A Phase II Randomized Study of HIV-Specific T-Cell Gene Therapy in Subjects with Undetectable Plasma Viremia on Combination Antiretroviral Therapy

Abstract

Highly active antiretroviral therapy (HAART) can suppress HIV replication to undetectable levels in plasma, but it is unlikely to eradicate cellular reservoirs of virus. Immunotherapies that are cytolytic may be useful adjuncts to drug therapies that target HIV replication. We have generated HIV-specific CD4(+) and CD8(+) T cells bearing a chimeric T-cell receptor (CD4zeta) composed of the extracellular and transmembrane domain of human CD4 (which binds HIVgp120) linked to the intracellular-zeta signaling chain of the CD3 T-cell receptor. CD4zeta-modified T cells can inhibit viral replication, kill HIV-infected cells in vitro, and survive for prolonged periods in vivo. We report the results of a phase II randomized trial of CD4zeta gene-modified versus unmodified T cells in 40 HIV-infected subjects on HAART with plasma viral loads <50 copies/ml. Serial analyses of residual blood and tissue HIV reservoirs were done for 6 months postinfusion. No significant between-group differences were noted in viral reservoirs following therapy. However, infusion of gene-modified, but not unmodified, T cells was associated with a decrease from baseline in HIV burden in two of four reservoir assays and a trend toward fewer patients with recurrent viremia. Both groups experienced a treatment-related increase in CD4(+) T-cell counts.

Gene transfer in humans using a conditionally replicating lentiviral vector

“…Viral load changes greater than 0.5 log were noted as meaningful because they are outside of the variation of the viral load assay. Transient increases in viral load was observed in patients shortly after dosing presumably because of cytokine release; this increase has previously been observed (9). Subject 1 entered the study with a mean baseline viral load of 188,500 (5.27 logs) copies per ml, and, at the 6 and 12 month points, his viral load declined to 12,700 copies per ml and 36,300 copies per ml, which correlates to a drop of 1.17 and 0.71 logs, respectively.…”

Engineering HIV-Resistant, Anti-HIV Chimeric Antigen Receptor T Cells

“…It is conceivable that this was a key limitation of the HIVCAR T cells studied in previous randomized trials. 30,31 We show that it is possible to protect HIVCAR T cells by independent disruption of CCR5 by NHEJ or HDR. Both methods produce functional CAR T cells that kill HIV-infected cells in the presence of ART, and both types of HIV-resistant CAR T cells outperformed HIVCAR T cells without CCR5 disruption in live viral assays.…”

“…8 In a randomized trial, this first-generation CAR was safe and reduced the HIV reservoir as measured by a viral outgrowth assay, and CAR + cells were detectable for 10 years despite the lack of clinical benefit. [30][31][32] The efficacy of this approach was likely compromised because of limited CAR activity in the absence of an intracellular co-stimulatory signaling domain and the potential for HIV infection of T cells expressing the CD4 CAR. 10,33 A panel of novel high-affinity, broadly neutralizing monoclonal antibodies (bNAbs) recognizing the HIV envelope glycoprotein have been isolated and characterized over the last decade.…”

HIV-1-Specific Chimeric Antigen Receptors Based on Broadly Neutralizing Antibodies

“…Based on these data, the CD4-based CAR, consisting of the CD4 extracellular and transmembrane domains fused to the CD3 intracellular signaling domain (CD4 Ϫ ), was advanced to clinical trials starting in the late 1990s, using retroviral transduction of autologous peripheral blood T lymphocytes and reinfusion. Unfortunately, this effort was abandoned after these trials showed safety but no clear benefits: one study with viremic subjects showed no reduction in viremia, although there appeared to be decreased rectal tissue virus burden (3), while another study of antiretroviral drug-treated subjects with baseline undetectable viremia not surprisingly showed no change in the persisting blood viral reservoir in the form of proviral DNA (4). Follow-up of these studies after more than a decade showed low-level persistence of transduced cells without evidence of malignancy (5).…”