A Randomised, Multicentric, Phase 2a Study Evaluating the Impact of an Immunotherapy by IL-7 on CD4 Lymphopenia, Risks of Severe Haematological Toxicity and Tumor Progression in Metastatic Breast Cancer Patients

The purpose of the study is to evaluate the impact of an immunotherapy by IL-7 on CD4 lymphopenia, risks of severe haematological toxicity and tumor progression in metastatic breast cancer patients.
The primary objective is to determine the optimal schedule to deliver CYT107 during chemotherapy based on restoration of CD4 count.
This study is a phase II, randomised, double-blind, placebo-controlled, single-centre.
24 patients will be included in the study.

开始日期2011-06-01

申办/合作机构

Centre Léon Bérard Lyon et Rhône-Alpes

[+1]

NCT01241643 / Terminated临床2期

A Multicenter, Open-labeled, Controlled, Randomized Study of Recombinant Interleukin-7 (CYT107) Treatment to Restore and Maintain CD4 T-lymphocyte Counts Above 500 Cells/µL in HIV-infected Patients With CD4 Counts Remaining Between 101-350 Cells/µL After at Least 2 Years of HAART and Plasma HIV RNA < 50 Copies/mL for 18 Months.

This is a Phase II multicenter, open-labeled, controlled, randomized study assessing weekly doses of Interleukin-7 (CYT107)

开始日期2010-09-01

申办/合作机构

Cytheris SA

NCT01019551 / Completed临床2期IIT

International, Multicenter, Randomized, Non-comparative Controlled Study of Therapeutic Intensification Plus Immunomodulation in HIV-infected Patients With Long-term Viral Suppression

Viral eradication in selected HIV-infected patients is possible with intensive antiretroviral therapy plus immunomodulation

开始日期2010-09-01

申办/合作机构

Pfizer Inc.

[+2]

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2008-07-07·The Journal of Experimental Medicine1区 · 医学

Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets

1区 · 医学

Article

作者: Chow, Catherine K. ; Korngold, Robert ; Brown, Margaret R. ; Hakim, Frances T. ; Chua, Kevin S. ; Fry, Terry J. ; Gress, Ronald E. ; Krumlauf, Michael C. ; Pecora, Andrew ; Babb, Rebecca R. ; Venzon, David J. ; Fleisher, Thomas A. ; Engels, Julie ; Zhang, Hua ; Amato, Robert J. ; Mackall, Crystal L. ; Buffet, Renaud ; Memon, Sarfraz A. ; Morre, Michel ; Sportès, Claude

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-human clinical 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 significant 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 profile, 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 immunodeficiency virus), or iatrogenic (chemotherapy) lymphocyte depletion.

2007-07-10·Proceedings of the National Academy of Sciences1区 · 综合性期刊

Expression of IL-7 receptor α is necessary but not sufficient for the formation of memory CD8 T cells during viral infection

1区 · 综合性期刊

Article

作者: Hand, Timothy W. ; Morre, Michel ; Kaech, Susan M.

During many acute viral and bacterial infections, IL-7 receptor α-chain (IL-7Rα) is expressed on a subset of effector CD8 T cells that preferentially develop into long-lived memory CD8 T cells. These cells functionally require IL-7Rα, but it is unclear whether IL-7Rα acts mainly to induce their differentiation into memory cells or to sustain their long-term survival. To examine this question, IL-7Rα was constitutively overexpressed on all antigen-specific effector CD8 T cells during viral infection. Constitutive IL-7Rα expression had minimal effects on the numbers or function of effector and memory CD8 T cells formed. This indicated that IL-7Rα expression is not sufficient to drive memory cell development. In particular, the forced IL-7Rα expression did not rescue the killer cell lectin-like receptor G1 (KLRG1) hi short-lived effector CD8 T cells from death, showing that the majority of effector CD8 T cells die in an IL-7Rα-independent manner. Moreover, we found that, regardless of the ectopic expression of IL-7Rα, the KLRG1 hi , but not the KLRG1 lo effector CD8 T cells, were unable to proliferate well to IL-7, which may be due to increased amounts of p27 kip in KLRG1 hi cells. Because IL-7 can destabilize p27 kip , this result suggested that KLRG1 hi and KLRG1 lo effector CD8 T cells naturally differ in their ability to transmit IL-7 signals. Altogether, these results reveal that IL-7Rα expression is permissive, but not instructive, to the creation of memory CD8 T cells.

