Cytheris announces results of phase II study indicating that recombinant Interleukin-7 (CYT107) expands CD4 T-cells in gut mucosa of chronically HIV infected immunological non-responder patients
Data from INSPIRE 2 HIV study show that CYT107 administration can significantly expand CD4 and CD8 T-cells while increasing the expression of gut homing molecules that may result in the restoration of the CD4 T-cell population of the gut mucosa
Paris, March 8, 2012 - Cytheris SA, a clinical stage
biopharmaceutical company focused on development of new therapies
for immune modulation, announces today results of a multi-center
phase II study designed to investigate the potential of recombinant
human Interleukin-7 (r-hIL-7, CYT107) therapy to reconstitute CD4
T-cells in chronically HIV-1 infected patients whose CD4 T-cell
counts remained low despite treatment with
anti-retroviral-therapies (HAART).
In addition to providing further evidence of the ability of r-hIL-7
to stimulate the expansion of CD4 and CD8 T-cells in peripheral
blood, the results demonstrate the importance of IL-7 in
stimulating T-cell repopulation of the lymphoid tissue layer in the
mucosa of the gastro-intestinal (GI) tract. This effect, previously
demonstrated in SIV infected monkeys, is now confirmed by analysis
of rectosigmoid biopsies in this study of HIV infected patients
defined as Immunological Non-Responders (INR). The data were
presented at the 2012 Conference on Retroviruses and Opportunistic
Infections (CROI) held in Seattle, March 5 to 8.
The results of the Phase II study (Abstract J-131: Gut mucosa T
Lymphocyte restoration in chronically HIV-infected patients treated
with recombinant Interleukin-7 (r-hIL-7) by Irini Sereti, Jacob
Estes, William Thompson, Margaret Fischl, Therese Croughs,
Stephanie Beq, Michael Yao, Mohamed Boulassel, Michael Lederman,
and Jean Pierre Routy were presented by William Thompson from the
laboratory of Irini Sereti, M.D., M.H.S., NIAID/NIH site study
investigator and INSPIRE 2 study co-chair.
"CD4 T cell depletion in the gut mucosa is an important pathogenic
event in HIV infection that is associated with T-cell activation
and partially restored by ART(1)," said Jean Pierre Routy, MD, site
study investigator in Mc Gill Hospital, Montreal. "It is now well
documented that significant AIDS and non-AIDS morbidity and
mortality persists in HIV infection, particularly in patients who
fail to restore normal CD4 T-cell counts. The results of the
current study indicate that r-hIL-7 administration can expand gut T
lymphocyte numbers, predominantly central memory CD4+ T-cells and
warrant further investigations of the clinical benefit of r-hIL-7
in HIV-INR patients."
Results of the Phase II (INSPIRE 2) Study
INSPIRE 2 is an open-label, multicenter Phase II study of CYT107
(r-hIL-7) in chronically HIV-infected persons with CD4 T-cell
counts between 101-400 cells/mm3 and plasma HIV RNA less than 50
copies/mL. Twenty two patients were enrolled and received 20
mcg/kg/week of CYT107 for three weeks. All were evaluated at the
planned primary end point (CD4 expansion) at week 12.
CYT107 was clinically well tolerated and without serious adverse
events. Median CD4 and CD8 T-cell counts were 260 and 650 cell/mm3
at baseline and increased to 645 and 1390 cells/microlitre at week
12, respectively (both P less than 0.001).
