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Follow-up of a Phase I Trial of the Infusion of Autologous ex vivo CD3/CD28 Co-stimulated and Expanded CD4+T Cells in HIV-1 Infection
Wendy Bernstein*1,2, B Levine3, N Aronson1,4, C Liebig2, H Flaks5, and C June3
1Uniformed Svcs Univ of the Hlth Sci, Bethesda, MD, US; 2Walter Reed Army Inst of Res, Washington, DC, US; 3Univ of Pennsylvania, Phil, PA, US; 4Walter Reed Army Med Ctr, Washington, DC, US; and 5Henry M Jackson Fndn, Rockville, MD, US
Background: We
previously reported on immune reconstitution observed in a phase I adoptive
immunotherapy trial in which 8 subjects with CD4 cell counts >250 received a
median of 43 x 109 ex vivo co-stimulated and expanded CD4+
T cells via serial infusions over a period of about 1 year. CD3/CD28 co-stimulation
results in polyclonal proliferation and down-regulation of CCR5 expression.
Immune reconstitution was demonstrated by increases in CD4% and CD4:CD8 ratios
in all subjects at the end of the study. Assays in vitro showed
improvement in T-cell repertoires and increased response to alloantigens,
mitogens, and recall antigens. The kinetics and magnitude of the CD4+
T cell response, the increase in Ki-67 positivity and T-cell receptor
recombination (TREC) data suggested that CD4 improvement was due to expansion
of the peripheral T-cell pool. Infused cells also affected CD4+ T
cell homeostasis as evidenced by a decreased expression of CCR5 in the
peripheral blood. We hypothesized that infusion of co-stimulated CD4+
T cells would provide a durable increase in CD4 counts, delaying progression to
symptomatic infection. We now report a follow-up on this cohort.
Methods: IRB
approval was obtained to review clinic records and the Composite Health Care
System for flow cytometry data, viral loads, and medical history from the end
of study apheresis (EOSA) of the adoptive immunotherapy trial until the present
or to a time when other immune-modulating therapy was initiated.
Results: Data
on all 8 subjects are summarized in the table. The median follow-up period was
3.3 years (range 2.5 to 6.5). Viral load was below detection in all subjects. The
number of HIV-related events was slightly lower during the follow-up period
(0.06 events/year) vs the pre-trial period (0.09 events/year). No AIDS-defining
diagnoses, evidence of graft versus host disease, autoimmune phenomena, nor
malignancy were observed during or after infusions.
Conclusions: The
previously reported increases in CD4 counts, percentage of CD4, and CD4:CD8
ratios now appear durable at a median of 3.3 years after completing adoptive
immunotherapy infusions. Disease stability is suggested by the constant rate of
HIV-related events. These data support the premise that infusions of ex vivo
co-stimulated and expanded CD4+ T cells can contribute to maintain
immune homeostasis in HIV-infected subjects.
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