Tumor in the Crossfire: Inhibiting TGF-β to Enhance Cancer Immunotherapy

Abstract

Cancer immunotherapy using monoclonal antibodies targeting immune checkpoints has undoubtedly revolutionized the cancer treatment landscape in the last decade. Immune checkpoint inhibitors can elicit long-lasting, previously unheard-of responses in a number of tumor entities. Yet, even in such tumors as metastatic melanoma and non-small cell-lung cancer, in which immune checkpoint inhibition has become the first-line treatment of choice, only a minority of patients will benefit considerably from these treatments. This has been attributed to a number of factors, including an immune-suppressive tumor microenvironment (TME). Using different modalities to break these barriers is of utmost importance to expand the population of patients that benefit from immune checkpoint inhibition. The multifunctional cytokine transforming growth factor-β (TGF-β) has long been recognized as an immune-suppressive factor in the TME. A considerable number of drugs have been developed to target TGF-β, yet most of these have since been discontinued. The combination of anti-TGF-β agents with immune checkpoint inhibitors now has the potential to revive this target as a viable immunomodulatory therapeutic approach. Currently, a limited number of small molecular inhibitor and monoclonal antibody candidates that target TGF-β are in clinical development in combination with the following immune checkpoint inhibitors: SRK 181, an antibody inhibiting the activation of latent TGF-β1; NIS 793, a monoclonal antibody targeting TGF-β; and SHR 1701, a fusion protein consisting of an anti-PD-L1 monoclonal antibody fused with the extracellular domain of human TGF-β receptor II. Several small molecular inhibitors are also in development and are briefly reviewed: LY364947, a pyrazole-based small molecular inhibitor of the serine-threonine kinase activity of TGFβRI; SB-431542, an inhibitor targeting several TGF-β superfamily Type I activin receptor-like kinases as well as TGF-β1-induced nuclear Smad3 localization; and galunisertib, an oral small molecular inhibitor of the TGFβRI kinase. One of the most advanced agents in this area is bintrafusp alfa, a bifunctional fusion protein composed of the extracellular domain of TGF-β receptor II fused to a human IgG1 mAb blocking PD-L1. Bintrafusp alfa is currently in advanced clinical development and as an agent in this space with the most clinical experience, is a focused highlight of this review.

Robot Target Localization and Visual Navigation Based on Neural Network

“…For example, this paper involves the world coordinate system and the camera coordinate system, by finding two 3D point set space, relative transformation relationship to the unified under the same coordinate system (usually refers to the world coordinate system); the purpose is to find in the global coordinate system to obtain the current view of the relative position of the camera and the direction, his appearance, makes the intersection area completely overlap between the two, the process said for registration. In the calculation process, registration is to find the 4 4 rigid transformation matrix T that makes the intersection area between the two points converge completely coincide and to calculate the optimal rigid body transformation by repeatedly selecting the corresponding point pairs until the accuracy requirements of convergence are met [5,6,8]. The rigid transformation matrix T mainly includes the aforementioned translation vector T, rotation matrix R, perspective transformation vector V, and scale factor S, because point cloud data is obtained according to a certain number of continuous pictures.…”

“…There are researches on positioning only from the perspective of images. An image retrieval and location method based on database is proposed [8]. In this method, the query image is matched with the image database annotated with location information (such The main idea of scene coordinate regression framework proposed by Tschernia is to map image blocks to corresponding points in 3D scene space, namely, scene coordinates [9].…”

m5C Regulator-mediated methylation modification clusters contribute to the immune microenvironment regulation of multiple myeloma

“…A set of immune reactions was correlated with m 5 C regulators, specifically the TGFβ family member and its receptor. The TGFβ family is a multifunctional cytokine and has long been recognized as an immune-suppressive factor ( Tschernia and Gulley, 2022 ). It plays a major role in the beneficial immunosuppressive microenvironment of MM patients’ bone marrow niches ( Alabanza et al, 2022 ), which indicates that m 5 C regulators are crucial to the progress of MM.…”

Inhibitors of Transforming Growth Factor Beta Receptor 1 (TGFβr1) May Enhance the Efficacy of Several Monoclonal Antibodies as Cancer Therapy

“…The data shows that the combination of the TGFβr1 inhibitor PF-06952229 with either the anti-4-1BB antibody MAB9371 or the anti-OX40 antibody OX86 led to better tumor growth inhibition relative to each of the monotherapy treatments alone. Data from study 3 with PF-0692229 and the anti-CTLA4 antibody UC10-4F10-11 in the CT26 syngeneic tumor model are summarized in Table 2 below. The data showed a significant delay of tumor growth from a combination of PF-0692229 + the anti-CTLA4 antibody relative to either monotherapy alone. − …”

“…Data from study 3 with PF-0692229 and the anti-CTLA4 antibody UC10-4F10-11 in the CT26 syngeneic tumor model are summarized in Table 2 below. The data showed a significant delay of tumor growth from a combination of PF-0692229 + the anti-CTLA4 antibody relative to either monotherapy alone. − …”