Activation of Human Effector Cells by a Tumor Reactive Recombinant Anti-Ganglioside Gd2 Interleukin-2 Fusion Protein

Hank, J. A.; Surfus, Jean E.; Gan, Jing; Jaeger, P; Gillies, Stephen D.; Reisfeld, R A; Pm, Sondel

doi:10.1097/00002371-199611000-00039

Cited by 35 publications

(45 citation statements)

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“…In contrast, Figure 2C shows that s.c. IC injected at a site on the flank away from the tumor had little antitumor effect on the tumor. Here, 1 of 3 animals receiving IT IC became tumor-free, while none of the 3 mice receiving s.c. IC in the flank showed tumor resolution (p = 0.04 for IT IC vs. s.c. IC, days [13][14][15][16]. This result suggests that the antitumor effect seen in the non-injected distant flank tumors following IT IC treatment of the primary tumor (Fig.…”

Section: It Ic Resulted In Antitumor Effects Against Both Primary Andmentioning

confidence: 87%

“…Figure 1B (Fig. 1C), treatment of s.c. NXS2 tumors with hu14.18-IL2 IC administered IT also resulted in significant antitumor effects compared to PBS-treated tumors (p < 0.0015, beginning on day 11), and enhanced antitumor effects compared to the same dose of hu14.18-IL2 IC given IV (p < 0.02, days [11][12][13][14][15][16][17][18]. In addition to significant differences in the mean calculated tumor volume based on caliper measurements of length and width (see Materials and Methods section), the IT IC-treated tumors also appeared visually flatter, with less elevation above the abdominal wall, compared to either PBS or IV IC-treated tumors.…”

Section: It Ic Resulted In Greater Antitumor Effects Than IV Icmentioning

confidence: 99%

“…This cell line was cultured in RPMI-1640 medium (Mediatech, Herndon, VA) with the same additives as described for NXS2 cells above. The GD 2 + M21 human melanoma cell line was also cultured in RPMI medium with the same additives as described above [15]. The MC-38.CEA cell line was generated by transfection of CEA into MC-38 cells as previouslydescribed, and cultured in RPMI media in the absence of antibiotics [7].…”

Section: Cell Linesmentioning

confidence: 99%

“…Our laboratories have been involved in the preclinical and clinical development of two ICs [39]: huKS-IL2, which consists of the humanized mAb huKS1/4 that recognizes epithelial cell adhesion molecule (EpCAM) and is linked to IL2; and hu14.18-IL2, which is an anti-disialoganglioside GD 2 mAb also linked to IL2. These ICs selectively bind tumor cells, activate IL2-responsive immune cells, and facilitate antibody dependent cell-mediated cytotoxicity (ADCC) by FcR + effector cells [15]. Both ICs were shown to activate a strong antitumor innate immune response involving NK cells that induced antimetastatic effects [18,23].…”

Section: Introductionmentioning

confidence: 99%

“…HuKS-IL2 IC recognizes B16-KSA melanoma, a subclone of the parental B16 cell line transfected with human EpCAM. Hu14.18-IL2 IC targets the GD 2 -expressing cells, including the murine NXS2 NB and human M21 melanoma [15,25]. The antitumor activity of IT hu14.18-IL2 was tested in a xenograft model consisting of human M21 melanoma tumors grown in nude mice.…”

Section: Introductionmentioning

confidence: 99%

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Intratumoral immunocytokine treatment results in enhanced antitumor effects