2006-11-16·Blood

IL7 Administration in Humans Results in Preferential Expansion of Naive and Memory CD4+ & CD8+ T Cells with a Relative Decrease in Regulatory T-Cells (T-Regs).

作者: Fry, Terry ; Foruraghi, Ladan ; Buffet, Renaud ; Fleisher, Thomas ; Daub, Janine ; Gress, Ronald ; Chua, Kevin ; Brown, Margaret ; Krumlauf, Michael ; Sportes, Claude ; Zhang, Hua ; Morre, Michel ; Chow, Catherine ; Mackall, Crystal ; Engel, Julie ; Memon, Sarfraz ; Babb, Rebecca ; Avila, Daniele ; Hakim, Frances

AbstractInterleukin-7 (IL7) is a multifunctional cytokine with critical and non-redundant roles in T-cell development, T-lymphopoiesis and peripheral T-cell homeostasis. We report preliminary results of the first phase I study of recombinant human IL7, “CYT 99-007” (rhIL7). Adults with incurable malignancy (11 men and 3 women), 20–71 years old (median 48) received escalating doses (3, 10, 30 or 60 μg/kg/dose) subcutaneously every other day for 2 weeks.IL7 was overall well tolerated with no Maximum Tolerated Dose yet reached. Dose-dependent and age independent biological effects consistent with murine and non-human primate pre-clinical models were observed in all patients receiving 10 μg/Kg/dose or more: enlargement of spleen and lymph nodes (but not thymus) by CT scan and marked proliferation and expansion of T-cells subsets. Increases in CD4+ and CD8+ T-cells were most prominent in naïve T-cells (CD27+CD45RA+), including Recent Thymic Emigrants (RTE) (CD4+/CD45RA+/CD31+) with a mean 6-fold expansion, and in memory T-cells (CD27+CD45RA−) but less so in effector T-cells (CD27−). Furthermore, IL7 therapy resulted in a decline in the relative frequency of T-regs (50–80% decline in FoxP3 mRNA copies normalized to Actin mRNA copies in sorted CD4+ T-cells).Although the magnitude of biological effects was variable, the kinetics were similar in all T-cell subsets and at all effective doses. After one week of therapy at 30μg/ Kg /dose, 30–70% of naïve CD4+ and CD8+ T-cells were in cycle (Ki-67+) and expressed elevated levels of Bcl-2. Bcl-2 up-regulation (maintained at week 2) and high proliferation rates resulted in T-cell expansion (mean of 6- and up to 14-fold in some individuals at the 30μg dose) persisting one to several weeks after treatment. Consistent with animal data, we observed IL7 receptor α-chain (IL7Rα) down-regulation: both IL7Rα mean fluorescent intensity by flow cytometry (CD127) and mRNA copy numbers declined more than 50% at one week. By the end of treatment, proliferation rates were halved and down to baseline by week 3, coincident with recovery of IL7Rα expression after cessation of treatment. The T-cell increase was primarily due to IL7 induced peripheral expansion. There was no dilution effect of T-Cell Receptor Excision Circles (TREC) numbers per 105 CD4+ sorted cells which suggests cell recruitment or expansion, consistent with preclinical data but does not exclude a thymic contribution.rhIL7 is safe at biologically active doses in humans and induces an expansion of naïve (including RTE) and memory T-cells. In contrast to IL2, IL7’s role in T-regs homeostasis appears to be minimal. rhIL7 may prove clinically valuable in adoptive immunotherapy as an immuno-restorative agent in conditions of disease (HIV) or chemotherapy induced T-cell depletion or as an adjunct to tumor vaccination for immune response modulation.

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