A single-domain bispecific antibody targeting CD1d and the NKT T-cell receptor induces a potent antitumor response

Lameris, Roeland; Shahine, Adam; Pellicci, Daniel G.; Uldrich, Adam P.; Gras, Stéphanie; Nours, Jérôme Le; Groen, Richard W.J.; Vree, Jana; Reddiex, Scott J. J.; Quiñones-Parra, Sergio M.; Richardson, Stewart K.; Howell, Amy R.; Zweegman, Sonja; Godfrey, Dale I.; Gruijl, Tanja D. de; Rossjohn, Jamie; Vliet, Hans J. van der

doi:10.1038/s43018-020-00111-6

Cited by 25 publications

(43 citation statements)

References 49 publications

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“…Luciferase-transduced or unmodified human MM cell lines UM9, MM1.s, and MM1.s-CD1d were previously described [ 41 , 58 , 59 ]. The MM cell lines were cultured in RPMI-1640 ((Life Technologies, Bleiswijk, The Netherlands)) with 10% HyClone FCS (Fisher Scientific, Amsterdam, The Netherlands) and antibiotics (penicillin; 100 U/mL, streptomycin; 100 µg/mL).…”

Section: Methodsmentioning

confidence: 99%

Preclinical Evaluation of Invariant Natural Killer T Cells Modified with CD38 or BCMA Chimeric Antigen Receptors for Multiple Myeloma

Poels

Drent

Lameris

et al. 2021

IJMS

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Due to the CD1d restricted recognition of altered glycolipids, Vα24-invariant natural killer T (iNKT) cells are excellent tools for cancer immunotherapy with a significantly reduced risk for graft-versus-host disease when applied as off-the shelf-therapeutics across Human Leukocyte Antigen (HLA) barriers. To maximally harness their therapeutic potential for multiple myeloma (MM) treatment, we here armed iNKT cells with chimeric antigen receptors (CAR) directed against the MM-associated antigen CD38 and the plasma cell specific B cell maturation antigen (BCMA). We demonstrate that both CD38- and BCMA-CAR iNKT cells effectively eliminated MM cells in a CAR-dependent manner, without losing their T cell receptor (TCR)-mediated cytotoxic activity. Importantly, iNKT cells expressing either BCMA-CARs or affinity-optimized CD38-CARs spared normal hematopoietic cells and displayed a Th1-like cytokine profile, indicating their therapeutic utility. While the costimulatory domain of CD38-CARs had no influence on the cytotoxic functions of iNKT cells, CARs containing the 4-1BB domain showed a better expansion capacity. Interestingly, when stimulated only via CD1d+ dendritic cells (DCs) loaded with α-galactosylceramide (α-GalCer), both CD38- and BCMA-CAR iNKT cells expanded well, without losing their CAR- or TCR-dependent cytotoxic activities. This suggests the possibility of developing an off-the-shelf therapy with CAR iNKT cells, which might even be boostable in vivo by administration α-GalCer pulsed DCs.

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Section: Methodsmentioning

confidence: 99%

Preclinical Evaluation of Invariant Natural Killer T Cells Modified with CD38 or BCMA Chimeric Antigen Receptors for Multiple Myeloma

Poels

Drent

Lameris

et al. 2021

IJMS

Self Cite

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“…1). In this issue of Nature Cancer, Lameris et al report a single-chain antibody that stabilizes invariant TCR (iTCR)-CD1d interactions through intrinsic bi-specificity and stimulates iNKT cells and consequent potent anti-tumor responses 7 .…”

Section: Immunotherapy a Nano-engager For Inkt Cells In Cancermentioning

confidence: 99%

“…A few iNKT cell-based therapies have also reached phase 1 clinical trials [4][5][6]10 , with evidence of safety and relative clinical efficacy [5][6][7] (Fig. 1b).…”

Section: Immunotherapy a Nano-engager For Inkt Cells In Cancermentioning

confidence: 99%

“…Furthermore, a variety of CD1d-specific monoclonal antibodies (mAbs) have been developed over the past 25 years, most of which target a series of externally accessible CD1d epitopes 2,6,9,10 ; these mAbs have traditionally been seen as iNKT cell blockers, as many of them prevent the interaction of the iNKT cells with CD1d + cells, as well as bypassing iNKT cells by stimulating CD1d + cells 9,12,13 . The work by Lameris et al described the structural basis of a serendipitous, unique, iNKT cellagonistic, bi-functional antibody 7 ; this antibody clone (1D12) was from a large collection of CD1d-specific, camelid (llama)-based, single-chain antibodies (also known as 'nanobodies' or 'VHHs') that lack the Fc fragment chain of mAbs. The VHH1D12 nanobody was singled out for this unique agonistic activity, which turned out to be based on simultaneous binding of CD1d and the iNKT cell TCR in the presence of their cognate lipid antigen and thus stabilized the ternary CD1d-lipid-iTCR complexes 7 (Fig.…”

Section: Immunotherapy a Nano-engager For Inkt Cells In Cancermentioning

confidence: 99%

“…The work by Lameris et al described the structural basis of a serendipitous, unique, iNKT cellagonistic, bi-functional antibody 7 ; this antibody clone (1D12) was from a large collection of CD1d-specific, camelid (llama)-based, single-chain antibodies (also known as 'nanobodies' or 'VHHs') that lack the Fc fragment chain of mAbs. The VHH1D12 nanobody was singled out for this unique agonistic activity, which turned out to be based on simultaneous binding of CD1d and the iNKT cell TCR in the presence of their cognate lipid antigen and thus stabilized the ternary CD1d-lipid-iTCR complexes 7 (Fig. 1e).…”

Section: Immunotherapy a Nano-engager For Inkt Cells In Cancermentioning

confidence: 99%

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The elevated levels of lactate in tumor tissue play a pivotal role in fostering an immunosuppressive microenvironment. Therefore, efficiently reducing lactate levels to reprogram tumor immune microenvironment (TIM) is considered a crucial step for boosted immunotherapy. Here, a high‐lactate‐metabolizing photosynthetic bacteria (LAB‐1) is selectively screened for TIM reprogramming, which then improves the efficacy of tumor immunotherapy. The culture medium for LAB‐1 screening is initially developed through an orthogonal experiment, simulating the tumor microenvironment (TME) and utilizing lactate as the sole organic carbon source. As demonstrated in a murine 4T1 model, LAB‐1 colonizes the TME selectively, resulting in a significant reduction in lactate levels and a subsequent increase in pH values within the tumor tissue. Furthermore, single‐cell RNA sequencing analysis reveals that LAB‐1 effectively reprograms the TIM, thereby enhancing the effectiveness of antitumor immune therapy. This approach of utilizing lactate‐consuming bacteria represents a potent tool for augmenting tumor immunotherapy efficiency.

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A single-domain bispecific antibody targeting CD1d and the NKT T-cell receptor induces a potent antitumor response

Cited by 25 publications

References 49 publications

Preclinical Evaluation of Invariant Natural Killer T Cells Modified with CD38 or BCMA Chimeric Antigen Receptors for Multiple Myeloma

Preclinical Evaluation of Invariant Natural Killer T Cells Modified with CD38 or BCMA Chimeric Antigen Receptors for Multiple Myeloma

A nano-engager for iNKT cells in cancer

High‐Lactate‐Metabolizing Photosynthetic Bacteria Reprogram Tumor Immune Microenvironment

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