Tumor-Specific T Cell Activation by Recombinant Immunoreceptors: CD3ζ Signaling and CD28 Costimulation Are Simultaneously Required for Efficient IL-2 Secretion and Can Be Integrated into One Combined CD28/CD3ζ Signaling Receptor Molecule

Hombach, Andreas; Wieczarkowiecz, Anja; Marquardt, Thomas P.; Heuser, Claudia; Usai, Loretta; Pohl, Christoph; Seliger, Barbara; Abken, Hinrich

doi:10.4049/jimmunol.173.1.695

Cited by 59 publications

(84 citation statements)

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“…The use of CD28-containing second-generation CARs was also associated with their increased persistence . Generally, the enhanced cytokine production will increase the cell proliferation and upregulation of anti-apoptotic proteins such as Bcl-xL in the secondgeneration CARs containing CD28, in comparison with the first-generation CARs (Beecham et al 2000, Haynes et al 2002, Hombach et al 2001a, 2001b, Kowolik et al 2006, Vera et al 2006. Other B7 family members such as inducible co-stimulation (ICOS) and tumor necrosis factor receptor consisting of CD137-4-1BB or CD134-OX-40 can be replaced with CD28-containing second-generation CARs (Finney et al 2004).…”

Section: Persistence Of Car T Cellsmentioning

confidence: 96%

CAR-modified T-cell therapy for cancer: an updated review

Haji-Fatahaliha

Hosseini

Akbarian

et al. 2015

Artificial Cells, Nanomedicine, and Biotechnology

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The use of chimeric antigen receptor (CAR)-modified T cells is a promising approach for cancer immunotherapy. These genetically modified receptors contain an antigen-binding moiety, a hinge region, a transmembrane domain, and an intracellular costimulatory domain resulting in T-cell activation subsequent to antigen binding. Optimal tumor removal through CAR-modified T cells requires suitable target antigen selection, co-stimulatory signaling domain, and the ability of CAR T cells to traffic, persist, and retain antitumor function after adoptive transfer. There are several elements which can improve antitumor function of CAR T cells, including signaling, conditioning chemotherapy and irradiation, tumor burden of the disease, T-cell phenotype, and supplementary cytokine usage. This review outlines four generations of CAR. The pre-clinical and clinical studies showed that this technique has a great potential for treatment of solid and hematological malignancies. The main purpose of the current review is to focus on the pre-clinical and clinical developments of CAR-based immunotherapy.

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Section: Persistence Of Car T Cellsmentioning

confidence: 96%

CAR-modified T-cell therapy for cancer: an updated review

Haji-Fatahaliha

Hosseini

Akbarian

et al. 2015

Artificial Cells, Nanomedicine, and Biotechnology

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“…A comparison of CEA-directed cIg fused to the Fc εRI-γ chain or the CD3-ζ chain found that despite similar levels of transgene expression, CD3-ζ-linked cIg were able to better control the growth of CEA-expressing tumors in murine models [155]. Recently, these constructs have been further engineered to incorporate a costimulatory signaling mechanism [156-159]. Constructs containing the heavy and light chain variable regions of an antibody, the CD28 signaling domain, and the CD3-ζ chain in series were first described by Finney et al in 1998.…”

Section: Enhancing Tumor Recognition By Modifying T Cellsmentioning

confidence: 99%

T cell avidity and tumor recognition: implications and therapeutic strategies

2005

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In the last two decades, great advances have been made studying the immune response to human tumors. The identification of protein antigens from cancer cells and better techniques for eliciting antigen specific T cell responses in vitro and in vivo have led to improved understanding of tumor recognition by T cells. Yet, much remains to be learned about the intricate details of T cell – tumor cell interactions. Though the strength of interaction between T cell and target is thought to be a key factor influencing the T cell response, investigations of T cell avidity, T cell receptor (TCR) affinity for peptide-MHC complex, and the recognition of peptide on antigen presenting targets or tumor cells reveal complex relationships. Coincident with these investigations, therapeutic strategies have been developed to enhance tumor recognition using antigens with altered peptide structures and T cells modified by the introduction of new antigen binding receptor molecules. The profound effects of these strategies on T cell – tumor interactions and the clinical implications of these effects are of interest to both scientists and clinicians. In recent years, the focus of much of our work has been the avidity and effector characteristics of tumor reactive T cells. Here we review concepts and current results in the field, and the implications of therapeutic strategies using altered antigens and altered effector T cells.

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“…IL-2 secretion by patient T cells, moreover, was significantly induced by the BW431/26-scFv-Fc-CD28-f costimulatory receptor in contrast with the BW431/26-scFv-Fc-f receptor, as previously shown in allogeneic systems. 26 Enhanced IL-2 secretion triggered by the costimulatory receptor will furthermore result in improved recruiting of cytolytic bystander cells to the tumour site. Taken together, the study here illustrates well that tolerance of peripheral blood T cells from colorectal cancer patients towards autologous tumour cells can be antigen specifically overcome by grafting with a CEA specific immunoreceptor that drives T cell activation on binding to CEA.…”

Section: Discussionmentioning

confidence: 99%