Disease progression after R-CHOP treatment associated with the loss of CD20 antigen expression

Bellesso, Marcelo; Xavier, Flávia Caló Aquino; Costa, Rogério A.; Pereira, Juliana; Siqueira, Sheila Aparecida Coelho; Chamone, Dalton A. F.

doi:10.5581/1516-8484.20110036

Cited by 6 publications

(3 citation statements)

References 9 publications

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“…Sequential loss of CD19 and CD22 tumor surface antigens in response to CAR19 T cell therapy followed by CAR22 T cell infusion in diffuse large B cell lymphoma was also reported (8). Likewise, loss of CD20 antigen in the course of treatment with the CD20-targeting antibody Rituximab has been reported in non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), and follicular lymphoma (9)(10)(11). To address tumor antigen escape, we have previously developed a tandem bispecific CAR20-19 construct that targets the CD19 and the CD20 antigens simultaneously and that has shown promising efficacy and tolerability in a phase 1 clinical trial (12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 89%

Trispecific CD19-CD20-CD22–targeting duoCAR-T cells eliminate antigen-heterogeneous B cell tumors in preclinical models

Schneider

Xiong

et al. 2021

Sci. Transl. Med.

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A substantial number of patients with leukemia and lymphoma treated with anti-CD19 or anti-CD22 monoCAR-T cell therapy relapse because of antigen loss or down-regulation. We hypothesized that B cell tumor antigen escape may be overcome by a chimeric antigen receptor (CAR) design that simultaneously targets three B cell leukemia antigens. We engineered trispecific duoCAR-T cells with lentiviral vectors encoding two CAR open reading frames that target CD19, CD20, and CD22. The duoCARs were composed of a CAR with a tandem CD19- and CD20-targeting binder, linked by the P2A self-cleaving peptide to a second CAR targeting CD22. Multiple combinations of intracellular T cell signaling motifs were evaluated. The most potent duoCAR architectures included those with ICOS, OX40, or CD27 signaling domains rather than those from CD28 or 4-1BB. We identified four optimal binder and signaling combinations that potently rejected xenografted leukemia and lymphoma tumors in vivo. Moreover, in mice bearing a mixture of B cell lymphoma lines composed of parental triple-positive cells, CD19-negative, CD20-negative, and CD22-negative variants, only the trispecific duoCAR-T cells rapidly and efficiently rejected the tumors. Each of the monoCAR-T cells failed to prevent tumor progression. Analysis of intracellular signaling profiles demonstrates that the distinct signaling of the intracellular domains used may contribute to these differential effects. Multispecific duoCAR-T cells are a promising strategy to prevent antigen loss–mediated relapse or the down-regulation of target antigen in patients with B cell malignancies.

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Section: Introductionmentioning

confidence: 89%

Trispecific CD19-CD20-CD22–targeting duoCAR-T cells eliminate antigen-heterogeneous B cell tumors in preclinical models

Schneider

Xiong

et al. 2021

Sci. Transl. Med.

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“…CD20 downregulation after treatment with rituximab has been repeatedly observed in rituximab resistant patients although the exact mechanism for development of rituximab resistance is not yet known. It could be potentially mediated by alterations in CD20 expression or signalling, both by genetic or epigenetic changes, elevated apoptotic threshold, modulation of complement activity or diminished cellular cytotoxicity .…”

Section: Discussionmentioning

confidence: 99%

Combination of ¹⁷⁷Lu‐lilotomab with rituximab significantly improves the therapeutic outcome in preclinical models of non‐Hodgkin's lymphoma

Repetto-Llamazares

Malenge

O’Shea

et al. 2018

European J of Haematology

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“…While the link between treatment and lineage switching is not clear, the precise mechanism of antigen loss following mAb therapy is identified in several B cell malignancies. Rituximab, a chimeric antibody against CD20, has become a standard therapeutic option for various B cell (CD20 + ) malignancies including non-Hodgkin lymphoma (NHL), follicular lymphoma, diffuse large B cell lymphoma, and CLL ( 26 , 27 ). The loss of CD20 antigen following rituximab therapy has been observed for follicular lymphoma ( 27 ), B cell NHL ( 28 ), and CLL ( 29 ).…”

Section: Occurrence Of Antigen Loss Variants In Leukemiamentioning

confidence: 99%

Antigen Loss Variants: Catching Hold of Escaping Foes

2017

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Since mid-1990s, the field of cancer immunotherapy has seen steady growth and selected immunotherapies are now a routine and preferred therapeutic option of certain malignancies. Both active and passive cancer immunotherapies exploit the fact that tumor cells express specific antigens on the cell surface, thereby mounting an immune response specifically against malignant cells. It is well established that cancer cells typically lose surface antigens following natural or therapy-induced selective pressure and these antigen-loss variants are often the population that causes therapy-resistant relapse. CD19 and CD20 antigen loss in acute lymphocytic leukemia and chronic lymphocytic leukemia, respectively, and lineage switching in leukemia associated with mixed lineage leukemia (MLL) gene rearrangements are well-documented evidences in this regard. Although increasing number of novel immunotherapies are being developed, majority of these do not address the control of antigen loss variants. Here, we review the occurrence of antigen loss variants in leukemia and discuss the therapeutic strategies to tackle the same. We also present an approach of dual-targeting immunoligand effectively retargeting NK cells against antigen loss variants in MLL-associated leukemia. Novel immunotherapies simultaneously targeting more than one tumor antigen certainly hold promise to completely eradicate tumor and prevent therapy-resistant relapses.

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Disease progression after R-CHOP treatment associated with the loss of CD20 antigen expression

Cited by 6 publications

References 9 publications

Trispecific CD19-CD20-CD22–targeting duoCAR-T cells eliminate antigen-heterogeneous B cell tumors in preclinical models

Trispecific CD19-CD20-CD22–targeting duoCAR-T cells eliminate antigen-heterogeneous B cell tumors in preclinical models

Combination of ¹⁷⁷Lu‐lilotomab with rituximab significantly improves the therapeutic outcome in preclinical models of non‐Hodgkin's lymphoma

Antigen Loss Variants: Catching Hold of Escaping Foes

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Disease progression after R-CHOP treatment associated with the loss of CD20 antigen expression

Cited by 6 publications

References 9 publications

Trispecific CD19-CD20-CD22–targeting duoCAR-T cells eliminate antigen-heterogeneous B cell tumors in preclinical models

Trispecific CD19-CD20-CD22–targeting duoCAR-T cells eliminate antigen-heterogeneous B cell tumors in preclinical models

Combination of 177Lu‐lilotomab with rituximab significantly improves the therapeutic outcome in preclinical models of non‐Hodgkin's lymphoma

Antigen Loss Variants: Catching Hold of Escaping Foes

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Combination of ¹⁷⁷Lu‐lilotomab with rituximab significantly improves the therapeutic outcome in preclinical models of non‐Hodgkin's lymphoma