Applications of Single B Cell Screening in Immunotherapy

How could Single B cell screening revolutionize cancer treatment?

Single-cell technology is capable of characterizing the molecular state of each cell within a tumor, enabling new exploration of tumor heterogeneity, microenvironment cell type composition, and cell state transition, especially in immunotherapy. Analyzing clinical samples is highly accurate but technically challenging. This article reviews the application of current sample processing and computational analysis methods of single-cell technology in translational cancer immunotherapy research.

Single-cell analysis has become a widely used tool in cancer research to characterize the cellular and molecular composition of tumors. Techniques for analyzing individual cells are currently capable of measuring tumor heterogeneity across molecular levels, including DNA, RNA, proteins, and epigenetics. Whereas bulk techniques are limited to average signals that typically represent the molecular states of the most abundant cell populations, single-cell approaches address the cellular composition of the tumor microenvironment (TME). This feature holds particular promise in the field of tumor immunology because comprehensive analysis can identify the cell types and pathways involved in anti-tumor response and immune evasion.

Current single-cell technologies span a range of rapidly evolving methodologies, with the most common examples of tumor immunotherapy including single-cell RNA sequencing (scRNA-seq) for transcription profiling, mass spectrometry (CyTOF) for proteomic profiling, and spatial molecular profiling. Each of these techniques provides a high-dimensional molecular profile for individual cells that can be computationally classified into distinct cell populations.

Figure 1: Mouse-to-human studies using high-dimensional analysis will advance the next generation of precise cancer immunotherapies.

How could Single B cell screening revolutionize autoimmune diseases?

B-cell depletion therapy is becoming increasingly important in the treatment of autoimmune diseases. Monoclonal antibodies that target B cells and plasma cells can effectively treat a wide range of autoimmune diseases, underscoring the importance of B cells in the pathogenesis of such diseases. Chimeric antigen receptor T (CAR-T) cell therapy, which targets B cells by identifying their highly specific and ubiquitous surface antigen CD19, has been applied in the field of hematological malignancies, bringing the treatment of autoimmune diseases into a new era. This article analyzes the mechanism of action and application of B-cell targeting monoclonal antibodies and CAR-T cell therapy and discusses the advantages and disadvantages of these treatment options.

In autoimmune diseases, B-cell-associated monoclonal antibodies mainly target CD20, CD19, CD22, CD38, and B-cell activating factor (BAFF). Some drugs have been approved by the US Food and Drug Administration, such as rituximab, Beliuzumab, orfathomumab, etc.

Antibodies targeting CD20 are currently the most widely used monoclonal antibodies, and although these antibodies have the same target, their structures and indications are quite different. Inellizumab is a humanized anti-CD19 monoclonal antibody that has been approved by the FDA for the treatment of neuromyelitis spectrum disorder (NMOSD). In addition, several drugs target other B cell surface antigens, such as epratuzumab, which targets CD22, and daratumumab, which targets CD38, that are being tried for the treatment of systemic lupus erythematosus.

Given the efficacy of chimeric antigen receptor T (CAR-T) cell immunotherapies in the treatment of diffuse large B-cell lymphoma and B-cell leukemia, they have also been used to eliminate B cells or plasma cells in autoimmune diseases.

Monoclonal antibody and CAR-T cell therapies have their advantages and disadvantages. Monoclonal antibodies, due to their short half-life, require multiple dosing to achieve the desired therapeutic effect. In contrast, CAR T cells act as a "living drug" that can multiply and expand in the body after infusion and can survive for a long time. However, CAR T cells require lymphocyte depletion chemotherapy with fludarabine and cyclophosphamide before administration, while monoclonal antibodies do not.

In clinical application, monoclonal antibodies cannot enter the autoreactive B cells in lymphoid organs and inflammatory tissues, so the effect of consumption of B cells is limited, and it is difficult to completely deplete B cells. CAR-T cell therapy works better in this regard, but higher efficacy is often accompanied by toxicity. Moreover, T cells in CAR-T cell therapy have intrinsic functional activity, leading to more complex and severe toxicity, such as fatal cytokine release syndrome (CRS). Therefore, to balance the safety and efficacy of CAR-T cell therapy, medication strategy is a key issue. In conclusion, while some clinical trials and cases have demonstrated the efficacy of CAR-based cell therapies, large cohort studies are still needed to evaluate their efficacy and safety before they can be widely used.

References

[1] Davis-Marcisak E F, Deshpande A, Stein-O'Brien G L, et al.From bench to bedside: single-cell analysis for cancer immunotherapy[J]. Cancer Cell, 2021, 39(8).DOI:10.1016/j.ccell.2021.07.004.

[2] Zhang Z, Xu Q, Huang L. B cell depletion therapies in autoimmune diseases: Monoclonal antibodies or chimeric antigen receptor-based therapy? Front Immunol. 2023 Feb 10;14:1126421. doi: 10.3389/fimmu.2023.1126421. PMID: 36855629; PMCID: PMC9968396.