Latest IL-7 study

[freewillie99]

Thought this was interesting.

http://www.earthtimes.org/articles/show/cytheris-announces-publication-of-il-7,820095.shtml

Cytheris Announces Publication of IL-7 Primate Study Showing Rapid and Massive T Cell Homing to the Gut

Posted : Tue, 12 May 2009 08:40:29 GMT
   
PARIS - (Business Wire) Cytheris SA, a clinical stage biopharmaceutical company focused on research and development of new therapies for immune modulation, today announced publication of data from a study in a non-human primate model identifying a new critical function of Interleukin-7 (IL-7) that induces massive and rapid T-cell migration from the blood into various organs, including lymph nodes, parts of the intestine and the skin. The study points towards the importance of evaluating the potential of IL-7 in combination with highly active antiretroviral therapy (HAART) in stimulating the T-cell repopulation of the gut, known to be a latent HIV reservoir where the virus can continue to replicate and suppress immune function. The massive T-cell depletion of the GI tract early in the course of HIV infection opens the patient to the effects of opportunistic infections and malignancies which are frequently associated with a weakened immune system in this patient population.

The paper entitled "Injection of Glycosylated Recombinant Simian IL-7 Provokes Rapid and Massive T-cell Homing in Rhesus Macaques" is prepublished online in Blood, the Journal of the American Society of Hematology (Beq S et al, April 7, 2009; doi: 10.1182/blood-2008-11-191288).

Studies such as the one described in this paper deal with the fundamental role of the gut in harbouring the HIV virus," said Michel Morre, DVM, President and CEO of Cytheris. "This is the question that lies at the heart of the challenge for improving the efficacy of antiretroviral therapy in GI lymphoid tissue. It may also be key to developing vaccines that provide more than a peripheral blood response by addressing the critical issue of mucosal immunity."

About the Study

In this study, conducted at the Institut Pasteur, Paris, and designed to measure early T-cell homing in the first hours post-injection, five healthy Rhesus macaques were subcutaneously inoculated with 80 micrograms/Kg of body weight of recombinant glycosylated simian IL-7 (R-sIL-7gly).

As observed in IL-7-treated human patients, all R-sIL-7gly-treated animals demonstrated a strong peripheral lymphopenia during the first day following injection. Notably, despite the fact that T-cell increase was not observed at Day 7 in one of the macaques (designated a poor responder), the initial decrease in lymphocyte counts was also observed in this animal. In contrast, two non-injected control animals sampled on the same schedule as the treated monkeys did not show a significant change in their circulating lymphocyte counts.

Four months later, when all the measured parameters had returned to baseline levels, a second injection of R-sIL-7gly given to two of the previously treated monkeys led to a similar drop in circulating lymphocytes.

Prior to euthanizing the animals, the investigators observed a strong and rapid T-cell migration out of the blood, with 70 percent of the circulating T-cells disappearing, including recent thymic emigrants, naïve, CM and EM T-cells in both CD4+ and CD8+ populations. At the same time, these T-cells up-regulated several chemokine receptors implicated in homing mechanisms, while plasma concentration of a number of chemokines/cytokines specifically implicated in migratory phenomenon was significantly increased.

In order to confirm that R-sIL-7gly injection effectively triggers T-cell homing to the lymph nodes, gut and skin, tissue samples from two animals euthanized 24 hours after R-sIL-7gly injection, one animal euthanized at Day 7 and from a fourth non-injected animal were subjected to immunohistological labeling with anti-CD3 monoclonal antibodies.

In these tissue samples, T-cell infiltration was observed in the skin and the lamina propria of the ileum, the colon and the rectum. Quantifying CD3+ T-cells in 7 to 10 fields (0.09 mm2 each) randomly selected from four slides for each organ confirmed that the number of CD3+ T-cells per field was significantly increased by Day 1 in the skin (p=0.001), the ileum (p=0.003), the colon (p=0.018) and the rectum (p=0.05). In all organs but the colon, T-cell numbers remained significantly higher at Day 7 as compared to the control animal. In contrast, the density of CD3+ T-cells was not significantly modified in the lymph nodes.

These data confirm that R-sIL-7gly induces T-cell homing into various non-lymphoid organs including the lamina propria of several parts of the gut (ileum, colon and rectum) and skin. Moreover, the expression of CCR7 and CXCR4 on circulating T-cells, the increase of CXCL12 plasma concentration and the production of CCL19 and/or CCL21 mRNA in lymph nodes also suggest homing into secondary lymphoid organs.

Similarly, the production of CCL19 in the ileum and the rectum and that of CCL21 in the jejunum suggest that R-sIL-7gly injection also triggers T-cell migration into the lymphoid follicles of the gut, where massive T-cell proliferation subsequently occurs.

Human and Non-Human Primate Studies

The IL-7 induced T-cell proliferation indicated in the long-term follow-up to the Phase I/II study discussed in a recently published paper ("Enhanced T cell recovery in HIV-1-infected adults through IL-7 treatment" published online in The Journal of Clinical Investigation, Lévy, Y et al, 2009, Vol. 119, No. 4) is now broadly confirmed by studies in non-human primates such as the one described here and others conducted by Cytheris in collaboration with the Seattle Biomedical Research Institute (SBRI), the Vaccine and Gene Therapy Institute (VGTI) and the Oregon National Primate Research Center (ONPRC) at Oregon Health and Science University, Emory University.

