Interleukin-7 (IL-7) is a homeostatic cytokine for resting T cells with increasing serum and tissue levels during T cell depletion. In preclinical studies, IL-7 therapy exerts marked stimulating effects on T cell immune reconstitution in mice and primates. First-in-humanclinical studies of recombinant human IL-7 (rhIL-7) provided the opportunity to investigate the effects of IL-7 therapy on lymphocytes in vivo. rhIL-7 induced in vivo T cell cycling, bcl-2 up-regulation, and a sustained increase in peripheral blood CD4 + and CD8 + T cells. This T cell expansion caused a signifi cant broadening of circulating T cell receptor (TCR) repertoire diversity independent of the subjects ' age as naive T cells, including recent thymic emigrants (RTEs), expanded preferentially, whereas the proportions of regulatory T (T reg) cells and senescent CD8 + effectors diminished. The resulting composition of the circulating T cell pool more closely resembled that seen earlier in life. This profi le, distinctive among cytokines under clinical development, suggests that rhIL-7 therapy could enhance and broaden immune responses, particularly in individuals with limited naive T cells and diminished TCR repertoire diversity, as occurs after physiological (age), pathological (human immunodefi ciency virus), or iatrogenic (chemotherapy) lymphocyte depletion. . Effects of rhIL-7 therapy on circulating T cells and spleen. rhIL-7 was administered every other day on day 1 -14 (8 injections, indicated by tick marks on X axis), at 4 dose levels: 3 μ g/kg/d (dashed line with ᭹ ; n = 3); 10 μ g/kg/d (dotted line with ᭝ ; n = 3); 30 μ g/kg/d (dashed line with ٗ ; n = 5); and 60 μ g/kg/d (solid line with ᭺ ; n = 4). Mean value for each cohort ( ± the SEM) are plotted at the indicated time points. (A) The absolute lymphocyte count from complete blood counts (left) and fl ow cytometry -based frequency were used to determine circulating absolute CD3 + / CD4 + and CD3 + /CD8 + counts, absolute numbers ± the SEM (bottom graphs), and percent change in absolute numbers over baseline (top graphs) of the respective subsets shown on day 1 (total lymphocytes only), 7, 14, 21, and 28 for all treated subjects, as well as day 55 -90 for subjects treated with 30 or 60 μ g/kg/d. Baseline values represent the mean of four separate analyses performed in each subject within 2 wk before initiation of rhIL-7 therapy. (B) Spleen size: bidimensional product by CT scan obtained at the time points shown; percent changes from the pretherapy scan are plotted. (C -F ) Baseline (1 value obtained on day 0) and day 7, 14, 21, and 28 data points were generated for CD3 + /CD4 + (left) and CD3 + /CD8 + subsets (right). augments antitumor responses, leading to improved survival when combined with antitumor vaccines ( 21,22 ). The capacity for supranormal levels of IL-7 to augment T cell cycling in response to antigens with low affi nity for the TCR appears largely responsible for homeostatic peripheral expansion, which involves increased T cell proliferation to self-antigens during...

Key Points Donor-derived anti-CD19-CAR T cells cause regressions of refractory malignancies after allogeneic transplantation.

