560
views
0
recommends
+1 Recommend
1 collections
    4
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Targeted cancer immunotherapy via combination of designer bispecific antibody and novel gene-engineered T cells

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Background

          Redirection of T lymphocytes against tumor antigens can induce dramatic regression of advanced stage malignancy. The use of bispecific antibodies (BsAbs) that bind both the T-cell receptor (TCR) and a target antigen is one promising approach to T-cell redirection. However, BsAbs indiscriminately bind all CD3+ T-cells and trigger TCR activation in the absence of parallel costimulatory signals required to overcome T-cell unresponsiveness or anergy.

          Methods

          To address these limitations, a combination platform was designed wherein a unique BsAb referred to as frBsAb exclusively engages T-cells engineered to express a novel chimeric receptor comprised of extracellular folate receptor fused to intracellular TCR and CD28 costimulatory signaling domains in tandem; a BsAb-binding immune receptor (BsAb-IR). As a surrogate TCR, the BsAb-IR allows for concomitant TCR and costimulatory signaling exclusively in transduced T-cells upon engagement with specific frBsAbs, and can therefore redirect T-cells on command to desired antigen. Human primary T-cells were transduced with lentiviral vector and expanded for 14–18 days. BsAb-IRs were harvested and armed with frBsAbs to test for redirected cytotoxicity against CD20 positive cancer cell lines.

          Results

          Using frBsAbs specific for CD20 or HER2, the lytic activity of primary human T-cells expressing the BsAb-IR was specifically redirected against CD20+ leukemic cells or HER2+ epithelial cancer cells, respectively, while non-engineered T-cells were not activated. Notably, elimination of the CD28 costimulatory domain from the BsAb-IR construct significantly reduced frBsAb-redirected antitumor responses, confirming that frBsAbs are capable of delivering simultaneous TCR activation and costimulatory signals to BsAb-IR T-cells.

          Conclusion

          In summary, our results establish the proof of concept that the combination of BsAbs with optimized gene-engineered T-cells provides the opportunity to specify and augment tumor antigen-specific T-cell activation and may improve upon the early success of conventional BsAbs in cancer immunotherapy.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12967-014-0347-2) contains supplementary material, which is available to authorized users.

          Related collections

          Most cited references46

          • Record: found
          • Abstract: found
          • Article: not found

          Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells.

          The success of adoptive T cell gene transfer for treatment of cancer and HIV is predicated on generating a response that is both durable and safe. We report long-term results from three clinical trials to evaluate gammaretroviral vector-engineered T cells for HIV. The vector encoded a chimeric antigen receptor (CAR) composed of CD4 linked to the CD3ζ signaling chain (CD4ζ). CAR T cells were detected in 98% of samples tested for at least 11 years after infusion at frequencies that exceeded average T cell levels after most vaccine approaches. The CD4ζ transgene retained expression and function. There was no evidence of vector-induced immortalization of cells; integration site distributions showed no evidence of persistent clonal expansion or enrichment for integration sites near genes implicated in growth control or transformation. The CD4ζ T cells had stable levels of engraftment, with decay half-lives that exceeded 16 years, in marked contrast to previous trials testing engineered T cells. These findings indicate that host immunosuppression before T cell transfer is not required to achieve long-term persistence of gene-modified T cells. Further, our results emphasize the safety of T cells modified by retroviral gene transfer in clinical application, as measured in >500 patient-years of follow-up. Thus, previous safety issues with integrating viral vectors are hematopoietic stem cell or transgene intrinsic, and not a general feature of retroviral vectors. Engineered T cells are a promising form of synthetic biology for long-term delivery of protein-based therapeutics. These results provide a framework to guide the therapy of a wide spectrum of human diseases.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Immunopharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell-engaging CD19/CD3-bispecific BiTE antibody blinatumomab.

