Interleukin 15 as a promising candidate for tumor immunotherapy

Jakóbisiak, Marek; Gołąb, Jakub; Lasek, Witold

doi:10.1016/j.cytogfr.2011.04.001

Cited by 111 publications

(105 citation statements)

References 167 publications

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“…Currently, the major function of IL-15 appears to focus on the generation, proliferation, and activation of NK cells and the support of the survival of CD8 þ memory T cells (7,8). Unlike IL-2, IL-15 rather inhibits activation-induced cell death (9) and seems not to exert crucial influence on regulatory T cells (10), important properties in view of an immunotherapeutic application.…”

Section: Introductionmentioning

confidence: 99%

An Antibody Fusion Protein for Cancer Immunotherapy Mimicking IL-15 trans-Presentation at the Tumor Site

Kermer

Baum²,

Hornig³

et al. 2012

Molecular Cancer Therapeutics

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Cytokines driving the immune response are powerful tools for cancer immunotherapy, but their application is generally limited by severe systemic toxicity. Targeted approaches by means of antibodycytokine fusion proteins might enable focus on the cytokine activity to the tumor site, thereby reducing unwanted side effects. Here, we investigated the possibility to improve the efficiency of interleukin (IL)-15 presentation in a targeted approach by the incorporation of an IL-15Ra chain fragment, mimicking physiologic trans-presentation. Therefore, an antibody cytokine fusion protein (scFv_RD_IL-15) composed of an antibody moiety targeting the tumor stromal fibroblast activation protein (FAP), an extended IL15Rasushi domain (RD) and IL-15 was generated, exhibiting antibody-mediated specific binding and cytokine activity in soluble and targeted form. Comparative analysis with a corresponding antibody fusion protein devoid of RD (scFv_IL-15) showed for scFv_RD_IL-15 in solution enhanced stimulatory activity on Mo7e (IL-15Rbg) cells and reduced proliferation response on CTLL-2 (IL-15Rabg) cells, while in FAPtargeted, that is, membrane-bound form, comparable proliferation of CTLL-2 (IL-15Rabg) cells was obtained. In addition, scFv_RD_IL-15 achieved in its soluble and target-bound form stronger proliferation and cytotoxicity on unstimulated and activated T cells, respectively. Furthermore, in vivo analysis in a lung metastasis tumor mouse model revealed a superior antitumor effect for scFv_RD_IL-15 in comparison with that obtained by an untargeted or RD missing version of IL-15 fusion protein. Thus, tumor-directed transpresentation of IL-15 in association with RD in form of an antibody fusion protein seems to be a promising approach to further improve the antitumor effect of IL-15.

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Section: Introductionmentioning

confidence: 99%

An Antibody Fusion Protein for Cancer Immunotherapy Mimicking IL-15 trans-Presentation at the Tumor Site

Kermer

Baum²,

Hornig³

et al. 2012

Molecular Cancer Therapeutics

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“…Obniżenie efektywności lub hamowanie mechanizmów zależnych od IL-6 i IFN-γ wiąże się m.in. ze spadkiem aktywności limfocytów T rozpoznających antygen, upośledzeniem różnicowania pobudzonych przez antygen limfocytów T w kierunku limfocytów cytotoksycznych Tc, zmniejszeniem aktywacji limfocytów Tc i komórek NK mających zdolność do bezpośredniego hamowania proliferacji komórek nowotworowych oraz działania cytolitycznego [46,47].…”

Section: Dyskusjaunclassified

“…hamowaniem ekspresji cząsteczek MHC klasy II na makrofagach, co prowadzi do zmniejszenia prezentacji antygenów nowotworowych, z hamowaniem powstawania limfocytów Th1 pobudzonych przez antygeny guza, blokowaniem działania limfocytów Th1 oraz makrofagów i wytwarzania przez nie cytokin, m.in. IFN-γ, IL-1α, IL-6, IL-8, IL-12 [46,47].…”

