A primary barrier to HIV cure is the large latent reservoir in tissues. Efforts to clear these cells are hampered by defects in both adaptive and cellular immune responses. IL-15, a cytokine that stimulates NK and T cells has potential to reverse these defects and to clear virus infected cells.
We are conducting a Phase 1 dose escalation trial of ALT-803 in HIV+ adults. ALT-803 is an IL-15 superagonist/IL-15 receptor α complex (IL-15N72D/IL-15Rα-Fc) and is in clinical trials for hematologic and solid organ malignancies. Clinical trials in cancer patients have shown that subcutaneous (SQ) administration (compared to intravenous (IV)) is well tolerated and gives favorable pharmacokinetics at doses between 10-20 mcg/kg weekly. HIV+ people on ART with plasma viral load < 20 copies/ml and CD4 T cells > 500 cells/µl receive an IV or SQ injection of ALT-803 weekly for 3 weeks. Blood is obtained for assessments of cell activation and proliferation, and changes to the virus reservoir. Three people are planned to receive the drug at each dose level. The dose escalation scheme is 0.3 mcg/kg IV then 1, 3, and 6 mcg/kg SQ.
A total of 7 individuals have been dosed to date. The mean age was 42 and mean CD4 T cell count was 865 cell/µl. The mean time from diagnosis was 9.7 years and the mean time on ART was 5.3 years. The first 2 participants received 0.3 mcg/kg IV and the remaining 5 received 1.0 mcg/kg SQ. SQ dosing was associated with an injection site rash and adenopathy. Eight of the first 13 doses were associated with transient low-level plasma viremia. We measured a 7.6-fold increase in NK cell activation, a 23-fold increase in CD4 activation and a 10-fold increase in CD8 T cell activation in LN 48 hours after dosing. We used the EDITS assay (Envelope Detection by Induced Transcription-based Sequencing, developed by Dr. Karn, CWRU) to measure inducible cell-associated HIV RNA. Prior to Con A stimulation we measured a significant increase in HIV transcription after the first 2 ALT-803 doses but after dose 3 there were fewer transcription events. With ConA stimulation there was a trend towards decreasing transcription events (Figure).
At these relatively low doses of ALT-803, the drug is safe and well-tolerated. The drug is biologically active and causes activation and proliferation of CD4, CD8 T cells and NK cells and induces transcription of HIV. These studies suggest ALT-803 reactivates virus from latency and activates NK and T cells.