Abstract
As a breakthrough immunotherapy, T cell bispecific antibodies (T-BsAbs) are a promising antibody therapy for various kinds of cancer. In general, T-BsAbs have dual-binding specificity to a tumor-associated antigen and a CD3 subunit forming a complex with the TCR. This enables T-BsAbs to crosslink tumor cells and T cells, inducing T cell activation and subsequent tumor cell death. Unlike immune checkpoint inhibitors, which release the brake of the immune system, T-BsAbs serve as an accelerator of T cells by stimulating their immune response via CD3 engagement. Therefore, they can actively redirect host immunity toward tumors, including T cell recruitment from the periphery to the tumor site and immunological synapse formation between tumor cells and T cells. Although the low immunogenicity of solid tumors increases the challenge of cancer immunotherapy, T-BsAbs capable of immune redirection can greatly benefit patients with such tumors. To investigate the detailed relationship between T-BsAbs delivery and their T cell redirection activity, it is necessary to determine how T-BsAbs deliver antitumor immunity to the tumor site and bring about tumor cell death. This review article discusses T-BsAb properties, specifically their pharmacokinetics, redirection of anticancer immunity, and local mechanism of action within tumor tissues, and discuss further challenges to expediting T-BsAb development.
Highlights
It is reasonable to assume that the following process occurs after T cell bispecific antibodies (T-BsAbs) administration: (i) the T-BsAb is first delivered to the tumor tissue, where it crosslinks a tumor cell and a preexisting T cell; (ii) crosslinking induces T cell activation and causes the tumor to develop the inflamed phenotype, exemplified by active secretion of cytokines and chemokines; and (iii) peripheral T cells that express CXCR3 are recruited toward the tumor tissue according to the concentration gradient of pro-migration factors
We demonstrated that secreted cytokines from T-BsAb-activated T cells damaged target cells in a cell contact-independent manner, cell contact-dependent tumor cell killing, which was presumably attributed to perforin and granzyme activity, showed stronger cytotoxicity [82]
Given that relatively more T-BsAbs have been clinically studied for hematologic tumors, in which tumor cells and T cells colocalize, future development should increasingly focus on understanding T-BsAb pharmacology in solid tumors
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Pharmaceuticals 2021, 14, 1172 patients who benefit from these treatments is very limited This is because the efficacy of CPIs is likely dependent on the degree of T cell infiltration within tumor tissues during the pre-treatment stage. Less effectiveness of CPI therapy against T cell-excluded tumors was reported in various types of cancer, highlighting the importance of T cell infiltration [15,16,17]. To overcome this problem, a novel immunotherapy that actively promotes T cell infiltration into tumors is required. T-BsAb-activated T cells release cytotoxic and proinflammatory cytokines, resulting in cell contact-independent cell killing and the FasL-mediated bystander effect, respec.
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