Nanobodies in cell-mediated immunotherapy: On the road to fight cancer

Abstract

The immune system is essential in recognizing and eliminating tumor cells. The unique characteristics of the tumor microenvironment (TME), such as heterogeneity, reduced blood flow, hypoxia, and acidity, can reduce the efficacy of cell-mediated immunity. The primary goal of cancer immunotherapy is to modify the immune cells or the TME to enable the immune system to eliminate malignancies successfully. Nanobodies, known as single-domain antibodies, are light chain-free antibody fragments produced from Camelidae antibodies. The unique properties of nanobodies, including high stability, reduced immunogenicity, enhanced infiltration into the TME of solid tumors and facile genetic engineering have led to their promising application in cell-mediated immunotherapy. They can promote the cancer therapy either directly by bridging between tumor cells and immune cells and by targeting cancer cells using immune cell-bound nanobodies or indirectly by blocking the inhibitory ligands/receptors. The T-cell activation can be engaged through anti-CD3 and anti-4-1BB nanobodies in the bispecific (bispecific T-cell engagers (BiTEs)) and trispecific (trispecific T-cell engager (TriTEs)) manners. Also, nanobodies can be used as natural killer (NK) cell engagers (BiKEs, TriKEs, and TetraKEs) to create an immune synapse between the tumor and NK cells. Nanobodies can redirect immune cells to attack tumor cells through a chimeric antigen receptor (CAR) incorporating a nanobody against the target antigen. Various cancer antigens have been targeted by nanobody-based CAR-T and CAR-NK cells for treating both hematological and solid malignancies. They can also cause the continuation of immune surveillance against tumor cells by stopping inappropriate inhibition of immune checkpoints. Other roles of nanobodies in cell-mediated cancer immunotherapy include reprogramming macrophages to reduce metastasis and angiogenesis, as well as preventing the severe side effects occurring in cell-mediated immunotherapy. Here, we highlight the critical functions of various immune cells, including T cells, NK cells, and macrophages in the TME, and discuss newly developed immunotherapy methods based on the targeted manipulation of immune cells and TME with nanobodies.

Recent advances in biomaterial designs for assisting CAR-T cell therapy towards potential solid tumor treatment

“…Secondly, the complex tumor microenvironment (TME) in a solid tumor provides physical and biological impediments, in cases of abnormal vascular distribution, 30 hypoxia, 7 or acidic microenvironment 31 within tumor tissues. 32 It also limits the proliferation and infiltration of CAR-T cells, resulting in poor outcomes in the treatment of solid tumors. 9,33 The TME also contains a variety of cells with immunosuppressive capacity, such as regulatory T cells and tumor-associated macrophage (TAM).…”

Tri-specific killer engager: unleashing multi-synergic power against cancer

“…Another is non-IgG-like formats which consists of antibody-derived building blocks without Fc region. So, the domain of non-IgG-like formats can be antigen-binding fragment (Fab) portion, scFv, or sdAb which have relatively smaller sizes than the IgG-like one with Fc portion [ 22 , 23 ]. Each domain is also linked together by flanking [ 7 ].…”

“…Notably, the newly incorporated anti-CD16 sdAb showcased superior efficacy in enhancing the impact of the IL-15 moiety. This achievement ensured that the use of mutated IL-15 within the construct was no longer necessary [ 22 , 23 , 25 ]. Building upon these notable findings, the second generation of TriKEs embraced the incorporation of anti-CD16 sdAbs, along with the critical presence of wild type IL-15 (wtIL-15).…”

Nanomaterials in tumor immunotherapy: new strategies and challenges

“…Although several antibodies which target CTLA-4 (such as ipilimumab) [ 64 ] and PD-1/PD-L1 (such as atezolizumab [ 273 ] and pembrolizumab [ 274 ]) have been approved by the US FDA, and the emerging strategies like bispecific T cell engagers (BiTEs), trispecific T cell engagers (TriTEs) based nanobodies have been thought to be a huge gain for therapeutic efficacy [ 275 , 276 ], many treatment issues were found as well [ 277 – 280 ]. For example, some common adverse effects include pruritus, rash, nausea, diarrhea and thyroid disorders.…”