Johnson

Lum

Rakhmilevich

et al. 2008

Cancer Immunol Immunother

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Immunocytokines (IC), consisting of tumor-specific monoclonal antibodies fused to the immunostimulatory cytokine interleukin 2 (IL2), exert significant antitumor effects in several murine tumor models. We investigated whether intratumoral (IT) administration of IC provided enhanced antitumor effects against subcutaneous tumors. Three unique ICs (huKS-IL2, hu14.18-IL2, and GcT84.66-IL2) were administered systemically or IT to evaluate their antitumor effects against tumors expressing the appropriate IC-targeted tumor antigens. The effect of IT injection of the primary tumor on a distant tumor was also evaluated. Here, we show that IT injection of IC resulted in enhanced antitumor effects against B16-KSA melanoma, NXS2 neuroblastoma, and human M21 melanoma xenografts when compared to intravenous (IV) IC injection. Resolution of both primary and distant subcutaneous tumors, and a tumor-specific memory response were demonstrated following IT treatment in immunocompetent mice bearing NXS2 tumors. The IT effect of huKS-IL2 IC was antigen-specific, enhanced compared to IL2 alone, and dose-dependent. Hu14.18-IL2 also showed greater IT effects than IL2 alone. The antitumor effect of IT IC did not always require T cells since IT IC induced antitumor effects against tumors in both SCID and nude mice. Localization studies using radiolabeled 111 In-GcT84.66-IL2 IC confirmed that IT injection resulted in a higher concentration of IC at the tumor site than IV administration. In conclusion, we suggest that IT IC is more effective than IV administration against palpable tumors. Further testing is required to determine how to potentially incorporate IT administration of IC into an antitumor regimen that optimizes local and systemic anticancer therapy.

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Section: It Ic Resulted In Antitumor Effects Against Both Primary Andmentioning

confidence: 87%

Section: It Ic Resulted In Greater Antitumor Effects Than IV Icmentioning

confidence: 99%

Section: Cell Linesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Intratumoral immunocytokine treatment results in enhanced antitumor effects

Johnson

Lum

Rakhmilevich

et al. 2008

Cancer Immunol Immunother

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Two new trifunctional antibodies for the therapy of human malignant melanoma

Rosenberger

Jäger²,

Ellwart

et al. 2003

Intl Journal of Cancer

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Therapy‐induced antitumor vaccination in neuroblastomas by the combined targeting of IL‐2 and TNFα

Balza

Bárbara

Mortara

et al. 2010

Intl Journal of Cancer

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L19-IL2 and L19TNFa are fusion proteins composed of L19(scFv), specific for the angiogenesis-associated ED-B containing fibronectin isoform and IL-2 or TNFa. Because of the tumor targeting properties of L19, IL-2 and TNFa concentrate at therapeutic doses at the tumor vascular level. To evaluate the therapeutic effects of L19-IL2 and L19mTNFa in neuroblastoma (NB)-bearing mice, A/J mice bearing Neuro2A or NIE115 NB were systemically treated with L19-IL2 and L19mTNFa, alone or in combination protocols. Seventy percent of Neuro2A-and 30% of NIE115-bearing mice were cured by the combined treatment with L19-IL2 and L19mTNFa, and further rejected a homologous tumor challenge, indicating specific antitumor immune memory. The immunological bases of tumor cure and rejection were studied. A highly efficient priming of CD4 1 T helper cells and CD8 1 CTL effectors was generated, paralleled by massive infiltration in the tumor tissue of CD4 1 and CD8 1 T cells at day 16 after tumor cell implantation, when, after therapy, tumor volume was drastically reduced and tumor necrosis reached about 80%. The curative treatment resulted in a long-lasting antitumor immune memory, accompanied by a mixed Th1/Th2 type of response. Concluding, L19-IL2 and L19mTNFa efficiently cooperate in determining a high percentage of NB cure that, in our experimental models, is strongly associated to the generation of adaptive immunity involving CD4 1 and CD8 1 T cells.

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Activation of Human Effector Cells by a Tumor Reactive Recombinant Anti-Ganglioside Gd2 Interleukin-2 Fusion Protein

Cited by 35 publications

References 0 publications

Intratumoral immunocytokine treatment results in enhanced antitumor effects

Intratumoral immunocytokine treatment results in enhanced antitumor effects

Two new trifunctional antibodies for the therapy of human malignant melanoma

Therapy‐induced antitumor vaccination in neuroblastomas by the combined targeting of IL‐2 and TNFα

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