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A Multifunctional Cytokine

Interleukin-7(IL-7) is a multifunctional cytokine, mainly produced by non-hematopoietic cells, which is active notably but not only on T cell development and the full maturation of T cells in primates. IL-7 has a critical and, at some points, a non-redundant stimulating effect on T lymphocyte development, on thymopoiesis and downstream from the thymus, on homeostatic expansion of peripheral T cells.

At least two properties of IL-7 justify its development as a drug, both in oncology and infectious disease:

• A quantitative effect consisting of a massive expansion of T cells, which not only contributes to improved immune recovery but also to the elimination of tolerance for chronic stimulation by virus- or tumor-derived antigens;
  
  
• A functional enhancement of αβ-T cell reactivity to weak immunogens, such as proteins, virus-causing chronic infections or tumor-associated antigens.

This broad activity of IL-7 leads to the consideration of several avenues of development for CYT107 (r-hIL-7 ):

• The restoration of the immune system and the prevention of opportunistic infections in patients who develop severe lymphopenia, such as in HIV infection or treatment with lympho-ablative chemo- or radio-therapies;
  
  
• The control of chronic viral infections such as HIV and HCV or in the treatment of cancers, either in the minimal residual disease or in more advanced tumors, where IL-7 could be used as a stand-alone agent or in combination with other immunotherapeutic agents, notably with vaccines or as an adjunct to antiviral drugs.

Considerable evidence from basic immunology, preclinical models and, more recently, from early clinical studies, confirms the unique role of IL-7 in the functioning of the immune system and especially in providing the right cells in sufficient numbers to support and improve specific immune responses against infectious agents and malignant cells. In that light, as with EPO for red blood cells and G-CSF for neutrophils, IL-7 plays a pivotal role in supporting T cell expansion and function.

The Main Features of IL-7 Activity

Two basic scientific findings emphasize the important role of IL-7 :

• The knockout of either the IL-7 gene or the gene of its receptor triggers a severe combined immunodeficiency in mice; and, the corresponding IL-7 R gene alteration in humans is also responsible for a SCID syndrome;
  
  
• IL-7 is the main homeostatic driver of T cell numbers: IL-7 blood levels are inversely correlated with peripheral T CD4 blood counts in the same way that EPO blood levels are inversely correlated with red blood cells counts.

Current Limitations of Most Immunotherapies

The global potential of immunotherapies is impressive because these new approaches could efficiently target most cancers and infectious diseases.  Nevertheless, although encouraging data have started to appear and a few therapeutic vaccines are approaching approval, as of today most immunotherapies have encountered serious hurdles that limit their full efficacy and development.

Examining these limitations in light of the encouraging set of activities now documented by the recently produced pre-clinical and clinical data for IL-7 , makes it possible to see how this cytokine can overcome most of these hurdles and thus open a significant number of indications to therapeutic approach.

The current limitations of most immunotherapies such as adoptive T cell therapies, cancer vaccines, and therapeutic vaccines include the following:

• Insufficient production of T cells;
  
  
• Production of short lived T cells, very sensitive to apoptosis;
  
  
• Inducement of very narrow responses, targeting a limited set of  epitopes;
  
  
• Boosting CD4 counts but not CD8 counts, or vice versa;
  
  
• Production of inefficient T cells that quickly reflect an “exhausted” profile;
  
  
• Production of effector T cells with short lived activity but not central memory T cells that are responsible for long term protection (the “Holy Grail” of immunotherapy);
  
  
• Occasional production of more Th-2 or suppressor T-regs than the required active Th-1 cells.

How IL-7 Resolves These Current Limitations

Based on some 10 years of preclinical and laboratory data and now partly confirmed in early clinical studies in oncology and HIV, it can reasonably be stated that IL-7 will fully or partly resolve most of the limitations of current immunotherapies in the following ways:

• IL-7 administration systematically increases the number of CD4 and CD8 T cells in both animal models and in clinical studies, including SIV infected monkeys and HIV infected patients;
  
  
• This effect is potent and sustained -- the more the animal or patient is lymphopenic, the more pronounced the effect;
  
  
• IL-7 administration is very potent at producing “new T cells” (i.e. naïve T cells and recent thymic emigrants);
  
  
• The T cells produced are long lived due to the various anti-apoptotic effects of IL-7 ;
  
  
• The repertoire of T cells produced by IL-7 is broad both because IL-7 supports thymopoïetic activity and because IL-7 promotes a response against sub-dominant epitopes;
  
  
• The improvement of various specific immune responses against tumors and viruses has been broadly documented at the preclinical level; Cytheris is now producing early confirmation of this effect in human clinical trials;
  
  
• Data are also accumulating to demonstrate that if IL-7 does not trigger the production of central memory T cells, it does very efficiently support this effect, at least for CD8 T cells;
  
  
• IL-7 is a modest activator of effector T cells, cells that quickly lose their IL-7 receptor after activation; this also explains why the global clinical tolerance of IL-7 is satisfactory and why IL-7 does not induce the typical cytokine “storm syndrome.”

Most Promising Targets for IL-7 Therapy

Two main immunological settings which correspond to various life threatening pathologies are currently under investigation by Cytheris:

• The specific case of lymphopenia, more precisely CD4 T cell lymphopenia, whatever the cause of the drop in CD4 counts;
  
  
• The case of inefficient specific immune response against massive antigen load such as that associated with chronic viral infections and cancer.

In the setting of lymphopenia, Cytheris has initiated clinical studies in:

• HIV infected patients who are immune non-responders, defined as patients treated with HAART therapy for more than a year who do not recover an appropriate number of T cells but whose viral load is controlled;

• Severe lymphopenia subsequent to allogeneic bone marrow transplantation (BMT) or stemcell transplantation (SCT) in the context of T cell depletion;

• Various cases of idiopathic lymphopenia where the patient has a documented history of opportunistic infection and where there is the possibility of documenting specific T cell response.

In the context of an inefficient specific immune response to massive antigen load, there are several therapeutic areas that appear promising:

In Chronic Infectious Diseases:

• Full recovery of immune status in HIV patients who do not recover a minimum of 500 CD4 T cells, sufficient to achieve a life expectancy comparable to the normal population;
  
  
• Possibility of responding to and clearing the virus in those HCV infected patients who are non-responders to the standard reference treatment (PEgIFN + Ribavirin).

In Oncology:

• Immune support of cancer therapeutic vaccines;
  
  
• Immune support of various chemotherapies to clear residual disease.