The focus of these non-human primate studies is the gastrointestinal tract, where the extraordinary size of the GI mucosa facilitates what is recognized as a fundamental role in the pathogenesis of HIV-1 infection. It is well known that the HIV virus is able to survive in these mucosal tissues of the human GI tract that effectively act as a viral reservoir. Current HAART therapy, which has been successful in reducing viral loads and increasing T-cells in the blood, has been largely ineffective in attacking the virus in the mucous membrane of the GI tract.

Left hiding in the gut lymphoid tissue, the HIV virus continues to replicate and suppress immune function by depleting its preferred target, the memory CD4+ T-cells which constitute the body's defence against the invading virus and whose decline precedes the profound reduction in CD4+ T cells circulating in the blood. This then leaves the body potentially vulnerable to a variety of opportunistic infections and/or progression to full-blown AIDS.

Summary and Potential Implications

The findings based on animal models and human studies emphasize the potential stability of the IL-7 effect on the production of T-cells over time as well as its possible impact in stimulating T-cell proliferation in the lymphoid tissue layer in the mucous membrane of the GI tract. By stimulating the body's immune response through T-cell migration into the gut mucosa where the viral reservoir hides, and thus taking the therapeutic battle directly into a known conduit for HIV entry, early infection and viral dissemination, IL-7 may eventually be shown to play an important therapeutic role in subverting HIV disease pathogenesis.

The sustained immunological efficacy seen in the long-term follow-up of the previously published Phase I/II trial (Lévy, Y et al, 2009. The Journal of Clinical Investigation, Vol. 119, No. 4) suggests that IL-7 may provide an important avenue for reconstituting 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.

About Interleukin-7

Investigational recombinant human Interleukin-7 (r-hIL-7) is a critical growth factor for immune T-cell recovery and enhancement. Cytokines that signal via the common gamma chain (gamma c) represent promising therapeutics based upon their potential to augment T cell expansion and increase the effectiveness of immune based therapies. Within this family, IL-7 is a prototypic homeostatic cytokine, produced constitutively by non-lymphoid cells. Its receptor (IL-7R alpha) is expressed on resting T cells, then rapidly down-regulated following T cell activation or IL-7 signaling.

IL-7 is essential for T cell development in mice and humans and for T cell homeostasis since it is required to maintain naïve CD4+ and CD8+ T cells in vivo. IL-7 levels rise in serum and tissues following T cell depletion and fall upon recovery.

In preclinical studies, IL-7 therapy exerts marked effects on T cell immune reconstitution in mice and primates. IL-7 augments effector and memory responses to vaccination in mice with preferential enhancement of responses to weak subdominant antigens. In preclinical models, IL-7 therapy augments anti-tumor responses leading to improved survival when combined with anti-tumor vaccines.

Clinical trials conducted on more than 110 patients in Europe, North America and Taiwan suggest the potential of IL-7 in expanding and protecting CD4+ and CD8+ T-cells. Cytheris is currently conducting multiple clinical studies of IL-7 in HIV, HCV and cancer.

[veritas]

Free,

This pre-clinical study for HIV is good to see. IL-7 doesn't seem to have the same problems that IL-2 has.
See the attached clinical trial for cancer patients:


IL-7 Therapy Boosts Immune Response in Cancer Patients
Roxanne Nelson

Authors and Disclosures

 Print This     
processing....

 
Information from Industry
An important therapy in the evolution of cancer treatment.
Xeloda (capecitabine) offers proven efficacy in the treatment of adjuvant stage III (Dukes' C) colon cancer, mCRC, and mBC.
Important Safety Information. Prescribing Information. July 4, 2008 — Data from a preliminary study suggest that recombinant human interleukin (r-hIL)-7 can enhance and broaden immune responses in patients with impaired immunity due to lymphocyte depletion.

The results of the phase 1 trial, published online June 23 in The Journal of Experimental Medicine, showed that when given to cancer patients, rhIL-7 induced a dramatic polyclonal prolonged expansion of CD4+ and CD8+ T cells, which in turn caused a significant broadening of circulating T cell receptor repertoire diversity. These effects were mediated primarily through an increase in peripheral T cell cycling and augmented cell survival.

Lymphopenia induced by cytotoxic chemotherapy, or pathologies such as HIV infection, can significantly weaken immune function; as a physiologic immuno-enhancer, IL-7 can enhance the restoration of T cells. CD4+ T cell recovery in adults who have experienced severe depletion requires the reemergence of a pool of naive T cells, which generally takes 18 to 24 months and might only occur in people younger than 40 to 45 years. Thus, the authors note, a strategy that can accelerate or promote the recovery of a widely diverse T cell repertoire in older people might be useful for a large number of clinical applications.

