Preliminary results from
a phase I clinical trial have demonstrated the safety and tolerability of a
cell therapy involving the ex vivo expansion of T
cells and their subsequent infusion into HIV-infected individuals
previously treated with antiretroviral
therapy (ART). The study appears September 21st in the journal Molecular
Therapy.
"This study is
focused on finding a way to re-educate the body's immune
system to better fight HIV infection," says co-senior study author
David Margolis of the University of North Carolina (UNC) at Chapel Hill.
"We found that this approach of re-educating the immune cells and
reinfusing them was safe, which was the primary goal of the study. The data
from this trial will continue to help us design improved immunotherapies
against HIV."
A game changer for
patients living with HIV, ART has turned what was once a death sentence into a
chronically managed disease. But it is not a cure, and the virus continues to
persist within a latent
reservoir that remains hidden from the immune system. Approaches using
pharmacological HIV-latency-reversal agents to induce latent virus to express
viral protein could make this reservoir vulnerable to T cells. However, the
existing HIV-specific immune response in ART-treated individuals is insufficient
to clear persistent infection, even in the presence of latency-reversal agents
that induce HIV expression.
One safe avenue for
harnessing T cell responses to fight HIV is adoptive cellular therapy. This
procedure involves collecting T cells from a patient, growing them in the
laboratory to increase their numbers, and then giving them back to the patient
to help the immune system fight disease. Earlier adoptive-T-cell-therapy
approaches for HIV had limited efficacy as a result of multiple factors. Since
these earlier attempts, the adoptive-T-cell-therapy field has made significant
advances, largely in the oncology field, that could help to overcome some of
the pitfalls encountered with earlier T-cell-therapy approaches for HIV. T
cells generated by these sophisticated methods of expansion have been safe and
well tolerated, as well as highly effective.
"Before we can
combine this approach with treatments meant to bring HIV out from hiding so the
improved immune response can clear it from the body, we need to first establish
that this immunotherapy
approach is safe on its own," says co-senior study author Catherine
Bollard of the Children's National Health System. "We have long-standing
experience treating patients with virus-specific T cells targeting latent
viruses such as Epstein-Barr
virus and cytomegalovirus. Therefore, we were extremely excited to work
with the UNC team to adapt this virus-specific T-cell-therapy approach to the
HIV setting."
In the small
proof-of-concept study, Margolis, Bollard, and their collaborators produced ex
vivo expanded HIV-specific
T cells (HXTCs); their long-term goal was to use HXTCs as part of a
strategy to clear persistent HIV infection. The researchers administered two
infusions of HXTCs over a 2 week period to six HIV-infected participants whose
viral load had been reduced to an undetectable level by ART.
This treatment was well
tolerated and had few adverse events. Moreover, two patients exhibited a
detectable increase in T-cell-mediated antiviral activity after the two infusions,
although the clinical significance of this mild-to-modest impact is unknown.
When evaluating participants in aggregate, the research team found no overall
enhancement of the magnitude of the HIV-specific
immune response. This could be due to the low dose of the two infusions and
the lack of strategies to promote the expansion of the T cells once they are in
the body.
There was also no
decrease in the size of the latent
reservoir, most likely because of the absence of therapies such as
latency-reversal agents, which are designed to perturb the reservoir and induce
recognizable expression of HIV proteins that trigger immune responses. In the
future, a critical question will be whether HXTC therapy in combination with
latency-reversal agents can deplete the HIV
reservoir to an extent that is measurable by current gold-standard assays
of HIV latency. A study of HXTC in combination with the latency-reversal agent
vorinostat is currently undergoing evaluation in an ongoing clinical trial.
"This is a promising
advancement for the field," says first author Julia Sung of UNC, although
she also cautions people against over-interpreting the results. "The study
did not cure HIV and should not be interpreted as doing so, but we also are
very encouraged by the safety data, so it should not be considered discouraging
either. This paves the way for the next step, which is to combine this immunotherapy
approach with latency-reversal therapy in order to wake up the HIV out of its
latent state, where it is invisible to the immune system, then clear it out
with the immunotherapy."