Patients with the acquired immune deficiency syndrome (AIDS) are highly susceptible to the development of fatal infection and cancer. If the durability of responses to highly active anti-retroviral therapy (HAART) is limited, then alternative or complementary therapeutic measures directed toward the preservation of immune competence will need to be considered to prevent fatal infection and/or malignant transformation. In the case of preventing systemic HIV lymphoma, such strategies appear necessary even with effective HAART. We have designed a novel strategy to modulate a component of the innate immune system (natural killer or NK cells) and to modulate the cytokine gene profile in patients with AIDS and AIDS malignancies. We believe this trial to be the first of its kind in the world, and it is based largely on studies performed in our laboratory and our clinic over the last seven years. We identified co-expression of the receptor tyrosine kinase c-kit and the interleukin (IL)-2 receptor on lymphocytes, and demonstrated functional synergy following the binding of their respective ligands, stem cell factor (SCF) and IL-2. We demonstrated the synergy of SCF plus low dose IL-2 in inducing expansion of human NK cells in vitro from CD34+ hematopoietic stem cells, compared to either SCF or IL-2 alone, followed by a similar demonstration in an in vivo animal model. We performed studies of low dose IL-2 alone in patients with AIDS and AIDS malignancies, along with correlative laboratory studies. We are now poised to assess the safety, feasibility, and immunomodulatory effects of administering a combination of SCF and IL-2 to patients with AIDS and AIDS malignancy. This application seeks support to perform correlative laboratory studies to assess the cytokine gene profile in vivo, and the phenotype and function of hematopoietic stem cells, T cells, and NK cells before, during and after patients receive IL-2 alone or SCF and IL-2 in a Phase I IRB-approved outpatient study. The overall objective of this application is to characterize the immunologic consequences of this innate immune modulation to better understand how to compensate for antigen-specific immune deficiency.
| Shah, Manisha H; Freud, Aharon G; Benson Jr, Don M et al. (2006) A phase I study of ultra low dose interleukin-2 and stem cell factor in patients with HIV infection or HIV and cancer. Clin Cancer Res 12:3993-6 |