"We know that IL-7 can enhance tumor vaccines in animals, so that would be a clear avenue of research," said lead author Claude Sportès, MD, senior staff clinician at the National Cancer Institute's Center for Cancer Research, Experimental Transplantation and Immunology Branch, in Bethesda, Maryland. "But it wouldn't only have to be tumor vaccines. Hopefully we will have a trial underway in the not-too-distant future looking at how it can enhance anti-viral and other immunizations, particularly in the elderly."

Treatment with IL-7 therapy exerted a marked effect on T cell immune reconstitution during preliminary trials with animal models. It also appeared to augment effector and memory responses to vaccination in mice; in preclinical models, IL-7 therapy was able to augment anti-tumor responses that might improve survival when combined with anti-tumor vaccines.

"In older individuals, therapy with IL-7 could lead to a rejuvenation of the phenotype," explained Dr. Sportès in an interview. "This in turn can lead to better vaccine responses in general and, in oncology, better tumor vaccine responses."

The implications for rhIL-7 are potentially vast, and there are many promising therapeutic avenues. "But as often happens in medicine," he cautioned, "things can be very promising at this stage and then fizzle out."

First Human Trial

In this phase 1 dose-escalation study, the first initiated in a human population, Dr. Sportès and colleagues evaluated the effects of IL-7 therapy on human lymphocytes in 16 patients, between the ages of 20 to 71 years, with nonhematologic, nonlymphoid refractory cancer. The doses, extrapolated from previous mouse and primate studies, were 3, 10, 30, and 60 μg/kg, and were administered by subcutaneous injection every other day for 14 days, for a total of 8 doses.

They found that after a very transient decrease, the numbers of circulating lymphocytes and CD4+ and CD8+ T cells increased in a dose-dependent manner. At the highest dose levels, increases approached 300% for CD4+ and exceeded 400% for CD8+ T cells. Overall, the treatment induced widespread T cell cycling and was able to expand the T cell pool in human patients while preserving T cell function.

Treatment with rhIL-7 also seems to have advantages over rhIL-2, explained Dr. Sportès. The expanded T cells retained significant functional capacity, and the CD4+ T cell expansion was not accompanied by a disproportionate increase in T regulatory cells, a phenomenon that has been observed after rhIL-2 therapy. Previous data have shown that in vivo IL-2 administration in humans has minimal effects on CD8+ T cell numbers, whereas rhIL-7 effects on CD8+ T cell expansion are at least comparable to the effects on CD4+ T cells.

The researchers noted that rhIL-7 increases T cell receptor repertoire diversity, and that although it appears to selectively expand CD4+ recent thymic emigrants, naive cells, and central-memory populations, it did not have the same effect on effector T cells.

The details of the clinical trial will be the focus of a separate paper, said Dr. Sportès. "But it was well tolerated and we went to full-dose escalation."

"Immune Rejuvenating" Properties

rhIL-7 appears to be an effective T cell growth factor with "immune rejuvenating" properties, suggesting that it is effective in augmenting immune reactivity in hosts with impaired immunity due to any number of factors, including age, chemotherapy, and infectious disease, the authors note.

In patients with both intact and deficient immune systems, the capacity of rhIL-7 to augment responses to weak antigens and to increase T cell cycling without expanding T regulatory cells might be clinically exploitable in the context of immunotherapy regimens for cancer and/or chronic infection, they write.

The study was supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute (NCI), and the Center for Cancer Research. It was made possible through a formal collaboration between the NCI and Cytheris Inc., the investigational new drug holder and manufacturer of rhIL-7. Dr. Sportès has disclosed no relevant financial relationships; 3 of his coauthors have reported financial interests in Cytheris.

J Exp Med. Published online before print June 23, 2008.

[CLOSE WINDOW]
Authors and Disclosures
Author(s)
Roxanne Nelson
Roxanne Nelson is a staff journalist for Medscape Hematology-Oncology.
[ CLOSE WINDOW ]
Information
Authors and Disclosures
Roxanne Nelson
Roxanne Nelson is a staff journalist for Medscape Hematology-Oncology.


Accreditation Statements
For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity noted above. For technical assistance, contact CME@medscape.net

This activity has expired.
The accredited provider can no longer issue certificates for this activity. Medscape cannot attest to the timeliness of expired CME activities.
 
 Print This
 
Medscape Medical News © 2008

 
 
 
Medscape    MedscapeCME    eMedicine    Drugs    MEDLINE    All
 
About MedscapePrivacy PolicyTerms of

It looks like progress is being made.

v

[freewillie99]

IL-7 doesn't seem to have the same problems that IL-2 has.

I hope not.  That's the fear, huh?  That said, most everything I've seen has been positive.  Guess like everything else time will tell.

[Inchlingblue]

I started a thread recently about high dose intravenous immunoglobulin possibly reducing latent reservoirs. The doctor who did the study said: "we don't know the mechanism. We found that IL-7 [interleukin-7] increased in all cases from baseline to day eight, but we don't know why this looks like it works."

Veritas: this is the kind of thing I mean when I mentioned recently that I hope researchers are putting all this science together, all these pieces to the puzzle.