title: Are BiTEs the "missing link" in cancer therapy?
abstract: Conventional treatment for cancer routinely includes surgical resection and some combination of chemotherapy and radiation. These approaches are frequently accompanied by unintended and highly toxic collateral damage to healthy tissues, which are offset by only marginal prognostic improvements in patients with advanced cancers. This unfortunate balance has driven the development of novel therapies that aim to target tumors both safely and efficiently. Over the past decade, mounting evidence has supported the therapeutic utility of T-cell-centered cancer immunotherapy, which, in its various iterations, has been shown capable of eliciting highly precise and robust antitumor responses both in animal models and human trials. The identification of tumor-specific targets has further fueled a growing interest in T-cell therapies given their potential to circumvent the non-specific nature of traditional treatments. Of the several strategies geared toward achieving T-cell recognition of tumor, bispecific antibodies (bsAbs) represent a novel class of biologics that have garnered enthusiasm in recent years due to their versatility, specificity, safety, cost, and ease of production. Bispecific T-cell Engagers (BiTEs) are a subclass of bsAbs that are specific for CD3 on one arm and a tumor antigen on the second. As such, BiTEs function by recruiting and activating polyclonal populations of T-cells at tumor sites, and do so without the need for co-stimulation or conventional MHC recognition. Blinatumomab, a well-characterized BiTE, has emerged as a promising recombinant bscCD19×CD3 construct that has demonstrated remarkable antitumor activity in patients with B-cell malignancies. This clinical success has resulted in the rapid extension of BiTE technology against a greater repertoire of tumor antigens and the recent US Food and Drug Administration's (FDA) accelerated approval of blinatumomab for the treatment of a rare form of acute lymphoblastic leukemia (ALL). In this review, we dissect the role of T-cell therapeutics in the new era of cancer immunotherapy, appraise the value of CAR T-cells in the context of solid tumors, and discuss why the BiTE platform may rescue several of the apparent deficits and shortcomings of competing immunotherapies to support its widespread clinical application.
authors.affiliation: Duke Brain Tumor Immunotherapy Program; Division of Neurosurgery; Department of Surgery; Duke University Medical Center ; Durham, NC, USA ; Department of Pathology; Duke University Medical Center ; Durham, NC, USA ; The Preston Robert Tisch Brain Tumor Center; Duke University Medical Center ; Durham, NC, USA.
authors.forename: Carter M
authors.initials: CM
authors.lastname: Suryadevara
authors.affiliation: Duke Brain Tumor Immunotherapy Program; Division of Neurosurgery; Department of Surgery; Duke University Medical Center ; Durham, NC, USA ; The Preston Robert Tisch Brain Tumor Center; Duke University Medical Center ; Durham, NC, USA ; Department of Biomedical Engineering; Duke University ; Durham, NC, USA.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Gedeon
authors.affiliation: Duke Brain Tumor Immunotherapy Program; Division of Neurosurgery; Department of Surgery; Duke University Medical Center ; Durham, NC, USA ; The Preston Robert Tisch Brain Tumor Center; Duke University Medical Center ; Durham, NC, USA.
authors.forename: Luis
authors.initials: L
authors.lastname: Sanchez-Perez
authors.affiliation: Duke Brain Tumor Immunotherapy Program; Division of Neurosurgery; Department of Surgery; Duke University Medical Center ; Durham, NC, USA ; The Preston Robert Tisch Brain Tumor Center; Duke University Medical Center ; Durham, NC, USA.
authors.forename: Terence
authors.initials: T
authors.lastname: Verla
authors.affiliation: Department of Neurosurgery; Massachusetts General Hospital and Harvard Medical School ; Boston, MA, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Alvarez-Breckenridge
authors.affiliation: Department of Neurosurgery; Massachusetts General Hospital and Harvard Medical School ; Boston, MA, USA.
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Choi
authors.affiliation: Duke Brain Tumor Immunotherapy Program; Division of Neurosurgery; Department of Surgery; Duke University Medical Center ; Durham, NC, USA ; The Preston Robert Tisch Brain Tumor Center; Duke University Medical Center ; Durham, NC, USA.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Fecci
authors.affiliation: Duke Brain Tumor Immunotherapy Program; Division of Neurosurgery; Department of Surgery; Duke University Medical Center ; Durham, NC, USA ; Department of Pathology; Duke University Medical Center ; Durham, NC, USA ; The Preston Robert Tisch Brain Tumor Center; Duke University Medical Center ; Durham, NC, USA ; Department of Biomedical Engineering; Duke University ; Durham, NC, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Sampson
keywords: ACT, adoptive cell therapy; AICD, activation induced cell death; ALL, acute lymphoblastic leukemia; APC, antigen presenting cell; BiTE, bispecific T-cell engager; BsAb, bispecific antibody; CAR, chimeric antigen receptors; CHO, chinese hamster ovary; CML, chronic myeloid leukemia; GBM, glioblastoma; MAb, monoclonal antibody; MHC, major histocompatibility complex; OS, overall survival; ScFv, single chain variable fragment; T lymphocytes; TAA, tumor associated antigens; TCR, T-cell receptor; TIL, tumor infiltrating lymphocytes; TREG, regulatory T-cells; TSA, tumor specific antigens; VV, vaccinia virus; bispecific antibodies; immunotherapy; malignancies