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Clinical and Developmental Immunology (1)
Clinical cancer research : an official journal of the American Association for Cancer Research (1)
Frontiers in Immunology (1)
Lamers, Cor (3)
Debets, Reno (2)
Straetemans, Trudy (2)
Broertjes, Marieke (1)
Bruggen, Pierre van Der (1)
Coulie, Pierre G. (1)
Davis, Jeremy L. (1)
Drexhage, Joost (1)
Govers, Coen (1)
Gratama, Jan W. (1)
Hegmans, Joost (1)
Kraan, Jaco (1)
Kunert, Andre (1)
Lambrecht, Bart N. (1)
Lamers, Cor H.J. (1)
Mallone, Roberto (1)
Martinuzzi, Emanuela (1)
Mathijssen, Ron (1)
Morgan, Richard A. (1)
Rosenberg, Steven A. (1)
Sillevis Smitt, Peter A.E. (1)
Sleijfer, Stefan (1)
Theoret, Marc R. (1)
Zheng, Zhili (1)
de Graaf, Marieke T. (1)
de Jongste, Adriaan H.C. (1)
van Brakel, Mandy (1)
van Steenbergen, Sabine (1)
van den Broek, Patricia D.M. (1)
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Three sensitive assays do not provide evidence for circulating HuD-specific T cells in the blood of patients with paraneoplastic neurological syndromes with anti-Hu antibodies
de Jongste, Adriaan H.C.
de Graaf, Marieke T.
van den Broek, Patricia D.M.
Gratama, Jan W.
Sillevis Smitt, Peter A.E.
Anti-Hu antibody–associated paraneoplastic neurological syndromes (Hu-PNSs) are severe and often precede the detection of a malignancy, usually small-cell lung cancer. In Hu-PNS, it is hypothesized that neuronal cells are destroyed by T cells targeted against HuD, a protein expressed by small-cell lung cancer cells and neurons. There is only limited evidence for the existence of HuD-specific T cells. To detect these T cells in the blood of Hu-PNS patients, we employed 3 highly sensitive assays that included T cell stimulation with dendritic cells (DCs) to specifically expand the number of any HuD-specific T cells. A total of 17 Hu-PNS patients were tested with 1 or more of the following 3 assays: (1) tetramer staining after stimulation of T cells with conventionally generated DCs (n = 9), (2) interleukin (IL)-13 enzyme-linked immunosorbent spot (ELISpot; n = 3), IL-4 and IL-5 and interferon (IFN)–γ multiplex cytokine bead array (n = 2) to assay cytokine production by T cells after stimulation with conventionally generated DCs, and (iii) IFN-γ ELISpot and tetramer staining after T cell stimulation with accelerated co-cultured DCs (n = 11). No circulating HuD-specific T cells were found. We suggest that either autoaggressive T cells in Hu-PNS are not targeted against HuD or that their numbers in the blood are too low for detection by highly sensitive techniques.
anti-Hu; CD8+ T cell; HuD-specific T cell; immune response; paraneoplastic neurological syndrome
TCR-Engineered T Cells Meet New Challenges to Treat Solid Tumors: Choice of Antigen, T Cell Fitness, and Sensitization of Tumor Milieu
Frontiers in Immunology
Adoptive transfer of T cells gene-engineered with antigen-specific T cell receptors (TCRs) has proven its feasibility and therapeutic potential in the treatment of malignant tumors. To ensure further clinical development of TCR gene therapy, it is necessary to target immunogenic epitopes that are related to oncogenesis and selectively expressed by tumor tissue, and implement strategies that result in optimal T cell fitness. In addition, in particular for the treatment of solid tumors, it is equally necessary to include strategies that counteract the immune-suppressive nature of the tumor micro-environment. Here, we will provide an overview of the current status of TCR gene therapy, and redefine the following three challenges of improvement: “choice of target antigen”; “fitness of T cells”; and “sensitization of tumor milieu.” We will categorize and discuss potential strategies to address each of these challenges, and argue that advancement of clinical TCR gene therapy critically depends on developments toward each of the three challenges.
antigens; inhibitory micro-milieu; solid tumors; T cell avidity; T cell co-stimulation; T cells; TCR affinity; TCR transgenes
TCR Gene Transfer: MAGE-C2/HLA-A2 and MAGE-A3/HLA-DP4 Epitopes as Melanoma-Specific Immune Targets
van Brakel, Mandy
van Steenbergen, Sabine
Lambrecht, Bart N.
Bruggen, Pierre van Der
Coulie, Pierre G.
Clinical and Developmental Immunology
Adoptive therapy with TCR gene-engineered T cells provides an attractive and feasible treatment option for cancer patients. Further development of TCR gene therapy requires the implementation of T-cell target epitopes that prevent “on-target” reactivity towards healthy tissues and at the same time direct a clinically effective response towards tumor tissues. Candidate epitopes that meet these criteria are MAGE-C2336-344/HLA-A2 (MC2/A2) and MAGE-A3243-258/HLA-DP4 (MA3/DP4). We molecularly characterized TCRαβ genes of an MC2/A2-specific CD8 and MA3/DP4-specific CD4 T-cell clone derived from melanoma patients who responded clinically to MAGE vaccination. We identified MC2/A2 and MA3/DP4-specific TCR-Vα3/Vβ28 and TCR-Vα38/Vβ2 chains and validated these TCRs in vitro upon gene transfer into primary human T cells. The MC2 and MA3 TCR were surface-expressed and mediated CD8 T-cell functions towards melanoma cell lines and CD4 T-cell functions towards dendritic cells, respectively. We intend to start testing these MAGE-specific TCRs in phase I clinical trial.
Development of Human Anti-Murine T-cell Receptor Antibodies in Both Responding and Non-responding Patients Enrolled in TCR Gene Therapy Trials
Davis, Jeremy L.
Theoret, Marc R.
Rosenberg, Steven A.
Morgan, Richard A.
Clinical cancer research : an official journal of the American Association for Cancer Research
Immune responses to gene-modified cells are a concern in the field of human gene therapy as they may impede effective treatment. We conducted two clinical trials in which cancer patients were treated with lymphocytes genetically engineered to express murine T cell receptors (mTCR) specific for tumor-associated antigens p53 and gp100.
Twenty-six patients treated with autologous lymphocytes expressing mTCR had blood and serum samples available for analysis. Patient sera were assayed for development of a humoral immune response. Adoptive cell transfer characteristics were analyzed to identify correlates to immune response.
Six of 26 (23%) patients post-treatment sera exhibited specific binding of human anti-mTCR antibodies to lymphocytes transduced with the mTCR. Antibody development was found in both responding and non-responding patients. Three of these six patients post-treatment sera mediated a 60 – 99% inhibition of mTCR activity as measured by a reduction in antigen-specific IFN-γ release. Detailed analysis of post-treatment serum revealed that antibody binding was beta chain specific in one patient whereas it was alpha chain specific in another.
A subset of patients treated with mTCR engineered T-cells developed antibodies directed to the mTCR variable regions and not to the constant region domains common to all mTCR. Overall, the development of a host immune response was not associated with the level of transduced cell persistence or response to therapy. In summary, patients treated with mTCR can develop an immune response to gene-modified cells in a minority of cases, but this may not affect clinical outcome.
Immunity; gene therapy; T-cell receptor
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