Advances and challenges in anti-cancer vaccines for multiple myeloma

Abstract

Multiple myeloma (MM) is a hematological cancer marked by plasma cell accumulation in the bone marrow. Despite treatment advancements, MM remains incurable in most patients. MM-associated immune dysregulation fosters disease progression, prompting research into immunotherapy to combat the disease. An area of immunotherapy investigation is the design of myeloma vaccine therapy to reverse tumor-associated immune suppression and elicit tumor-specific immune responses to effectively target MM cells. This article reviews vaccine immunotherapy for MM, categorizing findings by antigen type and delivery method. Antigens include idiotype (Id), tumor-associated (TAA), tumor-specific (TSA), and whole tumor lysate. Myeloma vaccination has so far shown limited clinical efficacy. However, further studies are essential to optimize various aspects, including antigen and patient selection, vaccine timing and sequencing, and rational combinations with emerging MM treatments.

Keywords: idiotype (Id); immunotherapy; multiple myeloma (MM); tumor-associated antigen (TAA); tumor-specific antigen (TSA); vaccine.

Figure 1

Consideration in designing vaccine. MM bone marrow microenvironment is consisted of immunosuppressive elements including MDSCs, TAM and Tregs. MDSCs stimulate TAM as well as Tregs via IL-10. MDSCs also inhibit CTLs via IL-10. Tregs inhibit CTL, and DC function by direct cellular interactions and via secretion of suppressive cytokines, such as TGF-β and IL-10. Moreover, MM cells secrete several cytokines including IL-6, TGF-β, and IL-10 that inhibit DCs, CTLs, and stimulate Tregs. Myeloma patients express multiple immune checkpoint receptors, including PD-1, CTLA-4, TIM-3, LAG-3, TIGIT. Terminal T cell exhaustion is associated with the loss of cytotoxicity by CD4+ and CD8+ T cells subsets that produce IFN-γ, a critical cytokine for tumor immunity. MM, Multiple myeloma; MGUS, Monoclonal gammopathy of undetermined significance; SMM, Smoldering MM; BM, Bone marrow; DC, Dendritic cells; BMSC, Bone marrow stromal cells; CTL, Cytotoxic T lymphocyte; MDSCs, myeloid-derived suppressor cells; TAM, Tumor-associated macrophages; Treg, Regulatory T-cells; PD-1, programmed cell death domain protein 1; CTLA-4, Cytotoxic T-lymphocyte-associated protein 4; TIM-3, T cell immunoglobulin mucin-3; LAG-3, lymphocyte activation gene 3; TIGIT, T cell immunoglobulin and ITIM domain; Interleukin (IL)-10; TGF-β1, transforming growth factor-β1; TAA, tumor-associated antigen; TSA, tumor-specific antigen. Parts of figures were used/adapted from pictures provided by Servier Medical Art (Servier; https://smart.servier.com/), licensed under a Creative Commons Attribution 4.0 Unported License (https://creativecommons.org/licenses/by/4.0/).