In vivo functional efficacy of tumor-specific T cells expanded using HLA-Ig based artificial antigen presenting cells (aAPC)

Abstract

Adoptive immunotherapy for treatment of cancers and infectious diseases is often hampered by a high degree of variability in the final T cell product and in the limited in vivo function and survival of ex vivo expanded antigen-specific cytotoxic T cells (CTL). This has stimulated interest in development of standardized artificial antigen presenting cells (aAPC) to reliably expand antigen specific CTL. However, for successful immunotherapy the aAPC ex vivo generated CTL must have anti-tumor activity in vivo. Here, we demonstrate that HLA-Ig based aAPC stimulated tumor-specific CTL from human peripheral blood T lymphocytes showed robust expansion and functional activity in a human/SCID mouse melanoma model. HLA-Ig based aAPC expanded CTL were detected in the peripheral blood up to 15 days after transfer. Non-invasive bioluminescence imaging of tumor bearing mice demonstrated antigen dependent localization of transferred CTL to the tumor site. Moreover, adoptive transfer of HLA-Ig based aAPC generated CTL inhibited the tumor growth both in prevention and treatment modes of therapy and was comparable to that achieved by dendritic cell expanded CTL. Thus, our data demonstrate potential therapeutic in vivo activity of HLA-Ig based aAPC expanded CTL to control tumor growth.

Dynamic regulation of functionally distinct virus-specific T cells

“…Phenotypic characterization of aAPC-generated melanoma antigen Mart-1-specific cytotoxic T lymphocytes (CTLs) showed they were effector memory T cells (CD45RA (41). Limited functional characterization of ex vivo-generated human CD8 + T cells suggests that they can also carry out effector functions in vivo with ex vivo-generated effector memory cell migration to nonlymphoid tissues and selective homing to tumors (41,42). In addition, investigators have shown that aAPC-generated T cell lines could be maintained in culture up to 1 year without becoming terminally differentiated.…”

CD47 EnhancesIn VivoFunctionality of Artificial Antigen-Presenting Cells

“…These aAPC demonstrated antigen-specific T cell generation and expansion favorable to autologous dendritic cells (DC)(13,14) and were successfully tested in different in vitro systems(15–17). In vivo aAPC-generated T cells inhibited tumor growth as efficient as DC-generated T cells(18). Furthermore, adoptively transferred low affinity T cells where efficiently activated by co-administration of aAPC and subsequently lead to tumor reduction in an in vivo melanoma tumor model (19).…”

Antigen presentation on artificial acellular substrates: modular systems for flexible, adaptable immunotherapy

“…The use of magnetic-bead-based aAPCs was investigated in a severe combined immunodeficiency (SCID) mice bearing human melanoma tumors [68]. These mice received MART-1 specific T cells generated from human PBMC after 1 month of in vitro culture with magnetic beads presenting MART-1-loaded human MHC dimers and anti-CD28 (1:1 ratio of aAPCs to cells) [68].…”

“…These mice received MART-1 specific T cells generated from human PBMC after 1 month of in vitro culture with magnetic beads presenting MART-1-loaded human MHC dimers and anti-CD28 (1:1 ratio of aAPCs to cells) [68]. Mice bearing 2-week-old tumors received an intravenous injection of 3 × 10 6 MART-1 specific cells and IL-2 injections (2 × 10 5 IU/mouse) on days 0 and 2 following cell transfer [68]. Magnetic-bead-expanded cells were compared with cells stimulated by monocyte-derived DC.…”