γ-Secretase inhibition increases efficacy of BCMA-specific chimeric antigen receptor T cells in multiple myeloma

Pont, Margot J.; Hill, Tyler; Cole, Gabriel O; Abbott, Joe James; Kelliher, Jessica L.; Salter, Alexander I.; Hudecek, Michael; Comstock, Melissa L.; Rajan, Anusha; Patel, Bharvin K.R.; Voutsinas, Jenna; Wu, Qian; Liu, Lingfeng; Cowan, Andrew J.; Wood, Brent L.; Green, Damian J.; Riddell, Stanley R.

doi:10.1182/blood.2019000050

Cited by 240 publications

(223 citation statements)

References 65 publications

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“…Knocking down BCMA itself or its transcription factor POU2AF1 (16) both resulted in significant downregulation of cell surface BCMA expression, thus validating the screen ( Fig 1C). Furthermore, all of the subunits of the gamma secretase complex were among the top hits, and their knockdown resulted in a significant increase in cell surface BCMA ( Fig 1C), consistent with previous reports from other groups (6,9). Moreover, we identified several functional categories of genes regulating expression levels of BCMA including subunits of the Sec61 translocon complex, peroxisome biogenesis, proteasome subunits, and regulators of transcription ( Fig 1C).…”

Section: Genome-wide Crispr Screens To Identify Genes Controlling Celsupporting

confidence: 89%

CRISPR-based screens uncover determinants of immunotherapy response in Multiple Myeloma

Ramkumar

Abarientos

Tian

et al. 2019

Preprint

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Cancer cells commonly develop resistance to immunotherapy by loss of antigen expression. Combinatorial treatments that increase levels of the target antigen on the surface of cancer cells have the potential to restore efficacy to immunotherapy. Here, we use our CRISPR interference and CRISPR activation-based functional genomics platform to systematically identify pathways controlling cell-surface expression of the multiple myeloma immunotherapy antigen - B cell maturation antigen, BCMA. We discovered that pharmacological inhibition of HDAC7 and the Sec61 complex increased cell-surface BCMA, including in primary patient cells. Importantly, pharmacological Sec61 inhibition enhanced the anti-myeloma efficacy of a BCMA-targeted antibody-drug conjugate. A CRISPR interference CAR-T coculture screen enabled us to identify both antigen-dependent and -independent mechanisms controlling response of myeloma cells to BCMA-targeted CAR-T cells. Thus, our study demonstrates the potential of CRISPR screens to uncover mechanisms controlling response of cancer cells to immunotherapy and to suggest potential combination therapies.Key PointsUsing CRISPR screens, we systematically identify mechanisms increasing expression of the immunotherapy target BCMA and ADC efficacy.We also identify antigen-independent mechanisms regulating response of cancer cells to BCMA-CAR-T cells.

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Section: Genome-wide Crispr Screens To Identify Genes Controlling Celsupporting

confidence: 89%

CRISPR-based screens uncover determinants of immunotherapy response in Multiple Myeloma

Ramkumar

Abarientos

Tian

et al. 2019

Preprint

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“…As BCMA is actively cleaved away from myeloma cell surface by the gamma-secretase complex, study has shown that small-molecule gamma-secretase inhibitor was able to increase BCMA expression on myeloma cells, hence able to increase CAR T-cell efficacy [220]. Combining CAR-T cell therapy with immunomodulatory drug [221] or checkpoint inhibitor [222] are interesting options to be explored.…”

Section: Durability Of Response With Car-t Cell Therapiesmentioning

confidence: 99%

Immunotherapy in Multiple Myeloma

Soekojo

Ooi

Mel

et al. 2020

Cells

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“…However, the variable density of BCMA on MM cells in different patients and the propensity of target escape after initial BCMA-targeting immunotherapy may compromise therapeutic efficacy. For example, BCMA on the cell surface can be cleaved by γ-secretase [77], and the resulting reduced cell surface level of BCMA and increased serum level of soluble BCMA could potentially limit the efficacy of BCMA-directed adoptive T-cell therapy by inhibiting CAR T-cell recognition of BCMA on myeloma cells [33,78,79]. Therefore, targeting other members in this ligand-receptor subgroup such as TACI, either alone or in combination with BCMA-targeting therapies, might achieve better clinical efficacy or improve the treatment outcome for MM patients.…”

Section: Targeting Taci In Immunotherapy Against MMmentioning

confidence: 99%

Transmembrane Activator and CAML Interactor (TACI): Another Potential Target for Immunotherapy of Multiple Myeloma?

Lam

2020

Cancers

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Multiple myeloma (MM) has emerged as the next most likely oncological or hematological disease indication amenable for cellular immunotherapy. Much of the attention has been focused on B cell maturation antigen (BCMA) as a unique cell surface protein on myeloma cells that is available for monoclonal antibodies, antibody drug conjugates (ADCs), T-cell redirecting bispecific molecules, and chimeric antigen receptor (CAR) T cell targeting. BCMA is a member of the tumor necrosis factor receptor (TNFR) superfamily that binds two ligands B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) and mediates the growth and survival of plasma and MM cells. Interestingly, transmembrane activator and CAML interactor (TACI), another TNFR superfamily member, also binds the same ligands and plays largely overlapping roles as BCMA in normal plasma and malignant MM cells. In this article, we review the biology of TACI, focusing on its role in normal B and plasma cells and malignant MM cells, and also discuss various ways to incorporate TACI as a potential target for immunotherapies against MM.

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γ-Secretase inhibition increases efficacy of BCMA-specific chimeric antigen receptor T cells in multiple myeloma

Cited by 240 publications

References 65 publications

CRISPR-based screens uncover determinants of immunotherapy response in Multiple Myeloma

CRISPR-based screens uncover determinants of immunotherapy response in Multiple Myeloma

Immunotherapy in Multiple Myeloma

Transmembrane Activator and CAML Interactor (TACI): Another Potential Target for Immunotherapy of Multiple Myeloma?

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