AIDSWEEKLY Plus, Monday, 14 July 1997
Daniel J. DeNoon, Senior Editor
An immune therapy being explored as a cancer treatment appears applicable to HIV disease.
The therapy calls for dendritic cells, which are potent antigen-presenting cells (APCs), to be pulsed with tumor or HIV antigens and infused into patients to stimulate potent immune responses.
"Both allogeneic and autologous dendritic-cell infusions were well-tolerated and, in patients with CD4(+) T-cell counts >400 [cells/(micro)L], administration of these antigen-pulsed cells enhanced the immune response to HIV without affecting viral load," concluded Edgar G. Engleman of Stanford University, Palo Alto, California.
Engleman described results of preliminary clinical trials of the therapy in a presentation to "New Opportunities for HIV Therapy - From Discovery to Clinical Proof-of-Concept," the 2nd Joint Conference of the National Institute of Allergy and Infectious Diseases (NIAID) Strategic Program for Innovative Research on AIDS Treatment (SPIRAT) and the National Cooperative Drug Discovery Groups for the Treatment of HIV Infection (NCDDG-HIV), held June 22-26, 1997, in Vienna, Virginia.
He noted that dendritic cells are the most potent of all known APCs. They are the only APCs capable of presenting antigen to naive T cells.
In vitro studies showed that DCs pulsed with tumor or viral antigens were able to prime cytotoxic lymphocyte (CTL) responses. The primed cells exhibited powerful antigen-specific lysis of tumor cells or virus-infected cells.
In their initial clinical trial, Engleman and colleagues treated six patients with malignant B-cell lymphoma. Tumor-idiotype antigens were mixed with autologous DC precursor cells, and after expansion the cells were reinfused to the patients. These infusions were followed 16 days later by immunization with soluble tumor antigens. Each patient underwent three infusion/immunization cycles.
Although the patients were severely immunosuppressed, all had peripheral blood mononuclear cell (PBMC) proliferative response to tumor antigen. Two of the patients had complete resolution of their tumors, and most of the patients remained stable or had only minimal disease progression during the study period.
Based on this successful proof of principle, the researchers initiated a pilot study to determine whether the approach could be applied to HIV disease.
Suspecting that DCs from HIV infected individuals might in some way be defective, they obtained DCs from HLA-A2 homologous siblings. After pulsing with HIV antigens (two Env, one Gag, and three Pol antigens), the DC were infused into five subjects with HIV infection six to nine times at monthly intervals.
"The results of the study were not nearly as exciting as those in the lymphoma trial," Engleman said.
Only the two study participants with CD4 counts of >400 cells/(micro)L responded to the infusions: one had increased Env-specific CTL and lymphocyte proliferative responses and increased production of interferon gamma and interleukin 2; the other had increased Env-specific lymphocyte proliferative responses.
The researchers also performed an infusion of antigen-pulsed autologous APCs in a patient with a CD4 count of 730 cells/(micro)L. After three infusions, this patient had increased antigen-specific lymphocyte proliferative responses.
No adverse effects were seen, and none of the patients had stable CD4 counts and viral loads.
Engleman et al. currently are pursuing new techniques for improving delivery of antigen to the DCs. One of these techniques uses a nontoxic HIV-1 Tat peptide (Tat[49-57]) to carry antigens into the cytosol and nucleus.
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