Cytheris SA, a clinical stage biopharmaceutical company focused on research and development of new therapies for immune modulation, announced results of a multi-centre phase IIa study designed to investigate the potential of Interleukin-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 IL-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 mucous membrane of the 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 analysis of these mucosal gut biopsies shows a 3.93-fold increase in CD4 T-cell counts following IL-7 treatment. The data were presented at the 2011 Conference on Retroviruses and Opportunistic Infections (CROI) held in Boston, February 27–March 2. The results of the phase IIa study (Abstract #H-113: Recombinant Interleukin-7 (CYT107) Expands CD4 T-cells in Peripheral Blood and Gut Mucosa of Chronically HIV-Infected Immunological Non-Responder Patients, Irini Sereti, Jean-Pierre Routy, Margaret Fischl, Thérèse Croughs, Stéphanie Beq, Michel Morre, M R Boulassel, Michael Yao, William Thompson, and Michael M. Lederman) were presented by Irini Sereti, M.D., M.H.S., NIAID/NIH Study Investigator and INSPIRE 2 Study Co-Chair.

“CD4 T-cell depletion in gut mucosa is an early and key pathogenic event in HIV infection that is associated with T-cell activation” said Michel Morre, DVM, president and CEO of Cytheris. “Despite successful anti-retroviral therapy (HAART), significant 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 suggest that IL-7, which targets expansion of the T-cell pool in both peripheral blood and mucosal sites, may be able to play a pivotal role in immune restoration in chronic HIV infection.”

Results of the phase IIa (INSPIRE 2) study Inspire 2 is an open-label, multi-centre phase IIa study of CYT107 (IL-7) in chronically HIV infected persons with CD4 T-cell counts between 101-400 cells/mm3 and plasma HIV RNA< 50 copies/mL. Twelve patients were enrolled and received 20 mcg/kg/week of CYT107 for 3 weeks.

All were evaluated at the planned primary end point at week 12 (CD4 expansion). The 12 enrolled patients received three weekly injections of CYT107 that were clinically well tolerated and without serious adverse events. Seven patients had transient increases in HIV RNA values (< 500 copies/mL). Median CD4 and CD8 T-cell counts were 272 and 554 cell/mm3 at baseline, increasing to 679 and 986 cells/mm3 at week 12, respectively.

Mean values and paired t-tests were used for statistical analyses. CYT107 also decreased PD-1 frequency, a marker of T cell exhaustion, in both CD4 and CD8 T-cells at W12 (p=0.008 and p=0.02). The decrease of PD-1 frequency on CD4 T-cells occurred as early as two weeks following the last administration of CYT107 (day 28, 1.8-fold decrease p=0.003).

Twelve patients underwent immunophenotypic analyses of cryopreserved PBMC by flow cytometry at baseline and at week 12. A sustained increase of the gut homing receptor a4ß7 integrin frequency on peripheral CD4 and CD8 T-cells was noted (1.4-fold in both) as early as day seven post first CYT107 administration (t test; p<0.002), with a peak increase at day 14 (p=0.0001). At week 12 a4ß7 remained elevated on peripheral CD8 (p=0.009) on T-cells.

A subset of 4 patients underwent rectosigmoid biopsies both at baseline and between weeks 10-24. Mucosal gut biopsy analysis showed an increase in both CD4 T-cell frequency (38.85 ± 9.07 pre vs. 53.08 ± 11.52 post p=0.0273) and counts (106 CD4/gr tissue: 2.29 ± 1.15 pre vs. 9.01 ± 7.85 post p=0.1709).

The findings in the current study confirm previously reported results in SIV infected monkeys showing the ability of IL-7 treatment to drive T-cells to the gut mucosa and facilitate their expansion3.

“This observation is a key prospective determinant of IL-7 therapeutic activity in the HIV-INR patient population,” said Thérèse Croughs, MD, chief medical officer of Cytheris. “In order to establish long term and stable restoration of CD4 counts in these patients, repopulation of Tcells in the gut is crucial to stopping the cell death induced by residual activation in the GI tract and to restoring local immune surveillance.”

In this study, not only did IL-7 confirm its potential for T-cell expansion, but it also showed its ability to send T-cells to the gut mucosa where it triggers local T-cell expansion. Numerous experimental and clinical studies confirm that T-cell reconstitution in the gut is critical for restoring control over the HIV virus.

The study therefore provides further evidence suggesting that administration of IL-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 stable level. The sustained immunological efficacy suggests that a short course of IL-7 treatment may provide an important avenue for enhancing the immune system and inducing broad spectrum proliferative activity of CD4 and CD8 T-cells in the blood, lymph nodes and small intestine, a key therapeutic effect in achieving long term disease stability in HIV-infected patients.

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, non-redundant stimulating effect on T lymphocyte development, notably on thymopoiesis and, downstream from the thymus, on homeostatic expansion of peripheral T-cells.

Clinical trials conducted on more than 160 patients in Europe, North America, South Africa and Taiwan has demonstrated the potential of IL-7 to expand and protect CD4 and CD8 T-cells. Currently, Cytheris is conducting multiple international investigations of IL-7 in HIV, HCV, HBV, post-BMT and cancer. Additional studies include a NIAID/NIH-sponsored trial (ICICLE) in Idiopathic CD4 Lymphocytopenia (ICL); a cancer vaccine study in children with Ewing's sarcoma family of tumours or similar genetic tumors sponsored by US National Cancer Institute; and, a multi-company/institutional study (EraMune 01) sponsored by ORVACS (the international HIV organization funded by the French Bettencourt Schueller Foundation) aimed at attacking the HIV viral reservoir.