Radiofrequency thermal ablation of breast tumors combined with intralesional administration of IL-7 and IL-15 augments anti-tumor immune responses and inhibits tumor development and metastasis

Habibi, Mehran; Kmieciak, Maciej; Graham, Lisa; Morales, Johanna K.; Bear, Harry D.; Manjili, Masoud H.

doi:10.1007/s10549-008-0024-3

Cited by 60 publications

(66 citation statements)

References 35 publications

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“…In contrast, IL-15 is less toxic than IL-2, inhibits activation-induced cell death, and stimulates the persistence of memory CD8 + T cells, appearing therefore as a better alternative than IL-2 in the treatment of cancer and as a component of vaccines directed to cancer (20,39). Its potential use as a cancer immunotherapeutic agent has already been suggested in several mouse cancer models (10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Its interest as adjuvant for enhancing the effect of chemotherapeutic agents and adoptive cell therapy on transplanted tumors has been widely established, but its therapeutic potential on its own was found limited, one of the reason being, as described for IL-2, its poor pharmacokinetics in vivo (21,22).…”

Section: Discussionmentioning

confidence: 99%

“…Daily administration of IL-15 prolonged the period of remission induced by cyclophosphamide in mice bearing rhabdomyosarcoma (15). In a 4T1 mammary carcinoma mouse model, coadministration of intralesional IL-7 and IL-15 following radiofrequency thermal ablation of tumor inhibited tumor development and lung metastasis (16). IL-15 protected against toxicity and potentiated the antitumor activity of 5-fluorouracil and irinotecan in rats bearing colorectal cancer (17,18).…”

Section: Introductionmentioning

confidence: 99%

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High antitumor activity of RLI, an interleukin-15 (IL-15)–IL-15 receptor α fusion protein, in metastatic melanoma and colorectal cancer

Bessard

Solé

Bouchaud

et al. 2009

Molecular Cancer Therapeutics

118

102

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Interleukin (IL)-15 has an important role in tumor immunosurveillance and has a contemplated use in tumor immunotherapy. We have previously engineered the fusion protein RLI, composed of the NH 2 -terminal (amino acids 1-77, sushi+) domain of IL-15 receptor α coupled via a linker to IL-15, and shown that it displayed far better efficacy than IL-15 in vitro. In this report, we investigated in vivo whether RLI would be a better alternative than IL-15 and IL-2 for cancer treatment using two distinct animal models. B16F10 mouse melanoma cells were injected in C57BL/6 mice either i.v. or intrasplenically for lung or liver metastasis, respectively. HCT-116 human colorectal cancer cells were injected in the cecum of nude mice. We show that RLI has a higher efficiency than IL-15 or IL-2 to reduce lung and liver metastasis and enhance survival in the mouse B16F10 melanoma model, a result that was associated with a higher half-life in vivo. We also found that the antitumoral effect of RLI was completely abolished by in vivo depletion of natural killer cells using anti-asialoGM1 antibody. Moreover, RLI was also efficient to reduce by 50% tumor growth and the progression of metastasis of human colon carcinoma cells in an orthotopic nude mouse model. The fusion protein RLI has revealed strong anticancer effect in two different cancer models overcoming the limited effect of IL-15 by increasing its bioavailability and efficiency. These findings hold significant importance for the use of RLI as a potential adjuvant/therapeutic. [Mol Cancer Ther 2009;8(9):2736-45]

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

High antitumor activity of RLI, an interleukin-15 (IL-15)–IL-15 receptor α fusion protein, in metastatic melanoma and colorectal cancer

Bessard

Solé

Bouchaud

et al. 2009

Molecular Cancer Therapeutics

118

102

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“…On the other hand, improved therapeutic effects could be achieved by the combination of IL-15 with other immunomodulatory approaches, for example, cytokines (IL-21, IL-7, IL-12; refs. 6,15,16), agonistic anti-CD40 mAb (17), or inhibitory checkpoint blockers (anti-CTLA-4 mAb, anti-PD-L1 mAb; ref. 18).…”

Section: Introductionmentioning

confidence: 99%

Combining Antibody-Directed Presentation of IL-15 and 4-1BBL in a Trifunctional Fusion Protein for Cancer Immunotherapy