SummaryLymphopenia is a serious consequence of HIV infection and the administration of cancer chemotherapeutic agents. Although growth factors can be administered to patients to increase circulating neutrophils, there is no effective method to stimulate CD8 + lymphocyte production in humans, in vivo. This report is the first to describe the administration of recombinant interleukin-7 to humans and demonstrates the ability of this cytokine to mediate selective increases in CD4 + and CD8 + lymphocytes along with a decrease in the percentage of CD4 + T-regulatory cells. These studies suggest an important role for interleukin-7 in the treatment of patients with lymphopenia. Keywordsinterleukin-7; regulatory T cells; human lymphocytes; lymphopoiesis Interleukin (IL) 7 is a 17.5 kd cytokine produced by a variety of stromal cells, as well as by keratinocytes, dendritic cells, neurons, and endothelial cells but is not produced by lymphocytes. 1,2 The IL-7 receptor contains a unique 75 kd α chain and a γ chain shared with 4,7,9,15,and 21. Homeostatic control of lymphocyte levels in mice seems to be dependent on the cytokine, IL-7. IL-7 receptor knockout mice exhibit thymic atrophy, arrest of T-cell development at the double positive stage, and severe lymphopenia. 3 Administration of IL-7 to mice results in an increase in thymic emigrants, increases in B and T cells, and increased recovery of T cells after cyclophosphamide administration or after bone marrow transplantation. 4-7 Transgenic mice overexpressing IL-7 exhibit expansion of immature B cells and can develop lymphoproliferative disorders. 8,9In vitro studies have suggested a role for IL-7 in human immune function. The addition of IL-7 to neonatal human thymic cultures increases the number of immature and mature T cells. 10 A mutation in the IL-7 receptor α chain in humans leads to an unusual form of combined immunodeficiency disease characterized by severe T-cell defects but normal B cells and natural Reprints: Steven A. Rosenberg, MD, PhD, Surgery Branch, National Cancer Institute, National Institutes of Health, CRC, Room 3-3940, 10 Center Drive, Bethesda, MD 20892-1201 (e-mail: sar@nih.gov MATERIALS AND METHODS PatientsAll patients were treated in the Surgery Branch, National Cancer Institute in a protocol approved by the Institutional Review Board, NCI. Eleven patients had metastatic melanoma and one (patient 7, Table 1) had metastatic sarcoma. All patients were HLA-A*0201 + and had measurable disease. Eligibility criteria included creatinine <1.4 mg/dL, liver function enzymes <3 times the normal limit, absolute neutrophil count >1000/mm 3 , absolute lymphocyte count >200/mm 3 , platelet counts >100,000/mm 3 , and coagulation parameters <1.5 times the upper limit of normal. Patients were not eligible if they had any form of immunosuppressive disease or had resting blood pressure >140/90. IL-7IL-7 (CYT 99-007) was produced according to good manufacturing practice and supplied to the National Cancer Institute under a Cooperative Research and Development Agreeme...

Chronic active EBV disease (CAEBV) is

Purpose: Interleukin-7 (IL-7) has critical and nonredundant roles in T-cell development, hematopoiesis, and postdevelopmental immune functions as a prototypic homeostatic cytokine. Based on a large body of preclinical evidence, it may have multiple therapeutic applications in immunodeficiency states, either physiologic (immunosenescence), pathologic (HIV), or iatrogenic (postchemotherapy and posthematopoietic stem cell transplant), and may have roles in immune reconstitution or enhancement of immunotherapy. We report here on the toxicity and biological activity of recombinant human IL-7 (rhIL-7) in humans.Design: Subjects with incurable malignancy received rhIL-7 subcutaneously every other day for 2 weeks in a phase I interpatient dose escalation study (3, 10, 30, and 60 μg/kg/dose). The objectives were safety and dose-limiting toxicity determination, identification of a range of biologically active doses, and characterization of biological and, possibly, antitumor effects.Results: Mild to moderate constitutional symptoms, reversible spleen and lymph node enlargement, and marked increase in peripheral CD3 + , CD4 + , and CD8 + lymphocytes were seen in a dose-dependent and age-independent manner in all subjects receiving ≥10 μg/kg/dose, resulting in a rejuvenated circulating T-cell profile, resembling that seen earlier in life. In some subjects, rhIL-7 induced in the bone marrow a marked, transient polyclonal proliferation of pre-B cells showing a spectrum of maturation as well as an increase in circulating transitional B cells. Conclusion: This study shows the potent biological activity of rhIL-7 in humans over a well-tolerated dose range and allows further exploration of its possible therapeutic applications.