Breaking T-cell tolerance to fight multiple myeloma Free

In this issue of Blood, Dutta et al¹ highlight a proof of concept for a therapeutic messenger RNA (mRNA) vaccine targeting B-cell maturation antigen (BCMA) using lipid nanoparticle (LNP) delivery that has the potential to advance multiple myeloma (MM) immunotherapy. The authors designed a BCMA-directed mRNA vaccine formulated with a biodegradable ionizable lipid (lipid 5) that effectively delivers mRNA to antigen-presenting cells, inducing strong antigen-specific cytotoxic T lymphocyte (CTL) responses. This approach holds promise as a novel therapeutic strategy for MM, a hematologic malignancy that remains incurable despite advances in treatment.

MM is a malignancy characterized by the clonal proliferation of plasma cells within the bone marrow. Despite recent therapeutic advances, including proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, and BCMA-targeted chimeric antigen receptor (CAR) T-cell therapies, disease relapse and resistance remain significant challenges.^2,3 Vaccination strategies that induce durable, antigen-specific immune responses could improve long-term disease control and patient outcomes.

The rapid development and success of mRNA vaccines during the COVID-19 pandemic have accelerated interest in their application to cancer therapy, given their capacity for rapid design and potent immunogenicity.^4,5 However, the efficient and safe delivery of mRNA remains a major hurdle, which can be overcome using LNPs.^6,7 

Due to the immunological tolerance of T cells toward self-antigen, many cancer types do not induce a sufficient T-cell response and antitumor reactivity. Dutta et al addressed this hurdle by developing a BCMA-mRNA vaccine that efficiently stimulates immune responses through mRNA delivery and adjuvant use. The vaccine incorporated lipid 5, a biodegradable ionizable lipid shown to enhance tissue distribution and reduce toxicity compared with earlier formulations.^6,8 The LNP-delivered BCMA mRNA was taken up by human monocyte-derived dendritic cells, presenting the BCMA antigen and activating CD8⁺ T cells that effectively killed BCMA-expressing MM cells, including autologous malignant plasma cells from patients. In the context of the in vivo effects, vaccination induced murine BCMA–specific CD8⁺ T-cell responses, tumor infiltration, and the inhibition of tumor growth in a murine syngeneic MM model, confirming its therapeutic potential. Coadministration with the toll-like receptor 3 agonist poly(I:C) further boosted both innate and adaptive immunity, significantly enhancing the vaccine’s immunogenicity. Intravenous injection generated a rapid and strong CTL response, whereas intramuscular injection with a booster dose achieved comparable immune activation.¹ 

However, a limitation of the experimental setting is the subcutaneous injection of MM cells that allowed convenient quantification of the tumor burden but lacked information about the infiltration of BCMA-specific T cells into the bone marrow. Hence, further research is required to investigate the interaction between BCMA-specific T cells and the suppressive microenvironment in the myeloma niche. Moreover, safety evaluations revealed no adverse effects in major organs, but the limited reflection of T-cell–mediated and immunotherapy-mediated toxicities in mouse models needs to be taken into account. The detection of anti-BCMA antibodies after vaccination further indicates the engagement of humoral immunity, which may complement the cellular immune response and needs to be investigated with respect to its contribution. In addition, it might be of interest for future studies to evaluate the T-cell response in an antigen downregulation scenario, which usually leads to resistance against other BCMA-targeting immunotherapies.

Given these promising results, clinical trials to evaluate safety, immunogenicity, and efficacy in patients with MM are warranted. The vaccine could also be combined with checkpoint inhibitors, bispecific T-cell engagers, or CAR T-cell therapies to overcome tumor immune evasion and improve long-term outcomes.⁹ This work exemplifies how advances in mRNA delivery technology and innate immune activation can drive the development of personalized cancer vaccines. By integrating tumor sequencing and neoantigen identification, future vaccines could be tailored to individual tumor profiles, addressing tumor heterogeneity and resistance mechanisms.¹⁰ The modular nature of the mRNA-LNP platform and the biodegradable lipid 5 system offer opportunities for rapid adaptation to other cancers and diseases that benefit from nucleic acid-based therapies.

Conflict-of-interest disclosure: M.L. is listed as inventor on patent application WO2021/058811A1, which includes the improvement engineering of CAR T cells using the microbial metabolite pentanoate.