Human primary and memory cytotoxic T lymphocyte responses are efficiently induced by means of CD40-activated B cells as antigen-presenting cells: potential for clinical application

Blood ◽  
2002 ◽  
Vol 99 (9) ◽  
pp. 3319-3325 ◽  
Author(s):  
Michael S. von Bergwelt-Baildon ◽  
Robert H. Vonderheide ◽  
Britta Maecker ◽  
Naoto Hirano ◽  
Karen S. Anderson ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Ex Vivo ◽  
Human Peripheral Blood ◽  
T Cell Responses ◽  
Antigen Presenting Cells ◽  
Cell Responses ◽  
Antigen Presenting ◽  
Activated B Cells

Abstract CD40 engagement is the major signal that induces B cells to efficiently present antigen to T cells. We previously demonstrated that human peripheral blood–derived CD40-activated B cells (CD40–B cells) function as antigen-presenting cells (APCs). Here, we have established a culture system to generate these APCs under clinically applicable conditions using guanylic acid–grade soluble trimeric CD40 ligand. To monitor APC function and antigen loading for these cells, simple and efficient quality control assays have been developed. Using this approach, we demonstrate that CD40–B cells from healthy donors and cancer patients are fully functional and equally expanded in long-term cultures. These B cells boost robust memory T-cell responses, but more importantly, they also prime naive T-cell responses against neoantigens ex vivo. CD40–B cells overcome current obstacles, such as the difficulty of isolation, generation, and long-term expansion observed with other APCs. Therefore, they are an excellent source of professional APCs for immune assessment, antigen discovery, and antigen-specific immunotherapy.

scholarly journals Development and Characterization of a Novel Non-Lytic Cancer Immunotherapy Using a Recombinant Arenavirus Vector Platform

2021 ◽  
Vol 11 ◽  
Author(s):  
Henning Lauterbach ◽  
Sarah Schmidt ◽  
Kia Katchar ◽  
Xiaoping Qing ◽  
Corinne Iacobucci ◽  
...  
Keyword(s):  
T Cell ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Phase 1 ◽  
T Cell Responses ◽  
Antigen Presenting Cells ◽  
T Cell Response ◽  
Cell Responses ◽  
Antigen Presenting

Engineered viral vectors represent a promising strategy to trigger antigen-specific antitumor T cell responses. Arenaviruses have been widely studied because of their ability to elicit potent and protective T cell responses. Here, we provide an overview of a novel intravenously administered, replication-competent, non-lytic arenavirus-based vector technology that delivers tumor antigens to induce antigen-specific anti-cancer T cell responses. Preclinical studies in mice and cell culture experiments with human peripheral blood mononuclear cells demonstrate that arenavirus vectors preferentially infect antigen-presenting cells. This, in conjunction with a non-lytic functional activation of the infected antigen-presenting cells, leads to a robust antigen-specific CD8+ T cell response. T cell migration to, and infiltration of, the tumor microenvironment has been demonstrated in various preclinical tumor models with vectors encoding self- and non–self-antigens. The available data also suggest that arenavirus–based vector therapy can induce immunological memory protecting from tumor rechallenge. Based on promising preclinical data, a phase 1/2 clinical trial was initiated and is currently ongoing to test the activity and safety of arenavirus vectors, HB-201 and HB-202, created using lymphocytic choriomeningitis virus and Pichinde virus, respectively. Both vectors have been engineered to deliver non-oncogenic versions of the human papilloma virus 16 (HPV16) antigens E7 and E6 and will be injected intravenously with or without an initial intratumoral dose. This dose escalation/expansion study is being conducted in patients with recurrent or metastatic HPV16+ cancers. Promising preliminary data from this ongoing clinical study have been reported. Immunogenicity data from several patients demonstrate that a single injection of HB-201 or HB-202 monotherapy is highly immunogenic, as evidenced by an increase in inflammatory cytokines/chemokines and the expansion of antigen-specific CD8+ T cell responses. This response can be further enhanced by alternating injections of HB-202 and HB-201, which has resulted in frequencies of circulating HPV16 E7/E6-specific CD8+ T cells of up to 40% of the total CD8+ T cell compartment in peripheral blood in analyses to date. Treatment with intravenous administration also resulted in a disease control rate of 73% among 11 evaluable patients with head and neck cancer dosed every three weeks, including 2 patients with a partial response.

