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      Perspective: Designing T-Cell Engagers With Better Therapeutic Windows

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          Abstract

          This perspective highlights the history and challenges of developing CD3-based bispecific T-cell engagers (TCEs) as cancer therapeutics as well as considerations and potential strategies for designing the next generation TCE molecules. The goal of this article is to raise awareness of natural T-cell biology and how to best harness the tumor cell killing capacity of cytotoxic T-cells with TCEs. In light of 30 years of concerted efforts to advance TCEs in early clinical development, many of the first-generation bispecific antibodies have exhibited lackluster safety, efficacy, and manufacturability profiles. As of January 2020, blinatumomab remains the only approved TCE. Many of the current set-backs in early clinical trials implicate the high-affinity CD3 binding domains employed and the respective bispecific platforms as potential culprits. The underlying conviction of the authors is that by taking corrective measures, TCEs can transform cancer therapy. Through openness, transparency, and much needed feedback from ongoing clinical studies, the field can continuously improve the design and effectiveness of next generation T-cell redirecting therapeutics.

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          Most cited references48

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          Elements of cancer immunity and the cancer–immune set point

          Immunotherapy is proving to be an effective therapeutic approach in a variety of cancers. But despite the clinical success of antibodies against the immune regulators CTLA4 and PD-L1/PD-1, only a subset of people exhibit durable responses, suggesting that a broader view of cancer immunity is
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            Top 10 Challenges in Cancer Immunotherapy

            Cancer immunotherapy is a validated and critically important approach for treating patients with cancer. Given the vast research and clinical investigation efforts dedicated to advancing both endogenous and synthetic immunotherapy approaches, there is a need to focus on crucial questions and define roadblocks to the basic understanding and clinical progress. Here, we define ten key challenges facing cancer immunotherapy, which range from lack of confidence in translating pre-clinical findings to identifying optimal combinations of immune-based therapies for any given patient. Addressing these challenges will require the combined efforts of basic researchers and clinicians, and the focusing of resources to accelerate understanding of the complex interactions between cancer and the immune system and the development of improved treatment options for patients with cancer.
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              Interferon-Gamma at the Crossroads of Tumor Immune Surveillance or Evasion

              Interferon-gamma (IFN-γ) is a pleiotropic molecule with associated antiproliferative, pro-apoptotic and antitumor mechanisms. This effector cytokine, often considered as a major effector of immunity, has been used in the treatment of several diseases, despite its adverse effects. Although broad evidence implicating IFN-γ in tumor immune surveillance, IFN-γ-based therapies undergoing clinical trials have been of limited success. In fact, recent reports suggested that it may also play a protumorigenic role, namely, through IFN-γ signaling insensitivity, downregulation of major histocompatibility complexes, and upregulation of indoleamine 2,3-dioxygenase and of checkpoint inhibitors, as programmed cell-death ligand 1. However, the IFN-γ-mediated responses are still positively associated with patient’s survival in several cancers. Consequently, major research efforts are required to understand the immune contexture in which IFN-γ induces its intricate and highly regulated effects in the tumor microenvironment. This review discusses the current knowledge on the pro- and antitumorigenic effects of IFN-γ as part of the complex immune response to cancer, highlighting the relevance to identify IFN-γ responsive patients for the improvement of therapies that exploit associated signaling pathways.
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                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                15 April 2020
                2020
                : 10
                : 446
                Affiliations
                Teneobio, Inc. , Newark, CA, United States
                Author notes

                Edited by: Christian Klein, Roche Innovation Center Zurich, Switzerland

                Reviewed by: John R. Desjarlais, Xencor Inc, United States; Aran Labrijn, Genmab, Netherlands

                *Correspondence: Omid Vafa ovafa@ 123456teneobio.com

                This article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Oncology

                Article
                10.3389/fonc.2020.00446
                7174563
                32076595
                f96810d3-47c4-4819-90a4-1b10bb4d9e3c
                Copyright © 2020 Vafa and Trinklein.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 10 January 2020
                : 13 March 2020
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 51, Pages: 7, Words: 5134
                Categories
                Oncology
                Perspective

                Oncology & Radiotherapy
                t-cell engager,bispecific,cd3 redirection,cancer,therapeutic window,cytokine release

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