A subset of 12 patients underwent rectosigmoid biopsies both at
baseline and between weeks 10-24 (most at week 12). The proportion
of gut mucosal CD4 (gated on CD3+) cells increased from 40.3 to
45.8 post-IL7 (P equals 0.05), as did the CD4 number (x10 to the
power of 6 cells/gr tissue) from 2.5 to 4.7 (P equals 0.02). The
increase was more evident in CD4 cells of central memory phenotype
(CD45RO+/CD27+) from 1.8 to 3.6x10 to the power of 6 cells/gr
tissue (P=0.01). The proportion and number of gut Th17+ cells did
not change significantly. The proportion of cycling (Ki67+) gut
mucosal CD4+ and CD8+ T-cells did not change post-IL7 (P equals 0.8
and P equals 0.2 respectively). Quantitative immunohistochemistry
confirmed significant increases in gut CD3+ cells in the lamina
propria (P equals 0.008). Interestingly, the immunophenotypic
analyses of cryopreserved PBMC by flow cytometry at baseline and at
week 12 in this subset of 12 patients showed a sustained increase
in the expression of the gut homing receptor alpha 4 beta 7
integrin on peripheral CD4 and CD8 T-cells (1.4-fold in both) as
early as day seven post first CYT107 administration with a peak
increase at day 14 (p equals 0.0001). At week 12, alpha 4 beta 7
integrin remained elevated on peripheral CD4 and CD8 (p equals
0.001:) on T-cells. In addition, administration of CYT107
decreased, at week 12, biomarkers of monocyte activation (sCD14; D0
vs Week 12: 1.93 x 10 to the power of 6 to 1.73 x 10 to the power
of 6, p less than 0.01:) and fibrin degradation (D-dimer; D0 vs
Week 12: 0.24 to 0.14, p equals 0.05:) that have been linked to
disease progression and mortality.
Summary of Presentation Results
The findings in the current study confirm previously reported
results in SIV infected monkeys showing the ability of r-hIL-7
treatment to drive T-cells to the gut mucosa and facilitate their
expansion (2).
CYT107 expanded both peripheral and gut mucosa T-cells. Numerous
experimental and clinical data confirm that T-cell reconstitution
in the gut is critical for restoring control over the HIV
virus.
"This observation further supports CYT107 therapeutic activity in
HIV-INR patient population," said Dr. Croughs, MD and CMO of
Cytheris. "In order to establish long term and stable restoration
of CD4 counts in these patients, repopulation of T-cells in the gut
is crucial to stop cell death induced by residual activation in the
GI tract and to restore local immune surveillance."
Administration of r-hIL-7 may have an important effect on
immunologic recovery in HIV-infected patients whose HAART regimens
have been unsuccessful in restoring CD4 T-cells to a satisfactory
level. The sustained immunological efficacy suggests that a short
course of CYT107 treatment provides an important avenue for
enhancing the immune system and inducing broad proliferative
activity of CD4 and CD8 T-cells in the blood, lymph nodes and
gastrointestinal tract.
About Recombinant Human Interleukin-7 (CYT107)
Recombinant human interleukin-7 (CYT107) is a critical
immune-modulator for immune T-cell recovery and enhancement. As a
growth factor and cytokine physiologically produced by marrow or
thymic stromal cells and other epithelia, IL-7 has a critical and,
at some steps, a non-redundant stimulating effect on T lymphocyte
development, notably on thymopoiesis and, downstream from the
thymus, and on homeostatic expansion of peripheral T-cells.
Clinical trials conducted on more than 240 patients in Europe,
North America, South Africa and Taiwan have demonstrated the
ability of IL-7 to expand and protect CD4 and CD8 T-cells and the
potential to induce an antiviral activity. Currently, Cytheris has
completed or is conducting multiple international investigations of
CYT107 in patients with HIV infections, chronic hepatitis, cancer
and after hematopoietic stem cell transplantation (HSCT).
About Cytheris -
Cytheris SA is a privately held clinical-stage biopharmaceutical
company focused on development of new therapies for immune
modulation. Cytheris develops CYT107 that aims at reconstituting
and enhancing the immune system of patients suffering from cancer,
chronic viral infections such as HIV and chronic hepatitis, or
lympho-depleting treatments such as chemotherapy, and hematopoietic
cell transplantation (HSCT). The company operates from its
headquarters and laboratories in Issy-les-Moulineaux, a suburb of
Paris, and its U.S. subsidiary in Rockville, Maryland.
(1) Mavigner M et al. Altered CD4+ T cell homing to the gut impairs
mucosal immune reconstitution in treated HIV-infected individuals.
J Clin Invest 2012; 122(1):62-9
(2) Beq S et al. Injection of glycosylated Recombinant Simian IL-7
provokes rapid and massive T-cell homing in rhesus macaques. Blood
2009; Jul 23; 114(4):816-25.
Mark Tidmarsh
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Posted: March 2012
