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Potential 'functional cure' engineered for AIDS.

FROM CROI 2014

By tinkering with a gene involved with the entry of HIV into cells, investigators have developed what they call a potential "functional cure" for HIV/AIDS.

The therapy is designed to keep HIV under control without additional antiretroviral drugs.

The technique involves collection of CD4 T cells from patients infected with HIV genetically engineering the cells to disable the gene for the HIV coreceptor CCR5, and reinfusing the treated cells after the patients have been conditioned with the chemotherapy drug cyclophosphamide (Cytoxan), which stimulates engraftment of the modified cells, reported Dr. Gary Blick of Circle Care Center in Norwalk, Conn.

"We are seeing what we believe to be dose-dependent marked increases in both absolute CD4 cell counts as well as the engraftment of CCR5 modified T cells with the increasing doses of Cytoxan," he said at the Conference on Retroviruses and Opportunistic Infections 2014.

Results from a phase I proof-of-concept study with the same technology were reported in the March 6 New England Journal of Medicine (2014;370:901-10).

In the phase I/II dose-escalation study reported at CROI, a total of 12 HIV patients with chronic aviremic HIV infection while on highly active antiretroviral therapy (HAART) were enrolled into one of three cohorts. Each patient received one dose of the autologous CD4+ T-cell product in which the gene for CCR5, a coreceptor for HIV entry, is modified via zinc-finger nuclease (ZFN)-mediated genome editing.

Three patients received cyclophosphamide 200 mg as preconditioning, six received cyclophosphamide 500 mg/[m.sup.2], and three received the drug at a dose of 1 g/ [m.sup.2].

Each patient then received a single infusion (8.2-36 billion cells) of his/her own CD4+ T cells, which had been genetically engineered using an adenoviral vector designed to carry a ZFN, an enzyme targeted at permanently disabling CCR5.

The primary endpoint of the study was the safety and tolerability of cyclophosphamide. The drug was generally well tolerated, except for low-grade gastrointestinal side effects commonly seen with this agent. The side effects were treated with antiemetics.

The investigators saw a dose-related increase in total CD4 T-cell counts and engraftment of the modified cells at the highest cyclophosphamide dose. The cell counts approached levels found in patients with the CCR5 delta-32 deletion that confers natural resistance to HIV

In addition, two patients at the 500-mg/[m.sup.2] dose had an approximate reduction of 0.8-1.1 [log.sub.10] in viral load after a 16-week treatment interruption, and one patient on the 1-g/[m.sup.2] dose had a 1.9 [log.sub.10] decrease after 16 weeks off HAART.

The data suggest that cyclophosphamide conditioning may optimize the antiviral and engraftment effects of the adoptive T-cell strategy, and that the drug may play an important role as an immunomodulator in immunotherapy strategies for treating HIV Dr. Blick said.

VITALS

Major finding: Three of 12 HlV-positive patients treated with modified autologous T cells had viral load reductions between 0.8 and 1.9 [log.sub.10] after 16 weeks of antiretroviral therapy interruption.

Data source: Phase I/II dose-escalation study in 12 patients.

Disclosures: The study was supported by Sangamo Biosciences. Dr. Blick reported having no relevant financial disclosures.

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Title Annotation:ACROSS SPECIALTIES
Author:Osterweil, Neil
Publication:Clinical Psychiatry News
Date:Apr 1, 2014
Words:540
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