Genetic engineering of T cells for adoptive immunotherapy

Abstract

To be effective for the treatment of cancer and infectious diseases, T cell adoptive immunotherapy requires large numbers of cells with abundant proliferative reserves and intact effector functions. We are achieving these goals using a gene therapy strategy wherein the desired characteristics are introduced into a starting cell population, primarily by high efficiency lentiviral vector-mediated transduction. Modified cells are then expanded using ex vivo expansion protocols designed to minimally alter the desired cellular phenotype. In this article, we focus on strategies to (1) dissect the signals controlling T cell proliferation; (2) render CD4 T cells resistant to HIV-1 infection; and (3) redirect CD8 T cell antigen specificity.

Human immunodeficiency virus type 1 long-term non-progressors: the viral, genetic and immunological basis for disease non-progression

“…Though preventive and prophylactive vaccines cannot rely on genetics to confer protection from HIV-1 infection, gene therapy can be administered as antiretroviral therapeutics to control infection in HIV-1 seropositive individuals. An example of gene therapy is genetically engineered CD4 + T cells that are resistant to HIV-1 based on coreceptor expression or secretion of antiviral soluble factors, which are adoptively transferred to recipients (Varela-Rohena et al, 2008). Genetic correlates of protection that should be targets for gene therapy include antiviral factors like APOBEC3G and TRIM5a that restrict HIV-1 replication at the post-entry, pre-integration stage.…”

“…Genetic correlates of protection that should be targets for gene therapy include antiviral factors like APOBEC3G and TRIM5a that restrict HIV-1 replication at the post-entry, pre-integration stage. Another possible example of using adoptive immunotherapy to control HIV-1 infection involves the transfer of Tcell receptor genes from a T cell specific for HLA-B57-restricted antigens that are inserted into a viral vector (Varela-Rohena et al, 2008). This would be especially useful in generating highly specific T-cell responses for conserved antigenic gag epitopes that are most strongly correlated with reducing viral load early in infection.…”

Engineering scalable biological systems

“…Standardized methods and technologies must be developed with input from regulatory agencies to evaluate these concerns. The most difficult regulatory hurdles pertain to the use of synthetic biological systems for human therapeutics such as adoptive immunotherapy, 65 cancer-seeking bacteria, 66 engineered phage targeting bacterial biofilms 67 and antibiotic-resistant organisms. 68 These hurdles include immunogenicity, biocontainment, recombinant DNA and manufacturing purity.…”

Engineering HIV-Specific Immunity with Chimeric Antigen Receptors

“…In the case of HIV infection, antigen-specific TCRs from HIV-reactive T cells obtained from infected individuals have been identified, cloned, and used to modify peripheral cells from the same patient. [19][20][21][22] While attempts to modify peripheral T cells with HIVspecific TCRs have been largely experimental and ineffective therapeutically thus far, genetically modified CD8 cells have in fact exhibited enhanced and polyfunctional immune responses against viral antigens in vivo and these cells have been demonstrated to have an increased ability to control HIV infection. 21,22 A potential benefit of this approach is due to the specificity of the TCR, which would likely limit issues with tolerance or self-reactivity.…”

“…[19][20][21][22] While attempts to modify peripheral T cells with HIVspecific TCRs have been largely experimental and ineffective therapeutically thus far, genetically modified CD8 cells have in fact exhibited enhanced and polyfunctional immune responses against viral antigens in vivo and these cells have been demonstrated to have an increased ability to control HIV infection. 21,22 A potential benefit of this approach is due to the specificity of the TCR, which would likely limit issues with tolerance or self-reactivity. However, an inherent limitation to this approach is the absolute requirement for a specific HLA molecule to present antigen to the T cell, limiting each TCR to persons with the right HLA type.…”