Accessory Cells of the Microenvironment Protect Multiple Myeloma from T-Cell Cytotoxicity through Cell Adhesion-Mediated Immune Resistance

Haart, Sanne J. de; Donk, Niels W.C.J. van de; Minnema, Monique C.; Huang, Julie H.; Aarts-Riemens, Tineke; Bovenschen, Niels; Yuan, Huipin; Groen, Richard W.J.; McMillin, Douglas W.; Jakubíková, Jana; Lokhorst, Henk M.; Martens, Anton C.; Mitsiades, Constantine S.; Mutis, Tuna

doi:10.1158/1078-0432.ccr-12-3676

Cited by 50 publications

(60 citation statements)

References 41 publications

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“…11,14 As expected, there was no CD38-CAR-specific lysis of the CD38 -U266 cell line ( Figure 2A). In contrast, all three types of CD38-CART cells, but not mock T cells, effectively lysed the CD38 + MM cell line UM9 in a cell-dose dependent manner ( Figure 2B), showing the feasibility of generating effective CART cells with any of the CD38 antibody sequences we used.…”

Section: Cd38-dependent Lysis Of Multiple Myeloma Cell Lines By Cd38-supporting

confidence: 75%

“…The luciferase signal produced by surviving malignant cells was determined after 16-24 h with a SpectraMax luminometer (Molecular Devices) within 15 min after the addition of 125 μg/mL beetle luciferin (Promega). 11 The percent lysis was then calculated as in the flow-based cytotoxicity assay above.…”

Section: Bioluminescence Imaging-based Cell Lysis Assaysmentioning

confidence: 99%

“…After a week of in vitro culture, humanized scaffolds were seeded with CD38 + UM9 cells and implanted subcutaneously into the mice, as described previously, 11,12 and in the Online Supplementary Methods.…”

Section: In Vivo Efficacy Of Cd38-chimeric Antigen Receptortransducedmentioning

confidence: 99%

“…-/-mice, in which a humanized bone marrow-like niche for MM cells is generated by subcutaneous implantation of ceramic scaffolds coated with human bone marrow stromal cells 11,12 ( Figure 4). Thus, we implanted such scaffolds seeded with luciferase-transduced UM9 MM cells in the back of the mice (6 scaffolds per mouse).…”

Section: γCmentioning

confidence: 99%

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Pre-clinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma

et al. 2016

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A doptive transfer of chimeric antigen receptor-transduced T cells is a promising strategy for cancer immunotherapy. The CD38 molecule, with its high expression on multiple myeloma cells, appears a suitable target for antibody therapy. Prompted by this, we used three different CD38 antibody sequences to generate second-generation retroviral CD38-chimeric antigen receptor constructs with which we transduced T cells from healthy donors and multiple myeloma patients. We then evaluated the preclinical efficacy and safety of the transduced T cells. Irrespective of the donor and antibody sequence, CD38-chimeric antigen receptor-transduced T cells proliferated, produced inflammatory cytokines and effectively lysed malignant cell lines and primary malignant cells from patients with acute myeloid leukemia and multi-drug resistant multiple myeloma in a cell-dose, and CD38-dependent manner, despite becoming CD38-negative during culture. CD38-chimeric antigen receptor-transduced T cells also displayed significant anti-tumor effects in a xenotransplant model, in which multiple myeloma tumors were grown in a human bone marrow-like microenvironment. CD38-chimeric antigen receptor-transduced T cells also appeared to lyse the CD38 + fractions of CD34 + hematopoietic progenitor cells, monocytes, natural killer cells, and to a lesser extent T and B cells but did not inhibit the outgrowth of progenitor cells into various myeloid lineages and, furthermore, were effectively controllable with a caspase-9-based suicide gene. These results signify the potential importance of CD38-chimeric antigen receptor-transduced T cells as therapeutic tools for CD38 + malignancies and warrant further efforts to diminish the undesired effects of this immunotherapy using appropriate strategies. Pre-clinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma

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Section: Cd38-dependent Lysis Of Multiple Myeloma Cell Lines By Cd38-supporting

confidence: 75%

Section: Bioluminescence Imaging-based Cell Lysis Assaysmentioning

confidence: 99%

Section: In Vivo Efficacy Of Cd38-chimeric Antigen Receptortransducedmentioning

confidence: 99%

Section: γCmentioning

confidence: 99%

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Pre-clinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma

et al. 2016

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“…Combination therapy with specific targeting of adhesion molecules or apoptotic pathways involved in cell-adhesion-mediated immune resistance could therefore contribute to the success of mHag-specific therapies. 99 …”

Section: Selection Of DC Source and Typementioning

confidence: 99%

Minor histocompatibility Ags: identification strategies, clinical results and translational perspectives

Oostvogels

Lokhorst

Mutis

2015

Bone Marrow Transplant

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Allogeneic stem cell transplantation (allo-SCT) and donor lymphocyte infusion are effective treatment modalities for various hematological malignancies. Their therapeutic effect, the graft-versus-tumor (GvT) effect, is based mainly on an alloimmune response of donor T cells directed at tumor cells, in which differences in the expression of minor histocompatibility Ags (mHags) on the cells of the patient and donor have a crucial role. However, these differences are also responsible for induction of sometimes detrimental GvHD. As relapse and development of GvHD pose major threats for a large proportion of allotransplanted patients, additional therapeutic strategies are required. To augment the GvT response without increasing the risk of GvHD, specific mHagdirected immunotherapeutic strategies have been developed. Over the past years, much effort has been put into the identification of therapeutically relevant mHags to enable these strategies for a substantial proportion of patients. Currently, the concept of mHag-directed immunotherapy is tested in clinical trials on feasibility, safety and efficacy. In this review, we will summarize the recent developments in mHag identification and the clinical data on mHag-specific immune responses and mHag-directed therapies in patients with hematological malignancies. Finally, we will outline the current challenges and future prospectives in the field.

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Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)

et al. 2019

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These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer‐reviewed by leading experts in the field, making this an essential research companion.

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Accessory Cells of the Microenvironment Protect Multiple Myeloma from T-Cell Cytotoxicity through Cell Adhesion-Mediated Immune Resistance

Cited by 50 publications

References 41 publications

Pre-clinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma

Pre-clinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma

Minor histocompatibility Ags: identification strategies, clinical results and translational perspectives

Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)

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