Development of a B-cell maturation antigen-specific T-cell antigen coupler receptor for multiple myeloma

Bezverbnaya, Ksenia; Moogk, Duane; Cummings, Derek T.; Baker, Christopher L.; Aarts, Craig; Denisova, Galina; Sun, Michael; McNicol, Jamie D.; Turner, Rebecca C.; Rullo, Anthony; Foley, Stephen Ronan; Bramson, Jonathan L.

doi:10.1016/j.jcyt.2021.05.007

Cited by 6 publications

(6 citation statements)

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“…Although we observed a slight enhancement to TAC T cell-mediated killing of multiple myeloma cells in vitro at high doses of LCL161 (5 μM), this effect did not persist with a 2-fold reduction in concentration. Indeed, we expanded our investigation to in vivo studies and similarly observed no benefit in anti-tumor activity of TAC T cells against system MM.1S xenografts (described in our recent publication ( 14 )) when mice were concomitantly treated with either 25 or 75 mg/kg LCL161 (data not shown). Our data indicate that the negative effects of the drug on the T cell population need to be carefully considered.…”

Section: Discussionmentioning

confidence: 86%

“…To characterize the costimulatory properties of LCL161, a dye-dilution proliferation assay using CellTrace Violet was used. To determine the dose of LCL161 that provided optimal costimulation, we stimulated non-engineered T cells and engineered BCMA-specific TAC T cells ( 14 ) through the TCR or TAC receptor alone using plate-bound agonistic anti-CD3 or 6-7 µm diameter polystyrene microbeads coated with BCMA, respectively. Both non-engineered and TAC-engineered T cells demonstrated increased entry into division and increased cell yield and viability after stimulation in the presence of increasing concentrations of LCL161, which plateaued between 0.5-1 μM ( Supplemental Figure 1 ).…”

Section: Resultsmentioning

confidence: 99%

“…Lentivirus encoding the BCMA-specific TAC receptor and truncated NGFR transduction marker ( 14 ) with or without FAIM3 was produced as previously described ( 43 ) using a third generation packaging system ( 44 ). Briefly, 12 x 10 6 HEK293T cells plated on a 15-cm dish (NUNC (Thermo Fisher Scientific)) were transfected with plasmids pRSV-REV (6.25 μg), pMD2.G (9 μg), pMDLg-pRRE (12.5 μg), and pCCL BCMA TAC (32 μg) encapsulated with Lipofectamine 2000 (Thermo Fisher Scientific) in Opti-MEM media (Gibco).…”

Section: Methodsmentioning

confidence: 99%

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LCL161 enhances expansion and survival of engineered anti-tumor T cells but is restricted by death signaling

et al. 2023

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BackgroundThe genesis of SMAC mimetic drugs is founded on the observation that many cancers amplify IAP proteins to facilitate their survival, and therefore removal of these pathways would re-sensitize the cells towards apoptosis. It has become increasingly clear that SMAC mimetics also interface with the immune system in a modulatory manner. Suppression of IAP function by SMAC mimetics activates the non-canonical NF-κB pathway which can augment T cell function, opening the possibility of using SMAC mimetics to enhance immunotherapeutics.MethodsWe have investigated the SMAC mimetic LCL161, which promotes degradation of cIAP-1 and cIAP-2, as an agent for delivering transient costimulation to engineered BMCA-specific human TAC T cells. In doing so we also sought to understand the cellular and molecular effects of LCL161 on T cell biology.ResultsLCL161 activated the non-canonical NF-κB pathway and enhanced antigen-driven TAC T cell proliferation and survival. Transcriptional profiling from TAC T cells treated with LCL161 revealed differential expression of costimulatory and apoptosis-related proteins, namely CD30 and FAIM3. We hypothesized that regulation of these genes by LCL161 may influence the drug’s effects on T cells. We reversed the differential expression through genetic engineering and observed impaired costimulation by LCL161, particularly when CD30 was deleted. While LCL161 can provide a costimulatory signal to TAC T cells following exposure to isolated antigen, we did not observe a similar pattern when TAC T cells were stimulated with myeloma cells expressing the target antigen. We questioned whether FasL expression by myeloma cells may antagonize the costimulatory effects of LCL161. Fas-KO TAC T cells displayed superior expansion following antigen stimulation in the presence of LCL161, suggesting a role for Fas-related T cell death in limiting the magnitude of the T cell response to antigen in the presence of LCL161.ConclusionsOur results demonstrate that LCL161 provides costimulation to TAC T cells exposed to antigen alone, however LCL161 did not enhance TAC T cell anti-tumor function when challenged with myeloma cells and may be limited due to sensitization of T cells towards Fas-mediated apoptosis.

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Section: Discussionmentioning

confidence: 86%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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LCL161 enhances expansion and survival of engineered anti-tumor T cells but is restricted by death signaling

et al. 2023

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“…This study complements different approaches based on other haptens or labelling methods [46] . Compared to other approaches such as ARMs or polymeric systems, [21–26,41–54] this approach presents the flexibility of a two‐step glycoengineering/labelling approach. Furthermore, the general approach described here could be leveraged by selective metabolic glycoengineering strategies targeting specifically cancer cells [34,35,46,47] .…”

Section: Discussionmentioning

confidence: 86%

“…This study complements different approaches based on other haptens or labelling methods. [46] Compared to other approaches such as ARMs or polymeric systems, [21][22][23][24][25][26][41][42][43][44][45][46][47][48][49][50][51][52][53][54] this approach presents the flexibility of a twostep glycoengineering/labelling approach. Furthermore, the…”

Section: Discussionmentioning

confidence: 99%

Antibody Recognition of Cancer Cells via Glycan Surface Engineering

Szponarski

Gademann

2022

ChemBioChem

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Stimulation of the body's immune system toward tumor cells is now well recognized as a promising strategy in cancer therapy. Just behind cell therapy and monoclonal antibodies, small molecule-based strategies are receiving growing attention as alternatives to direct immune response against tumor cells. However, the development of small-molecule approaches to modulate the balance between stimulatory immune factors and suppressive factors in a targeted way remains a challenge. Here, we report the cell surface functionalization of LS174T cancer cells with an abiotic hapten to recruit antibodies to the cell surface. Metabolic glycoengineering followed by covalent reaction with the hapten results in antibody recognition of the target cells. Microscopy and flow cytometry studies provide compelling evidence that metabolic glycoengineering and small molecule stimulators can be combined to direct antibody recognition.

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Strategies for modifying the chimeric antigen receptor (CAR) to improve safety and reduce toxicity in CAR T cell therapy for cancer

Sayadmanesh,

Yekehfallah,

Valizadeh

et al. 2023

International Immunopharmacology

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Development of a B-cell maturation antigen-specific T-cell antigen coupler receptor for multiple myeloma

Cited by 6 publications

References 70 publications

LCL161 enhances expansion and survival of engineered anti-tumor T cells but is restricted by death signaling

LCL161 enhances expansion and survival of engineered anti-tumor T cells but is restricted by death signaling

Antibody Recognition of Cancer Cells via Glycan Surface Engineering

Strategies for modifying the chimeric antigen receptor (CAR) to improve safety and reduce toxicity in CAR T cell therapy for cancer

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