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.

Targeting of GD2-positive tumor cells by human T lymphocytes engineered to express chimeric T-cell receptor genes

“…While the chimeric receptor‐transduced cells described here may be of clinical value, past experience indicates that cells of this type rapidly lose functionality in vivo. 43, 44 This effect is manifest in our own system by our data showing a substantial decrease in tumor‐specific cytokine release during in vitro culture. We also show here that stimulation of transduced T cells with G D2 ‐expressing tumor cells alone does not provide a sufficient stimulus for commitment to proliferation, continued T‐cell expansion and long‐term in vitro persistence.…”

Targeting reservoirs of HIV replication in lymphoid follicles with cellular therapies to cure HIV

“…Several clinical trials that tested therapeutic infusion of autologous T cells have been completed . These trials included treatments with expanded autologous HIV‐specific T cells, treatments with HIV Env targeting CAR‐T cells, and CCR5‐modified CD4 T cells . While these therapeutic T cell trials were shown to be safe, they did not result in a functional cure for HIV.…”

“…Interestingly, the very first clinical tests of CAR technology were directed against HIV‐1 infection, using first‐generation CAR constructs employing CD4 as the targeting motif. Whilst minimal virus suppression was achieved, the CAR‐T cells were found to be safe, and had stable levels of engraftment with a decay half‐life exceeding 16 years . There are several advantages to using HIV targeting CAR‐T cells or CAR‐NK cell immunotherapy.…”

Adoptive immunotherapy for cancer: the next generation of gene‐engineered immune cells

“…The transferred T cells were well tolerated in patients and circulating anti‐gp120 CD4 + and CD8 + transduced T cells could be detected up to 42 weeks post infusion, with evidence of trafficking to mucosal HIV reservoirs. Gene‐modified virus‐specific T cells showed sustained cell survival in these patients, independent of exogenous IL‐2 administration (83). In a subsequent Phase II trial involving a cohort of 40 patients, some reduction in levels of HIV burden and a trend toward reduced recurrent viremia was observed (84).…”