Tumor antigen–specific induction of transcriptionally targeted retroviral vectors from chimeric immune receptor–modified T cells

Abstract

High-level systemic delivery of viral vectors to tumors has proved problematic as a result of immune neutralization, nonspecific adhesion, and clearance of circulating viral particles. Some cell types localize to tumors in response to particular biological properties associated with tumor growth. Their use to deliver viral vectors to tumors would allow precious viral stocks to be protected until they can be released at high local concentrations. Here, we describe a mechanism by which retroviral vector production by T cells can be regulated by a tumor-specific trigger through engagement of a chimeric immune receptor (CIR) with its target antigen. The virus that is released from the T cells can also be transcriptionally targeted. Finally, we show that it is possible to use vector-loaded, antigen-triggered human T cells as therapeutic, tumor-specific vector delivery cells in models of both local intratumoral and systemic delivery to both lung and liver metastases. This strategy incorporates multiple levels of targeting into the delivery system at the stages of surface targeting, viral production, and gene expression.

Loading of oncolytic vesicular stomatitis virus onto antigen-specific T cells enhances the efficacy of adoptive T-cell therapy of tumors

“…injected viral particles. [16][17][18][19][20][21][22][23] Moreover, by associating virus with such T cells it may also be possible to ameliorate some the problems of virus neutralization, sequestration and nonspecific adhesion. 5 Indeed, we and others have shown that antigen-specific T cells can be used very effectively, in both immunecompetent and immune-deficient mice, to chaperone virus particles to tumors, to induce their local release at the tumor site and to promote increased therapy over and above the therapy induced by the cytolytic activity of the T cells alone.…”

“…5 Indeed, we and others have shown that antigen-specific T cells can be used very effectively, in both immunecompetent and immune-deficient mice, to chaperone virus particles to tumors, to induce their local release at the tumor site and to promote increased therapy over and above the therapy induced by the cytolytic activity of the T cells alone. [16][17][18][19][20][21][22][23] In addition to T cells, several other types of cells have been used as carriers of genes/viruses to protect the virus from the multiple neutralizing and sequestering antiviral systems which the host normally uses to remove unwanted viral infections. [24][25][26][27] It is now clear that although the type of carrier and virus can differ it is possible to use cells to chaperone therapeutic viral particles to sites of tumor growth, either on, 21,23 or inside 16,17,24 the cells, and to generate potent antitumor therapy even in the presence of a fully intact immune system.…”

Antitumor efficacy of oncolytic herpes simplex virus adsorbed onto antigen-specific lymphocytes

“…20 Various carriers have been evaluated and antigen-specific T cells have often been used. [24][25][26][27][28][29] Oncolytic viruses adsorbed onto lymphocytes are systemically delivered and released at the tumor site, a protease-rich environment; there, the oncolytic virus spreads and replicates in the tumor cells. 27,33,37 This strategy is called the 'hitchhiking method'.…”

“…23 Various carriers have been evaluated, and antigen-specific T cells have often been used as a vector carrier. [24][25][26][27][28][29] Tumor antigenspecific T lymphocytes are a logical carrier for systemic virus delivery. 20,30 Moreover, tumor antigen-specific lymphocytes have been clearly shown to have inherent antitumor effects on their own.…”

Transient foamy virus vector production by adenovirus vectors

“…In attempts to exploit the advantages offered by each of these virus vectors, several groups have constructed hybrids [1][2][3][4][5][6][7][8][9][10][11][12][13][14] that combine the high-titre and efficient transduction of adenoviruses with the stable transgene expression of the retroviral murine leukaemia virus (MLV). While this system induces long-term in vivo transgene expression, several natural characteristics of MLV may hinder its future clinical exploitation, not least the recent development of a leukaemia-like disease in two children following treatment with an MLV vector, which resulted in the suspension of the clinical trials.…”