Rational design of a trimeric APRIL-based CAR-binding domain enables efficient targeting of multiple myeloma

Schmidts, Andrea; Ormhøj, Maria; Choi, Bryan D.; Taylor, Allison; Bouffard, Amanda A.; Scarfò, Irene; Larson, Rebecca C.; Frigault, Matthew J.; Gallagher, Kathleen M.E.; Castaño, Ana P.; Riley, Lauren S.; Cabral, Maria L.; Boroughs, Angela C.; Cárdenas, Rubí M.-H. Velasco; Schamel, Wolfgang W. A.; Zhou, Jing; Mackay, Sean; Tai, Yu Tzu; Anderson, Kenneth C.; Maus, Marcela V.

doi:10.1182/bloodadvances.2019000703

Cited by 79 publications

(76 citation statements)

References 75 publications

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“…TACI is almost solely expressed on plasma cells and found at high levels on most myeloma cells. By preserving the trimeric structure of APRIL, a proliferation-inducing ligand for both BCMA and TACI, it would allow enhanced binding to BCMA and TACI, which would in turn allow efficient targeting of both BCMA + and BCMA − MM [224]. Further studies would be needed.…”

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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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, developing agents that can specifically target therapeutic agents into the BM and disrupt BM communication with high efficacy without producing non-specific systemic toxicity has been a challenge and is an area that needs more investigation. Towards that goal, ligand targeting CAR therapy is in the early stages of development in hematological malignancies with BM involvement [129]. However, natural ligands such as CAR antigen-binding domains may require further engineering to promote optimal binding and multimerization to adequately trigger T-cell activation.…”

Section: Newer Therapies Targeting Bm Microenvironmentmentioning

confidence: 99%

Impact and Intricacies of Bone Marrow Microenvironment in B-cell Lymphomas: From Biology to Therapy

Sircar

Chowdhury

Hart

et al. 2020

IJMS

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Lymphoma, a group of widely prevalent hematological malignancies of lymphocyte origin, has become the focus of significant clinical research due to their high propensity for refractory/relapsed (R/R) disease, leading to poor prognostic outcomes. The complex molecular circuitry in lymphomas, especially in the aggressive phenotypes, has made it difficult to find a therapeutic option that can salvage R/R disease. Furthermore, the association of lymphomas with the Bone Marrow (BM) microenvironment has been found to portend worse outcomes in terms of heightened chances of relapse and acquired resistance to chemotherapy. This review assesses the current therapy options in three distinct types of lymphomas: diffuse large B-cell lymphoma, follicular lymphoma and mantle cell lymphoma. It also explores the role of the BM tumor microenvironment as a secure ‘niche’ for lymphoma cells to grow, proliferate and survive. It further evaluates potential mechanisms through which the tumor cells can establish molecular connections with the BM cells to provide pro-tumor benefits, and discusses putative therapeutic strategies for disrupting the BM-lymphoma cell communication.

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“…In another recent study using APRIL-based, 2nd generation CAR that targets BCMA and TACI simultaneously, it was further shown that APRIL in a trimeric format (Tr-iAPRIL) as the antigen-binding domain, displayed enhanced binding to BCMA and TACI and exhibited greater target cytolysis activity against MM compared to monomeric APRIL CAR [85]. This study also demonstrated that the Tri-APRIL CAR-T cells could achieve long-term proliferation and acquire better polyfunctionality than the monomeric APRIL CAR-T cells in a xenograft mouse model.…”

Section: Incorporating Taci In Car-t Cells Targeting Of 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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Rational design of a trimeric APRIL-based CAR-binding domain enables efficient targeting of multiple myeloma

Abstract: Key Points A trimeric extracellular moiety of APRIL has enhanced binding to BCMA and TACI compared with monomeric APRIL when incorporated into a CAR. T cells transduced with a trimeric APRIL-based CAR are a promising approach for the treatment of MM.

Cited by 79 publications

References 75 publications

Immunotherapy in Multiple Myeloma

Immunotherapy in Multiple Myeloma

Impact and Intricacies of Bone Marrow Microenvironment in B-cell Lymphomas: From Biology to Therapy

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

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