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14 pages, 1686 KiB

Open AccessReview

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

by Shengli Xu and Kong-Peng Lam

Cancers 2020, 12(4), 1045; https://doi.org/10.3390/cancers12041045 - 23 Apr 2020

Cited by 9 | Viewed by 7061

Abstract

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. Full article

(This article belongs to the Special Issue Cellular Immunotherapies for Multiple Myeloma)

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15 pages, 1063 KiB

Open AccessReview

Challenges for Immunotherapy in Multiple Myeloma: Bone Marrow Microenvironment-Mediated Immune Suppression and Immune Resistance

by Lisa C. Holthof and Tuna Mutis

Cancers 2020, 12(4), 988; https://doi.org/10.3390/cancers12040988 - 17 Apr 2020

Cited by 44 | Viewed by 5310

Abstract

The power of immunotherapy in the battle of Multiple Myeloma (MM) started with allogeneic stem cell transplantation, and was rediscovered with immunomodulatory drugs and extended with the outstanding results achieved with targeted antibodies. Today, next to powerful antibodies Elotuzumab and Daratumumab, several T-cell-based immunotherapeutic approaches, such as bispecific antibodies and chimeric antigen receptor-transduced T-cells (CAR T-cells) are making their successful entry in the immunotherapy arena with highly promising results in clinical trials. Nonetheless, similar to what is observed in chemotherapy, MM appears capable to escape from immunotherapy, especially through tight interactions with the cells of the bone marrow microenvironment (BM-ME). This review will outline our current understanding on how BM-ME protects MM-cells from immunotherapy through immunosuppression and through induction of intrinsic resistance against cytotoxic effector mechanisms of T- and NK-cells. Full article

(This article belongs to the Special Issue Cellular Immunotherapies for Multiple Myeloma)

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19 pages, 743 KiB

Open AccessReview

Towards Physiologically and Tightly Regulated Vectored Antibody Therapies

by Audrey Page, Floriane Fusil and François-Loïc Cosset

Cancers 2020, 12(4), 962; https://doi.org/10.3390/cancers12040962 - 13 Apr 2020

Cited by 8 | Viewed by 3120

Abstract

Cancers represent highly significant health issues and the options for their treatment are often not efficient to cure the disease. Immunotherapy strategies have been developed to modulate the patient’s immune system in order to eradicate cancerous cells. For instance, passive immunization consists in the administration at high doses of exogenously produced monoclonal antibodies directed either against tumor antigen or against immune checkpoint inhibitors. Its main advantage is that it provides immediate immunity, though during a relatively short period, which consequently requires frequent injections. To circumvent this limitation, several approaches, reviewed here, have emerged to induce in vivo antibody secretion at physiological doses. Gene delivery vectors, such as adenoviral vectors or adeno-associated vectors, have been designed to induce antibody secretion in vivo after in situ cell modification, and have driven significant improvements in several cancer models. However, anti-idiotypic antibodies and escape mutants have been detected, probably because of both the continuous expression of antibodies and their expression by unspecialized cell types. To overcome these hurdles, adoptive transfer of genetically modified B cells that secrete antibodies either constitutively or in a regulated manner have been developed by ex vivo transgene insertion with viral vectors. Recently, with the emergence of gene editing technologies, the endogenous B cell receptor loci of B cells have been modified with the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated endonuclease (Cas-9) system to change their specificity in order to target a given antigen. The expression of the modified BCR gene hence follows the endogenous regulation mechanisms, which may prevent or at least reduce side effects. Although these approaches seem promising for cancer treatments, major questions, such as the persistence and the re-activation potential of these engineered cells, remain to be addressed in clinically relevant animal models before translation to humans. Full article

(This article belongs to the Special Issue Cellular Immunotherapies for Multiple Myeloma)

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