RNA-loaded CD40-activated B cells stimulate antigen-specific T cell responses in dogs with spontaneous lymphoma

2009 ◽  
Vol 128 (1-3) ◽  
pp. 341-342
Author(s):  
Nicola J. Mason ◽  
Christina M. Coughlin ◽  
Jarish N. Cohen ◽  
Theresa A. Colligon ◽  
Craig A. Clifford ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
T Cell Responses ◽  
Cell Responses ◽  
Stimulate Antigen ◽  
Activated B Cells

The role of antigen-presenting cells in the regulation of allergen-specific T cell responses

1998 ◽  
Vol 10 (6) ◽  
pp. 607-613 ◽  
Author(s):  
Martien L Kapsenberg ◽  
Catherien MU Hilkens ◽  
Eddy A Wierenga ◽  
Pawel Kalinski
Keyword(s):  
T Cell ◽  
T Cell Responses ◽  
Antigen Presenting Cells ◽  
Cell Responses ◽  
Antigen Presenting

Antigen-Specific Transfer of Functional Programmed Death Ligand 1 From Antigen Presenting Cells Onto Human CD8+ T Cells Via Trogocytosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 584-584
Author(s):  
Regina Gary ◽  
Simon Voelkl ◽  
Ralf Palmisano ◽  
Andreas Mackensen
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
T Cell Responses ◽  
Antigen Presenting Cells ◽  
Programmed Death Ligand 1 ◽  
Cell Responses ◽  
Surface Molecules ◽  
Programmed Death ◽  
Antigen Presenting

Abstract Abstract 584 Specific T-cell responses are initiated by T-cell receptor (TCR) recognition of peptide-MHC-complexes on antigen presenting cells (APCs). Upon specific interaction of T cells with APCs T cells capture membrane fragments and surface molecules of APCs in a process termed trogocytosis. Exchange of membrane molecules/antigens between immune cells has been observed for a long time, but the mechanisms and functional consequences of these transfers remain unclear. Here, we demonstrate that human antigen-specific CD8+ T cells do acquire the co-inhibitory molecule programmed death ligand 1 (PD-L1) from mature monocyte-derived dendritic cells (mDC) and tumor cells in an antigen-specific manner. The kinetics of PD-L1 transfer revealed a maximal PD-L1 expression on antigen-specific T cells within 3–4 hours after co-incubation with antigen-pulsed APCs, being detectable up to 72 hours. Antigen-pulsed immature DCs were less effective in transfering surface molecules such as PD-L1 onto CD8+ T cells after antigen-specific recognition. Using a transwell system we could show that the acquisition of PD-L1 requires cell-cell contact. Furthermore, PD-L1 cannot be acquired by T cells from a lysate of mDCs. The transfer process is impaired after pretreatment of T cells with concanamycin A, a specific inhibitor of vacuolar ATPases, playing an important role in membrane trafficking. Moreover, fixation of DCs with glutaraldehyde completely abrogated the acquisition of PD-L1 on T cells suggesting that an active interaction between APCs and T cells is required for trogocytosis. Of importance, CD8+ T cells which acquired PD-L1 complexes, were able to induce apoptosis of neighbouring PD-1 expressing CD8+ T cells, that could be completely blocked by an anti-PD-L1 antibody. In summary our data demonstrate for the first time that human antigen-specific CD8+ T cells take up functionally active PD-L1 from APCs in an antigen-specific fashion, leading to apoptosis of PD-1 expressing T cells. The transfer of functionally active co-inhibitory molecules from APCs onto human CD8+ T cells may serve to limit clonal expansion of antigen-specific T-cell responses but may also play a major role for T-cell exhaustion in chronic infection and tumor immunosurveillance. Disclosures: No relevant conflicts of interest to declare.

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