            T cell-engaging CD19/CD3-bispecific BiTE Ab blinatumomab has shown an 80% complete molecular response rate and prolonged leukemia-free survival in patients with minimal residual B-lineage acute lymphoblastic leukemia (MRD(+) B-ALL). Here, we report that lymphocytes in all patients of a phase 2 study responded to continuous infusion of blinatumomab in a strikingly similar fashion. After start of infusion, B-cell counts dropped to < 1 B cell/μL within an average of 2 days and remained essentially undetectable for the entire treatment period. By contrast, T-cell counts in all patients declined to a nadir within < 1 day and recovered to baseline within a few days. T cells then expanded and on average more than doubled over baseline within 2-3 weeks under continued infusion of blinatumomab. A significant percentage of reappearing CD8(+) and CD4(+) T cells newly expressed activation marker CD69. Shortly after start of infusion, a transient release of cytokines dominated by IL-10, IL-6, and IFN-γ was observed, which no longer occurred on start of a second treatment cycle. The response of lymphocytes in leukemic patients to continuous infusion of blinatumomab helps to better understand the mode of action of this and other globally T cell-engaging Abs. The trial is registered with www.clinicaltrials.gov identifier NCT00560794.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              CD27 costimulation augments the survival and antitumor activity of redirected human T cells in vivo.

              The costimulatory effects of CD27 on T lymphocyte effector function and memory formation has been confined to evaluations in mouse models, in vitro human cell culture systems, and clinical observations. Here, we tested whether CD27 costimulation actively enhances human T-cell function, expansion, and survival in vitro and in vivo. Human T cells transduced to express an antigen-specific chimeric antigen receptor (CAR-T) containing an intracellular CD3 zeta (CD3ζ) chain signaling module with the CD27 costimulatory motif in tandem exerted increased antigen-stimulated effector functions in vitro, including cytokine secretion and cytotoxicity, compared with CAR-T with CD3ζ alone. After antigen stimulation in vitro, CD27-bearing CAR-T cells also proliferated, up-regulated Bcl-X(L) protein expression, resisted apoptosis, and underwent increased numerical expansion. The greatest impact of CD27 was noted in vivo, where transferred CAR-T cells with CD27 demonstrated heightened persistence after infusion, facilitating improved regression of human cancer in a xenogeneic allograft model. This tumor regression was similar to that achieved with CD28- or 4-1BB-costimulated CARs, and heightened persistence was similar to 4-1BB but greater than CD28. Thus, CD27 costimulation enhances expansion, effector function, and survival of human CAR-T cells in vitro and augments human T-cell persistence and antitumor activity in vivo.
                Bookmark

                Author and article information

                Contributors
                katu@upenn.edu
                ralynn@upenn.edu
                caitlin.stashwick@uphs.upenn.edu
                thakur@karmanos.org
                luml@karmanos.org
                poda@mail.med.upenn.edu
                Journal
                J Transl Med
                J Transl Med
                Journal of Translational Medicine
                BioMed Central (London )
                1479-5876
                13 December 2014
                13 December 2014
                2014
                : 12
                : 1
                : 347
                Affiliations
                [ ]Department of Pathology and Laboratory Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Blvd, Bldg 421, Smilow CTR, Rm 08-103, Philadelphia, PA 19104-5156 USA
                [ ]Department of Obstetrics and Gynecology, Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA
                [ ]Department of Oncology, Wayne State University, Detroit, MI USA
                Article
                347
                10.1186/s12967-014-0347-2
                4272781
                25496493
                00ae55c0-b389-4737-996b-342c23868aae
                © Urbanska et al.; licensee BioMed Central. 2014

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 23 September 2014
                : 29 November 2014
                Categories
                Research
                Custom metadata
                © The Author(s) 2014

                Medicine
                immunotherapy,adoptive t cell transfer,chimeric immunoreceptor,cancer,bispecific antibody,trastuzumab,rituximab

                Comments

                added an editorial note to Cancer Immunotherapy
                This article was selected by ScienceOpen Consulting Editor, Richard Gallagher, to appear in the Collection entitled "Cancer Immunotherapy" which can be found here http://ow.ly/Jy1HH. 1. Why this article was chosen: it introduces a platform that teams T cells expressing engineered antigen receptors with bispecific antibodies that target these T cells to the tumor. 2. What this article shows: This approach augments the immune response in two tumor models. 3. A key quote from the article: “…we believe that the principles established in this study will significantly enhance anti-tumor activity of targeted BsAb-based tumor immunotherapy.” 4. Corresponding author: Daniel J. Powell is a Research Associate Professor of Pathology and Laboratory Medicine at the University of Pennsylvania in Philadelphia, PA, USA. His research builds on interrogations in basic T cell biology to develop T cell-based therapies for cancer.
                2015-02-24 00:52 UTC
                +1
                One person recommends this

                Comment on this article