Prolonged survival and tissue trafficking following adoptive transfer of CD4ζ gene-modified autologous CD4+ and CD8+ T cells in human immunodeficiency virus–infected subjects

Abstract

We have genetically engineered CD4+ and CD8+ T cells with human immunodeficiency virus (HIV) specificity by inserting a gene, CD4ζ, containing the extracellular domain of human CD4 (which binds HIV env) linked to the zeta (ζ) chain of the T-cell receptor (which mediates T-cell activation). Twenty-four HIV-positive subjects received a single infusion of 2 to 3 × 1010 autologous CD4ζ-modified CD4+and CD8+ T cells administered with (n = 11) or without (n = 13) interleukin-2 (IL-2). Subjects had CD4 counts greater than 50/μL and viral loads of at least 1000 copies/mL at entry. T cells were costimulated ex vivo through CD3 and CD28 and expanded for approximately 2 weeks. CD4ζ was detected in 1% to 3% of blood mononuclear cells at 8 weeks and 0.1% at 1 year after infusion, and survival was not enhanced by IL-2. Trafficking of gene-modified T cells to bulk rectal tissue and/or isolated lamina propria lymphocytes was documented in a subset of 5 of 5 patients at 14 days and 2 of 3 at 1 year. A greater than 0.5 log mean decrease in rectal tissue–associated HIV RNA was observed for at least 14 days, suggesting compartmental antiviral activity of CD4ζ T cells. CD4+ counts increased by 73/μL at 8 weeks in the group receiving IL-2. There was no significant mean change in plasma HIV RNA or blood proviral DNA in either treatment arm. This sustained, high-level persistence of gene-modified T cells demonstrates the feasibility of ex vivo T-cell gene therapy in HIV-infected adults and suggests the importance of providing HIV-specific T-helper function.

Expression of Chimeric Receptor CD4ζby Natural Killer Cells Derived from Human Pluripotent Stem Cells Improves In Vitro Activity but Does Not Enhance Suppression of HIV Infection In Vivo

“…The CD4f construct has been extensively tested in multiple systems such primary T and NK cells against HIV [36][37][38][39][40]. Some of these trials transduced CD4f into primary T-cells of HIV-infected patients with varying effects [37,39]. Here, we combined the unique advantages of the hESCs/ iPSCs system and the specificity and efficacy of CARs together to genetically modify hESCs/iPSCs.…”

“…As the CD4 protein is an absolute requirement for HIV entry, it is plausible to use this as an effective "antigen recognition" domain independent of human leukocyte antigen restriction. Several groups pioneered this approach to both basic research and clinical trials [36][37][38][39][40]; however, this had varying efficacy in vivo when transduced into patients autologous T-cells. Here, we modified both hESCs and iPSCs with a CD4f construct to generate NK cells that express the specific HIV CD4f chimeric receptor.…”

Current status of chimeric antigen receptor therapy for haematological malignancies

“…Coadministration of systemic IL2 has been reported to enhance the persistence of adoptively transferred human CD8 + T cells (Yee et al, 2002). However, others have found that using autologous human CD4 + T and CD8 + T cells in combination eliminates the benefit of concomitant IL2 therapy (Mitsuyasu et al, 2000). Recent studies also seem to indicate that IL2 might actually reduce memory T cells and increase the number of T regs (Zhang et al, 2005).…”

Anti‐CD3/28 mediated expansion of macaque CD4+ T cells is polyclonal and provides extended survival after adoptive transfer

“…One such promising supportive approach was pioneered by the laboratory of Carl June whereby CD4 + T cells from HIV-infected patients were shown to expand vigorously with a concomitant elimination of HIV when cultured with beads coated with anti-CD3 and anti-CD28 monoclonal antibodies (mAb) [12,31,45]. Such an approach and variants thereof have allowed for the readministration of long lived autologous CD4 + T cells to patients [17,38]. Furthermore, the pilot administration of autologous anti-CD3/28 expanded CD4 T cells transduced with an antisense vector for HIV was shown to markedly decrease viral load set points in patients in which HAART was discontinued following adoptive transfer [32].…”