Recombinant human interleukin-7 (CYT107) enhances CD4 and CD8 T cell recovery following T-Cell depleted allogeneic hematopoietic stem cell transplant in patients with myeloid malignancies Meeting Abstract

Authors: Perales, M. A.; Goldberg, J. D.; Lechner, L.; Yuan, J.; Papadopoulos, E.; Young, J. W.; Jakubowski, A. A.; Koehne, G.; Gallardo, H.; Kendle, R.; Liu, C.; Rasalan, T.; Xu, Y.; Zaidi, B.; Wolchok, J. D.; Croughs, T.; Morre, M.; Maloy, M.; Heller, G.; van den Brink, M. R. M.
Abstract Title: Recombinant human interleukin-7 (CYT107) enhances CD4 and CD8 T cell recovery following T-Cell depleted allogeneic hematopoietic stem cell transplant in patients with myeloid malignancies
Meeting Title: 52nd Annual Meeting of the American Society of Hematology (ASH)
Abstract: Immune recovery is an important determinant in multiple outcomes following allogeneic hematopoietic stem cell transplant (allo-HSCT). Delays in B and T cell reconstitution are associated with an increased risk of infection, relapse and secondary malignancy. Strategies to enhance post-transplant T-cell reconstitution could therefore improve morbidity and mortality after allo-HSCT. The cytokine Interleukin-7 (IL-7) is a unique therapeutic candidate to promote immune reconstitution because it has a central role in T cell development and survival. Murine models of allo-HSCT have demonstrated that IL-7 can enhance thymopoiesis as well as promote peripheral T cell survival and expansion. Initial clinical trials performed with recombinant human IL-7 (rhIL-7) have demonstrated a dose-dependent expansion of CD4+ and CD8+ T cells with an acceptable toxicity profile in Patients With solid tumors or HIV infection. Hence we are conducting a phase I trial of post-transplant administration of rhIL-7 (CYT107, Cytheris Inc) in recipients of a T cell depleted (TCD) allo-HSCT to determine the safety, toxicity and biological activity on T Cell reconstitution. To date, 9 patients (AML=7, MDS=2), with a median age of 59.3 years (range 27-67 years) have been treated with escalating doses of rhIL-7 (3 at 10 mcg/kg, 6 at 20 mcg/kg) administered subcutaneously weekly for 3 weeks following TCD allo-HSCT from an HLA compatible donor. Accrual is ongoing in the final cohort (30 mcg/kg). Recombinant hIL-7 Was started at a median of 96 days post allo-HSCT (range 61-244 days). Most patients experienced transient minor injection site reactions. One patient (20 mcg/kg) developed a biopsy proven hypersensitivity drug rash a week after the first injection and was removed from the study (evaluable for toxicity but dot immune recovery endpoints): No other significant injection-related toxicities have occurred, and no patients have developed GVHD. No anti-IL-7 antibodies or neutralizing antibodies have developed following rhIL-7 injection. Two of 9 patients with high-risk AML have relapsed (4 and 9 months post rhIL-7), an incidence consistent with published data in patients undergoing allo-HSCT for AML in CR, irrespective of T-cell depletion. Eight patients remain alive With a median follow-up of 14.5 months post rhIL-7 administration. At baseline, the median T cell counts were 91/mm(3) (range 5 - 219/mm(3)), 43/mm(3) (range 9 - 299/mm(3)) and 0 (range 0 - 17/mm(3)) for CD4+, CD8+ and CD45RA+ T cells, respectively. Preliminary assessment of the immunological effects of rhIL-7 in 8 evaluable patients has demonstrated an increase in CD4+ T cells exhibiting a halve or central memory phenotype (69% median increase over baseline at day 21 - range 8% to 35-fold increase), and CD8+ T cells exhibiting a naive or effector memory phenotype (94% median increase over baseline at day 28 - range 0 to 11-fold increase). There was no,observed effect on the frequency of CD4+CD25+FoxP3+ T cells or CD19+ B cells. TCR excision circles (TREC) analysis performed on CD4+ and CD8+ subsets in the first 6 patients, using absolute quantification real-time PCR, demonstrated increases in TRECs in 5/6 patients indicating enhanced T cell. production. Finally, all 3 CMV-seropositive patients developed CD8+ T cell CMV-specific responses detected by intracellular. IFN gamma production to overlapping CMV-pp65 pentadecapeptides peptide pools after administration Of rhIL-7.In one patient, we also analyzed CMV-specific T-cell frequency using HLA-A*0201 restricted MC-tetramers. The highest CMV-specific response levels were noted in this patient with a history of CMV viremia and low-level CMV-specific CD8+ T cells prior to rhIL-7 (5.3-fold increase to the A0201-restricted immunodominant NLV peptide by tetramer assay after rhIL-7). Our pre-clinical data and early clinical results suggest that administration of rhIL-7 in recipients of a TCD allo-HSCT has minimal toxicity and can enhance post-transplant immune recovery without causing GVHD.
Keywords: memory phenotype; cell reconstitution
Journal Title: Blood
Volume: 116
Issue: 21
Meeting Dates: 2010 Dec 4-7
Meeting Location: Orlando, FL
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2010-11-19
Start Page: 296
Language: English
PROVIDER: biosis
PUBMED: 22276300
Notes: --- - Meeting Abstract: 674 - 52nd Annual Meeting of the American-Society-of-Hematology (ASH) - Orlando, FL, USA - December 04 -07, 2010 - Amer Soc Hematol - "Source: Biosis"