CD1d-Invariant Natural Killer T Cell-Based Cancer Immunotherapy: α-Galactosylceramide and Beyond

CD1d-restricted invariant natural killer T (iNKT) cells are considered an attractive target for cancer immunotherapy. Upon their activation by glycolipid antigen and/or cytokines, iNKT cells can induce direct lysis of tumor cells but can also induce an antitumor immune response via their rapid production of proinflammatory cytokines that trigger the cytotoxic machinery of other components of the innate and adaptive immune system. Here, we provide an overview of various therapeutic approaches that have been evaluated or that are currently being developed and/or explored. These include administration of α-GalCer or alternative (glyco) lipid antigens, glycolipid-loaded antigen-presenting cells and liposomes, strategies that enhance CD1d expression levels or are based on ligation of CD1d, adoptive transfer of iNKT cells or chimeric antigen receptor iNKT cells, and tumor targeting of iNKT cells

Corrigendum: CD1d-Invariant Natural Killer T Cell-Based Cancer Immunotherapy: α-Galactosylceramide and Beyond

by King, L. A., Lameris, R., de Gruijl, T. D., and van der Vliet, H. J. (2018). Front. Immunol. 9:1519. doi: 10.3389/fimmu.2018.01519 In the original article, we neglected to disclose that authors Lisa A. King and Roeland Lameris are currently funded by Lava Therapeutics and that Hans J. van der Vliet also acts as chief scientific officer of Lava Therapeutics. Hans J. van der Vliet's affiliation has been updated to reflect this. The corrected Conflict of Interest statement appears below

Enhanced CD1d phosphatidylserine presentation using a single-domain antibody promotes immunomodulatory CD1d-TIM-3 interactions

Background: CD1d is a monomorphic major histocompatibility complex class I-like molecule that presents lipid antigens to distinct T-cell subsets and can be expressed by various malignancies. Antibody-mediated targeting of CD1d on multiple myeloma cells was reported to induce apoptosis and could therefore constitute a novel therapeutic approach. Methods: To determine how a CD1d-specific single-domain antibody (VHH) enhances binding of the early apoptosis marker annexin V to CD1d+ tumor cells we use in vitro cell-based assays and CRISPR-Cas9-mediated gene editing, and to determine the structure of the VHH1D17-CD1d(endogenous lipid) complex we use X-ray crystallography. Results: Anti-CD1d VHH1D17 strongly enhances annexin V binding to CD1d+ tumor cells but this does not reflect induction of apoptosis. Instead, we show that VHH1D17 enhances presentation of phosphatidylserine (PS) in CD1d and that this is saposin dependent. The crystal structure of the VHH1D17-CD1d(endogenous lipid) complex demonstrates that VHH1D17 binds the A′-pocket of CD1d, leaving the lipid headgroup solvent exposed, and has an electro-negatively charged patch which could be involved in the enhanced PS presentation by CD1d. Presentation of PS in CD1d does not trigger phagocytosis but leads to greatly enhanced binding of T-cell immunoglobulin and mucin domain containing molecules (TIM)-1 to TIM-3, TIM-4 and induces TIM-3 signaling. Conclusion: Our findings reveal the existence of an immune modulatory CD1d(PS)-TIM axis with potentially unexpected implications for immune regulation in both physiological and pathological conditions

Polymerase chain reaction amplifying mycobacterial DNA from aspirates obtained by endoscopic ultrasound allows accurate diagnosis of mycobacterial disease in HIV-positive patients with abdominal lymphadenopathy

Abdominal lymphadopathy in Human Immunodeficiency Virus (HIV) infection remains a diagnostic challenge. We performed a prospective cohort study recruiting thirty-one symptomatic HIV+ patients with abdominal lymphadenopathy assessing diagnostic yield of endoscopic ultrasound (EUS) fine needle aspiration (FNA). Mean age was 38 years, 52% were female, mean CD4 count and viral load were 124 cells/pl, and 4 log respectively. EUS confirmed additional mediastinal nodes in 26 %. Porta- hepatis was the most common abdominal site. EUS FNA was subjected to cytology, culture and polymerase chain reaction (PCR) analysis. Mycobacterial infections were confirmed in 67.7% and 31% had reactive lymphadenopathy. Cytology and culture had low sensitivity whereas PCR identified 90% of mycobacterial infections. Combining appearance of EUS FNA and cytology a diagnostic algorithm was developed to indicate when analysis with PCR would be useful. PCR performed on an EUS guided aspirate was highly accurate in confirming mycobacterial disease and determining genotypic drug resistance.South African Gastroenterological Society (SAGES)/ Astra Zeneca Fellowship in Gastroenterology awarded to Schalk van der Merwehttp://www.journals.elsevier.com/ultrasound-in-medicine-and-biology/hb201

A visceral pseudoaneurysm : management by EUS-guided thrombin injection

No abstract available

Polymerase chain reaction amplifying mycobacterial DNA from aspirates obtained by endoscopic ultrasound allows accurate diagnosis of mycobacterial disease in HIV-positive patients with abdominal lymphadenopathy

Abdominal lymphadenopathy in human immunodeficiency virus (HIV) infection remains a diagnostic challenge. We performed a prospective cohort study by recruiting 31 symptomatic HIV + patients with abdominal lymphadenopathy and assessing the diagnostic yield of endoscopic ultrasound fine-needle aspiration (EUS-FNA). Mean age was 38 years; 52% were female; and mean CD4 count and viral load were 124 cells/μL and 4 log, respectively. EUS confirmed additional mediastinal nodes in 26%. The porta hepatis was the most common abdominal site. Aspirates obtained by EUS-FNA were subjected to cytology, culture and polymerase chain reaction (PCR) analysis. Mycobacterial infections were confirmed in 67.7%, and 31% had reactive lymphadenopathy. Cytology and culture had low sensitivity, whereas PCR identified 90% of mycobacterial infections. By combining the appearance of aspirates obtained by EUS-FNA and cytologic specimens, we developed a diagnostic algorithm to indicate when analysis with PCR would be useful. PCR performed on material obtained by EUS-FNA was highly accurate in confirming mycobacterial disease and determining genotypic drug resistance.status: publishe

Preclinical evaluation of invariant natural killer t cells modified with cd38 or bcma chimeric antigen receptors for multiple myeloma

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 nor-mal hematopoietic cells and displayed a Th1-like cytokine profile, indicating their therapeutic util-ity. 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

Generation and characterization of CD1d-specific single-domain antibodies with distinct functional features

Ligation of the CD1d antigen-presenting molecule by monoclonal antibodies (mAbs) can trigger important biological functions. For therapeutic purposes camelid-derived variable domain of heavy-chain-only antibodies (VHH) have multiple advantages over mAbs because they are small, stable and have low immunogenicity. Here, we generated 21 human CD1d-specific VHH by immunizing Lama glama and subsequent phage display. Two clones induced maturation of dendritic cells, one clone induced early apoptosis in CD1d-expressing B lymphoblasts and multiple myeloma cells, and another clone blocked recognition of glycolipid-loaded CD1d by CD1d-restricted invariant natural killer T (iNKT) cells. In contrast to reported CD1d-specific mAbs, these CD1d-specific VHH have the unique characteristic that they induce specific and well-defined biological effects. This feature, combined with the above-indicated general advantages of VHH, make the CD1d-specific VHH generated here unique and useful tools to exploit both CD1d ligation as well as disruption of CD1d–iNKT interactions in the treatment of cancer or inflammatory disorders

A visceral pseudoaneurysm: management by EUS-guided thrombin injection

No abstract available