Section: Dyskusjaunclassified

“…poprzez wzmaganie proliferacji i różnicowania limfocytów B, para-i autokrynnego oddziaływania na monocyty i makrofagi, chemotaktycznego oddziaływania na makrofagi i neutrofile oraz mediację ich cytotoksyczności, zwiększenie właściwości fagocytarnych neutrofili oraz bezpośrednie działanie cytotoksyczne i antyproliferacyjne na komórki guza lub indukcję martwicy krwotocznej nowotworu dzięki działaniu prokoagulacyjnemu. Nie należy jednak wykluczać negatywnego działania TNF w zaawansowanym raku krtani poprzez zwiększanie ekspresji cząsteczek adhezyjnych ELAM-1 (endothelial-leukocyte adhesion molecule 1) i ICAM-1 (inter-cellular adhesion molecule 1), co może się przyczyniać do zwiększonego ryzyka inwazji nowotworowej i powstawania przerzutów [46,47]. Uzyskane w pracy wyniki oraz dane innych autorów przedstawione w dostępnym piśmien-nictwie, dotyczące wzajemnych związków między stężeniem generowanych cytokin a wykładnikami klasyfikacji TNM, nie zawsze są zbieżne.…”

Section: Dyskusjaunclassified

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Secretion of inflammatory and regulatory cytokines and the association with depth and type of tumour invasion in patients with cancer of the larynx

Starska¹,

Lewy-Trenda²,

Woś³

et al. 2010

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“…35,36 Thus, we hypothesized that a low day 7 IL15 level could be a surrogate of slow reconstitution of CD8 T cells or NK cells, which could be a result of a high ATG level. If this was true, we would expect a positive correlation between IL15 levels and CD8 T-cell or NK cell counts, and negative correlation between IL15 and ATG levels.…”

Section: Validation Cohortmentioning

confidence: 99%

IL15 levels on day 7 after hematopoietic cell transplantation predict chronic GVHD

Pratt

Liu

Ugarte-Torres

et al. 2012

Bone Marrow Transplant

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Chronic GVHD (cGVHD) is an important complication of allogeneic hematopoietic cell transplantation (HCT). As preemptive therapy might be efficacious if administered early post transplant, we set out to determine whether cGVHD can be predicted from the serum level of a biomarker on day 7 or 28. In a discovery cohort of 153 HCT recipients conditioned with BU, fludarabine and rabbit antithymocyte globulin (ATG), we determined serum levels of B-cell-activating factor, vascular endothelial growth factor, soluble TNF-a receptor 1, soluble IL2 receptor a, IL5, IL6, IL7, IL15, g-glutamyl transpeptidase, cholinesterase, total protein, urea and ATG. Patients with low levels of IL15 (o30.6 ng/L) on day 7 had 2.7-fold higher likelihood of developing significant cGVHD (needing systemic immunosuppressive therapy) than patients with higher IL15 levels (Po0.001). This was validated in a validation cohort of 105 similarly-treated patients; those with low IL15 levels had 3.7-fold higher likelihood of developing significant cGVHD (P ¼ 0.001). Low IL15 was not associated with relapse; it trended to be associated with acute GVHD and was associated with low infection rates. In conclusion, low IL15 levels on day 7 are predictive of cGVHD, and thus could be useful in guiding preemptive therapy.

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Interleukin 15 as a promising candidate for tumor immunotherapy

Cited by 111 publications

References 167 publications

An Antibody Fusion Protein for Cancer Immunotherapy Mimicking IL-15 trans-Presentation at the Tumor Site

An Antibody Fusion Protein for Cancer Immunotherapy Mimicking IL-15 trans-Presentation at the Tumor Site

Secretion of inflammatory and regulatory cytokines and the association with depth and type of tumour invasion in patients with cancer of the larynx

IL15 levels on day 7 after hematopoietic cell transplantation predict chronic GVHD

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