Exploiting B Cell Transfer for Cancer Therapy: Engineered B Cells to Eradicate Tumors

Abstract

Nowadays, cancers still represent a significant health burden, accounting for around 10 million deaths per year, due to ageing populations and inefficient treatments for some refractory cancers. Immunotherapy strategies that modulate the patient’s immune system have emerged as good treatment options. Among them, the adoptive transfer of B cells selected ex vivo showed promising results, with a reduction in tumor growth in several cancer mouse models, often associated with antitumoral immune responses. Aside from the benefits of their intrinsic properties, including antigen presentation, antibody secretion, homing and long-term persistence, B cells can be modified prior to reinfusion to increase their therapeutic role. For instance, B cells have been modified mainly to boost their immuno-stimulatory activation potential by forcing the expression of costimulatory ligands using defined culture conditions or gene insertion. Moreover, tumor-specific antigen presentation by infused B cells has been increased by ex vivo antigen loading (peptides, RNA, DNA, virus) or by the sorting/ engineering of B cells with a B cell receptor specific to tumor antigens. Editing of the BCR also rewires B cell specificity toward tumor antigens, and may trigger, upon antigen recognition, the secretion of antitumor antibodies by differentiated plasma cells that can then be recognized by other immune components or cells involved in tumor clearance by antibody-dependent cell cytotoxicity or complement-dependent cytotoxicity for example. With the expansion of gene editing methodologies, new strategies to reprogram immune cells with whole synthetic circuits are being explored: modified B cells can sense disease-specific biomarkers and, in response, trigger the expression of therapeutic molecules, such as molecules that counteract the tumoral immunosuppressive microenvironment. Such strategies remain in their infancy for implementation in B cells, but are likely to expand in the coming years.

Neoepitope-specific vaccination of a patient with diffuse midline glioma targeting H3K27M induces polyclonal B and T cell responses across diverse HLA alleles

“…The presence of such tumor-reactive B cells and their intrinsic ability to process and present antigens may support the maintenance of a functional memory CD4 + T cell population 32 . Interestingly, the formation of B cells in tertiary lymphoid structures as well as neoantigen-targeted antibodies have been shown to be correlated with responsiveness to immunotherapy 33-35 . Although not yet explored in detail, genetically engineered B cells carrying tumor-reactive BCRs may comprise another potential immunotherapeutic strategy 36 . In addition to their beneficial effects on CD4 + T cells, they could also indirectly promote tumor killing by activating the complement system upon secretion of neoantigen-specific antibodies, which may recognize HLA-bound neo-epitopes in vivo 36 .…”

New opportunities for immunomodulation of the tumour microenvironment using chemical tools

“…Methods above activated B cells through combining vaccines with various methods and successfully induce strong B cellmediated immune response. B cells can also be engineered in vitro to load antigens or regulate the expression of certain ligands, such as tumour-specific BCRs and co-stimulatory ligands (reviewed in detail by Cosset et al 49 ). Moreover, there has been increasing interest in the importance of B cells in immunotherapy recently, with several studies focusing on the relevance of B cells in therapeutic outcomes 14,50,51 and the putative mechanisms involved in B cell-mediated immunity.…”

The soldiers needed to be awakened: Tumor-infiltrating immune cells

“…Thus, researchers exploited this trait to edit a specific BCR toward tumor antigens in vitro . The editing BCR strategies are attractive, but they have are yet to be applied to treat tumors ( Page et al, 2021 ). Antibodies, targeting B cells, are mainly used to treat hematological malignancy, such as anti-CD19 and anti-CD20, which results in a conducive prognosis (NCT04160195), and currently, relevant trials are on the way.…”