Dataset Information

Adoptive Cellular Therapy for Multiple Myeloma Using CAR- and TCR-Transgenic T Cells: Response and Resistance.

ABSTRACT: Despite the substantial improvement of therapeutic approaches, multiple myeloma (MM) remains mostly incurable. However, immunotherapeutic and especially T cell-based approaches pioneered the therapeutic landscape for relapsed and refractory disease recently. Targeting B-cell maturation antigen (BCMA) on myeloma cells has been demonstrated to be highly effective not only by antibody-derived constructs but also by adoptive cellular therapies. Chimeric antigen receptor (CAR)-transgenic T cells lead to deep, albeit mostly not durable responses with manageable side-effects in intensively pretreated patients. The spectrum of adoptive T cell-transfer covers synthetic CARs with diverse specificities as well as currently less well-established T cell receptor (TCR)-based personalized strategies. In this review, we want to focus on treatment characteristics including efficacy and safety of CAR- and TCR-transgenic T cells in MM as well as the future potential these novel therapies may have. ACT with transgenic T cells has only entered clinical trials and various engineering strategies for optimization of T cell responses are necessary to overcome therapy resistance mechanisms. We want to outline the current success in engineering CAR- and TCR-T cells, but also discuss challenges including resistance mechanisms of MM for evading T cell therapy and point out possible novel strategies.

SUBMITTER: Fuchsl F

PROVIDER: S-EPMC8834324 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Adoptive Cellular Therapy for Multiple Myeloma Using CAR- and TCR-Transgenic T Cells: Response and Resistance.

Füchsl Franziska F Krackhardt Angela M AM

Cells 20220125 3

Despite the substantial improvement of therapeutic approaches, multiple myeloma (MM) remains mostly incurable. However, immunotherapeutic and especially T cell-based approaches pioneered the therapeutic landscape for relapsed and refractory disease recently. Targeting B-cell maturation antigen (BCMA) on myeloma cells has been demonstrated to be highly effective not only by antibody-derived constructs but also by adoptive cellular therapies. Chimeric antigen receptor (CAR)-transgenic T cells lead ...[more]

PMID: 35159220

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Project description:BackgroundThe tumor antigen NY-ESO-1 has been shown to be an effective target for transgenic adoptive cell therapy (ACT) for the treatment of sarcoma and melanoma. However, despite frequent early clinical responses, many patients ultimately develop progressive disease. Understanding the mechanisms underlying treatment resistance is crucial to improve future ACT protocols. Here, we describe a novel mechanism of treatment resistance in sarcoma involving loss of expression of NY-ESO-1 in response to transgenic ACT with dendritic cell (DC) vaccination and programmed cell death protein-1 (PD-1) blockade.MethodsA HLA-A*02:01-positive patient with an NY-ESO-1-positive undifferentiated pleomorphic sarcoma was treated with autologous NY-ESO-1-specific T-cell receptor (TCR) transgenic lymphocytes, NY-ESO-1 peptide-pulsed DC vaccination, and nivolumab-mediated PD-1 blockade.ResultsPeripheral blood reconstitution with NY-ESO-1-specific T cells peaked within 2 weeks of ACT, indicating rapid in vivo expansion. There was initial tumor regression, and immunophenotyping of the peripheral transgenic T cells showed a predominantly effector memory phenotype over time. Tracking of transgenic T cells to the tumor sites was demonstrated in on-treatment biopsy via both TCR sequencing-based and RNA sequencing-based immune reconstitution, and nivolumab binding to PD-1 on transgenic T cells was confirmed at the tumor site. At the time of disease progression, the promoter region of NY-ESO-1 was found to be extensively methylated, and tumor NY-ESO-1 expression was completely lost as measured by RNA sequencing and immunohistochemistry.ConclusionsACT of NY-ESO-1 transgenic T cells given with DC vaccination and anti-PD-1 therapy resulted in transient antitumor activity. NY-ESO-1 expression was lost in the post-treatment sample in the setting of extensive methylation of the NY-ESO-1 promoter region.Biological/clinical insightAntigen loss represents a novel mechanism of immune escape in sarcoma and a new point of improvement in cellular therapy approaches.Trial registration numberNCT02775292.

Dataset Information

Adoptive Cellular Therapy for Multiple Myeloma Using CAR- and TCR-Transgenic T Cells: Response and Resistance.

Publications

Adoptive Cellular Therapy for Multiple Myeloma Using CAR- and TCR-Transgenic T Cells: Response and Resistance.

Similar Datasets

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