To address this issue, Ruiz et al. 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. Keywords:T cell bispecific antibody, T-BsAb, pharmacokinetics, T cell redirection, mechanism of action, drug development == 1. Introduction == In the last two decades, cancer immunotherapy L161240 has been developed as the fourth pillar of cancer therapy, in addition to surgery, radiation, and chemotherapy [1]. Cancer immunotherapies are designed to exploit host immunity and eliminate tumors either by promoting the antitumor immune system or by suppressing immune inhibitory factors. Many types of immune cells, such as T cells, NK cells, and dendritic cells, are associated with the immune response, and their effector functions are utilized to bring about tumor eradication. Among them, T cells are the central component of adaptive immunity and have been most commonly applied due to their potent cytotoxicity and abundance in blood. Indeed, increasing therapeutic agents that redirect T cell cytotoxicity to tumor cells have achieved great success in clinical practice [2,3,4,5,6]. The most successful immunotherapy modality is antibody therapeutics, which is characterized by antibodies that block immune inhibitory receptors (e.g., programmed cell death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4)) or ligands (e.g., PD-L1). These so-called immune checkpoint inhibitory antibodies (CPIs) have been approved for the treatment of various cancers, including unresectable or metastatic melanoma, metastatic non-small cell lung cancer, and colorectal cancer with microsatellite instability [7,8,9]. Moreover, combination therapies with various CPIs have yielded positive outcomes thus far [10,11,12]. Although these agents have shown remarkable effectiveness for particular indications, the number of 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. Supporting this idea, the relevance of immune cell infiltration to the response to CPIs was demonstrated [13,14]. In addition, 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. Genetically engineered T cell therapies L161240 that are specific for tumor cells are an emerging approach to eliminate tumors with low T cell infiltration. T cell receptor-engineered T cells (TCR-T) and chimeric antigen receptor T cells (CAR-T) are designed to selectively engage a specific neoantigen presented on major histocompatibility complex (MHC) molecules or a specific tumor-associated antigen (TAA), respectively, on tumor cells [18]. These tumor-specific T cells actively migrate to the tumor mass and kill the engaged tumor cells [19,20]. Aside from adoptive T cell transfer therapy, another technology that evokes T cell infiltration is L161240 T cell bispecific antibody (T-BsAb) therapy [21]. T-BsAbs are typically composed of two antigen-binding sites capable of recognizing either a TAA on tumor cells or a CD3 subunit forming a complex with the TCR on T cells. This simultaneous binding to two antigens induces crosslinking between tumor cells and T cells, allowing T cells to recognize the tumor cells independently of MHC engagement [22]. In contrast with CPIs, which block inhibitory signals against effector T cells, T-BsAbs can directly and preferentially activate memory T cells, and presumably to a lesser extent, nave T cells [23,24]. Therefore, it is thought that T-BsAbs promote the redirection of host immunity toward solid tumors with low immunogenicity, a process that includes T cell recruitment and immunological synapse (IS) formation. Despite the promise of this approach, no regulatory authorities worldwide have approved T-BsAbs for the treatment of solid cancers [25]. One reason is that T-BsAbs show insufficient clinical efficacy due to the complexity of the immune response to solid tumors. In fact, the distinctive pharmacokinetics (PK) of T-BsAbs, which result L161240 from their multispecificity, may make it difficult to understand the mechanism of T-BsAb-induced T cell regulation. Thus, it is necessary to explore the complex relationship between an individual BsAb agent, immunity, and cancers. From this viewpoint, we highlight the following three properties of T-BsAbs: (1) their unique PK, (2) their redirection Rabbit polyclonal to ANKRD45 of antitumor immunity, and (3) their local mechanism of action within tumor tissues (Figure.