T cell activation upon exposure to patient-derived tumor tissue: A functional assay to select patients for adoptive T cell therapy

Schroten, Caroline; Kraaij, Robert; Veldhoven, Joke L.M.; Berrevoets, Cor; Bakker, Michael A. den; Ma, Qiangzhong; Sadelain, Michel; Bangma, Chris H.; Willemsen, Ralph A.; Debets, Reno

doi:10.1016/j.jim.2010.04.006

Cited by 9 publications

(6 citation statements)

References 27 publications

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“…Many of the normal TCR‐mediated signalling events are known to take place during CAR‐driven T cell activation, including tyrosine phosphorylation of CD3ζ , recruitment of ZAP70 , initiation of the mitogen‐activated protein kinase (MAPK) cascade and induction of nuclear factor of activated T cells (NFAT) . It has also been shown that a cytoplasmic domain‐deficient CAR containing the FcεRIγ chain can activate T cells via heterodimerization with endogenous CD3ζ .…”

Section: Introductionmentioning

confidence: 99%

CD3ζ-based chimeric antigen receptors mediate T cell activation viacis- andtrans-signalling mechanisms: implications for optimization of receptor structure for adoptive cell therapy

Bridgeman

Ladell

Sheard

et al. 2014

Clinical and Experimental Immunology

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Chimeric antigen receptors (CARs) can mediate redirected lysis of tumour cells in a major histocompatibility complex (MHC)-independent manner, thereby enabling autologous adoptive T cell therapy for a variety of malignant neoplasms. Currently, most CARs incorporate the T cell receptor (TCR) CD3ζ signalling chain; however, the precise mechanisms responsible for CAR-mediated T cell activation are unclear. In this study, we used a series of immunoreceptor tyrosine-based activation motif (ITAM)-mutant and transmembrane-modified receptors to demonstrate that CARs activate T cells both directly via the antigen-ligated signalling chain and indirectly via associated chains within the TCR complex. These observations allowed us to generate new receptors capable of eliciting polyfunctional responses in primary human T cells. This work increases our understanding of CAR function and identifies new avenues for the optimization of CAR-based therapeutic interventions.

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Section: Introductionmentioning

confidence: 99%

CD3ζ-based chimeric antigen receptors mediate T cell activation viacis- andtrans-signalling mechanisms: implications for optimization of receptor structure for adoptive cell therapy

Bridgeman

Ladell

Sheard

et al. 2014

Clinical and Experimental Immunology

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“…Recombinant IL-2 is being tested (1) in combination with the adoptive transfer of natural killer (NK) cells, 55 , 98 in patients with relapsed or refractory acute myeloid leukemia (AML) (NCT01898793), multiple myeloma (MM) (NCT01884688), and v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (ERBB2) + breast or gastric carcinoma (NCT02030561), in the latter setting coupled to the ERBB2-targeting monoclonal antibody (mAb) trastuzumab; 99 - 104 (2) in combination with autologous peripheral blood lymphocytes engineered to express a NY-ESO-1-specific T-cell receptor, alone or coupled to ipilimumab 105 - 107 in individuals affected by diverse solid tumors (NCT01967823; NCT02070406); (3) as an adjuvant to T cells expressing a chimeric antigen receptor specific for folate hydrolase 1 (FOLH1, best known as PSMA), 108 , 109 in prostate cancer patients subjected to non-myeloablative conditioning (NCT01929239); and (4) in combination with G-CSF, GM-CSF and a mAb specific for ganglioside GD2, 110 for the treatment of minimal residual disease in children with advanced neuroblastoma treated with aggressive induction chemotherapy and stem cell transplantation (NCT01857934). Moreover, various studies have recently been launched to test the clinical profile of IL-2 variants retargeted to cancer cells by means of tumor-associated antigen (TAA)-specific antibodies or antibody fragments, i.e., IL-2-based immunocytokines 111 - 113 .…”

Section: Update On Ongoing Clinical Trialsmentioning

confidence: 99%

Trial watch

et al. 2014

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Tumor-targeting immune responses provide a significant contribution to (when they do not entirely account for) the clinical activity of diverse antineoplastic regimens, encompassing not only a large panel of immunotherapeutic strategies but also conventional cytotoxic molecules, targeted anticancer agents and irradiation. In line with this notion, several approaches have been devised to elicit novel or boost existing anticancer immune responses, including the administration of immunomodulatory cytokines. Such a relatively unspecific intervention suffices to mediate clinical effects in (at least a subset of) patients bearing particularly immunogenic tumors, like melanoma and renal cell carcinoma. More often, however, immunostimulatory cytokines are administered to boost the immunogenic potential of other agents, including (but not limited to) immune checkpoint-blocking antibodies, anticancer vaccines, oncolytic viruses and immunogenic chemotherapeutics. Here, we summarize the latest advances in the clinical development of recombinant cytokines as an immunomodulatory intervention for cancer therapy.

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“…Full functionality is only ensured if both the afferent function (tumor recognition) as well as the efferent function (tumor kill) are operative. Assays to measure T-cell activation on exposure to patient-derived tumor tissue may help to determine the individual effectiveness in vitro (40). …”

Section: What Are Immunological Acceptance Criteria For T-cell and Nkmentioning

confidence: 99%

Immunotherapy: opportunities, risks and future perspectives

Hildebrandt¹,

Peggs²,

Uharek³

et al. 2014

Cytotherapy

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This review is intended to reflect upon the current status and perspectives of cell-based immunotherapy at a time when the promise of extensive pre-clinical research has been translated into encouraging clinical responses. However, some of these have also been complicated by significant adverse reactions. As the field moves towards definitive late stage trials, with a growing interest from pharmaceutical companies, we realize that novel cell therapy strategies pose questions that are familiar to traditional drug development, along with new considerations due to the potential of T cells to persist long term and to expand after adoptive transfer. These questions address the safety of the product, the efficacy, the mode of action, and the anticipation of risks. From different perspectives, we intend to address exciting opportunities and safety concerns in current concepts of cellular immunotherapy.

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T cell activation upon exposure to patient-derived tumor tissue: A functional assay to select patients for adoptive T cell therapy

Cited by 9 publications

References 27 publications

CD3ζ-based chimeric antigen receptors mediate T cell activation viacis- andtrans-signalling mechanisms: implications for optimization of receptor structure for adoptive cell therapy

CD3ζ-based chimeric antigen receptors mediate T cell activation viacis- andtrans-signalling mechanisms: implications for optimization of receptor structure for adoptive cell therapy

Trial watch

Immunotherapy: opportunities, risks and future perspectives

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