Kermer

Hornig

Harder

et al. 2014

Molecular Cancer Therapeutics

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Influencing the cytokine receptor network that modulates the immune response holds great potential for cancer immunotherapy. Although encouraging results have been obtained by focusing on individual members of the common g-chain (gc) receptor family and TNF receptor superfamily so far, combination strategies might be required to further improve the effectiveness of the antitumor response. Here, we propose the combination of interleukin (IL)-15 and 4-1BBL in a single, tumor-directed molecule. Therefore, a trifunctional antibody fusion protein was generated, composed of a tumor-specific recombinant antibody, IL-15 linked to a fragment of the IL-15Ra chain (RD) and the extracellular domain of 4-1BBL. In soluble and targeted forms, the trifunctional antibody fusion protein RD_IL-15_scFv_4-1BBL was shown to stimulate activated T-cell proliferation and induce T-cell cytotoxicity to a similar degree as the bifunctional scFv_RD_IL-15 fusion protein. On the other hand, in targeted form, the trifunctional fusion protein was much more effective in inducing T-cell proliferation and IFN-g release of unstimulated peripheral blood mononuclear cells (PBMC). Here, the additional signal enhancement could be attributed to the costimulatory activity of 4-1BBL, indicating a clear benefit for the simultaneous presentation of IL-15 and 4-1BBL in one molecule. Furthermore, the trifunctional antibody fusion protein was more effective than the corresponding bifunctional fusion proteins in reducing metastases in a tumor mouse model in vivo. Hence, the targeted combination of IL-15 and 4-BBL in the form of a trifunctional antibody-fusion protein is a promising new approach for cancer immunotherapy.

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“…MDSCs have also been reported to accumulate in many murine cancer models including EL-4 thymoma, Lewis lung carcinoma (3LL), B16-F10 melanoma, DA3 mammary carcinoma, CT26 colon carcinoma, MethA sarcoma, neuoverexpressing mouse mammary carcinoma (MMC), and 4T1 mammary carcinoma [20][21][22][23]. These murine MDSCs are typically described as CD11b ?…”

Section: Introductionmentioning

confidence: 99%

Serum inhibits the immunosuppressive function of myeloid-derived suppressor cells isolated from 4T1 tumor-bearing mice

Hamilton

Banáth

Lam

et al. 2011

Cancer Immunol Immunother

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As more groups investigate the role of myeloid-derived suppressor cells (MDSCs) in promoting the growth of primary tumors and distant tumor metastases, it is imperative to ensure the accurate detection and quantification of MDSC immunosuppression ex vivo. MDSCs are defined by their ability to suppress immune responses. Although different in vitro culture conditions have been used to study MDSCs, the effect of different culture conditions on MDSC immunosuppression is unknown. We therefore isolated MDSCs from the lungs and spleens of 4T1 murine mammary tumor-bearing mice and assayed MDSC-mediated suppression of T cell responses under different culture conditions. We found that 4T1-induced MDSCs effectively suppressed T cell proliferation under serum-free conditions, but not when fetal calf serum (FCS) was present. FCS neither altered the immunosuppressive activities of other myeloid cell types (i.e., peritoneal or tumor-associated macrophages) nor modified the susceptibility of T cells to myeloid cell-mediated suppression, but instead acted directly on 4T1-induced MDSCs to significantly reduce their immunosuppressive function. Importantly, we found that bovine serum albumin was a major contributor to the antagonistic effects of FCS on 4T1-induced MDSC immunosuppression by inhibiting reactive oxygen species production from MDSCs. This work reveals that in vitro culture conditions influence the immunosuppressive properties of MDSCs and highlights the importance of testing different culture conditions on MDSC phenotype to ensure that MDSC immunosuppression is not being masked. These data have important implications for the accurate detection and identification of MDSCs, as well as for determining the influence of MDSC-mediated immunosuppression on primary and metastatic tumor growth.

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Radiofrequency thermal ablation of breast tumors combined with intralesional administration of IL-7 and IL-15 augments anti-tumor immune responses and inhibits tumor development and metastasis

Cited by 60 publications

References 35 publications

High antitumor activity of RLI, an interleukin-15 (IL-15)–IL-15 receptor α fusion protein, in metastatic melanoma and colorectal cancer

High antitumor activity of RLI, an interleukin-15 (IL-15)–IL-15 receptor α fusion protein, in metastatic melanoma and colorectal cancer

Combining Antibody-Directed Presentation of IL-15 and 4-1BBL in a Trifunctional Fusion Protein for Cancer Immunotherapy

Serum inhibits the immunosuppressive function of myeloid-derived suppressor cells isolated from 4T1 tumor-bearing mice

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