Abstract
The selective delivery of bioactive agents to tumors reduces toxicity and enhances the efficacy of anticancer therapies. In this study, we show that the antibody F8, which recognizes perivascular and stromal EDA-fibronectin (EDA-Fn), when conjugated to interleukin-2 (F8-IL2) can effectively inhibit the growth of EDA-Fn-expressing melanomas in combination with paclitaxel. We obtained curative effects with paclitaxel administered before the immunocytokine. Coadministration of paclitaxel increased the uptake of F8 in xenografted melanomas, enhancing tumor perfusion and permeability. Paclitaxel also boosted the recruitment of F8-IL2-induced natural killer (NK) cells to the tumor, suggesting a host response as part of the observed therapeutic benefit. In support of this likelihood, NK cell depletion impaired the antitumor effect of paclitaxel plus F8-IL2. Importantly, this combination reduced both the tumor burden and the number of pulmonary metastatic nodules. The combination did not cause cumulative toxicity. Together, our findings offer a preclinical proof that by acting on the tumor stroma paclitaxel potentiates the antitumor activity elicited by a targeted delivery of IL2, thereby supporting the use of immunochemotherapy in the treatment of metastatic melanoma.
| Original language | English |
|---|---|
| Pages (from-to) | 1814-1824 |
| Number of pages | 11 |
| Journal | Cancer Research |
| Volume | 72 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - Apr 1 2012 |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
Paclitaxel enhances therapeutic efficacy of the F8-IL2 immunocytokine to EDA-fibronectin-positive metastatic human melanoma xenografts. / Moschetta, Michele; Pretto, Francesca; Berndt, Alexander; Galler, Kerstin; Richter, Petra; Bassi, Andrea; Oliva, Paolo; Micotti, Edoardo; Valbusa, Giovanni; Schwager, Kathrin; Kaspar, Manuela; Trachsel, Eveline; Kosmehl, Hartwig; Bani, Maria Rosa; Neri, Dario; Giavazzi, Raffaella.
In: Cancer Research, Vol. 72, No. 7, 01.04.2012, p. 1814-1824.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Paclitaxel enhances therapeutic efficacy of the F8-IL2 immunocytokine to EDA-fibronectin-positive metastatic human melanoma xenografts
AU - Moschetta, Michele
AU - Pretto, Francesca
AU - Berndt, Alexander
AU - Galler, Kerstin
AU - Richter, Petra
AU - Bassi, Andrea
AU - Oliva, Paolo
AU - Micotti, Edoardo
AU - Valbusa, Giovanni
AU - Schwager, Kathrin
AU - Kaspar, Manuela
AU - Trachsel, Eveline
AU - Kosmehl, Hartwig
AU - Bani, Maria Rosa
AU - Neri, Dario
AU - Giavazzi, Raffaella
PY - 2012/4/1
Y1 - 2012/4/1
N2 - The selective delivery of bioactive agents to tumors reduces toxicity and enhances the efficacy of anticancer therapies. In this study, we show that the antibody F8, which recognizes perivascular and stromal EDA-fibronectin (EDA-Fn), when conjugated to interleukin-2 (F8-IL2) can effectively inhibit the growth of EDA-Fn-expressing melanomas in combination with paclitaxel. We obtained curative effects with paclitaxel administered before the immunocytokine. Coadministration of paclitaxel increased the uptake of F8 in xenografted melanomas, enhancing tumor perfusion and permeability. Paclitaxel also boosted the recruitment of F8-IL2-induced natural killer (NK) cells to the tumor, suggesting a host response as part of the observed therapeutic benefit. In support of this likelihood, NK cell depletion impaired the antitumor effect of paclitaxel plus F8-IL2. Importantly, this combination reduced both the tumor burden and the number of pulmonary metastatic nodules. The combination did not cause cumulative toxicity. Together, our findings offer a preclinical proof that by acting on the tumor stroma paclitaxel potentiates the antitumor activity elicited by a targeted delivery of IL2, thereby supporting the use of immunochemotherapy in the treatment of metastatic melanoma.
AB - The selective delivery of bioactive agents to tumors reduces toxicity and enhances the efficacy of anticancer therapies. In this study, we show that the antibody F8, which recognizes perivascular and stromal EDA-fibronectin (EDA-Fn), when conjugated to interleukin-2 (F8-IL2) can effectively inhibit the growth of EDA-Fn-expressing melanomas in combination with paclitaxel. We obtained curative effects with paclitaxel administered before the immunocytokine. Coadministration of paclitaxel increased the uptake of F8 in xenografted melanomas, enhancing tumor perfusion and permeability. Paclitaxel also boosted the recruitment of F8-IL2-induced natural killer (NK) cells to the tumor, suggesting a host response as part of the observed therapeutic benefit. In support of this likelihood, NK cell depletion impaired the antitumor effect of paclitaxel plus F8-IL2. Importantly, this combination reduced both the tumor burden and the number of pulmonary metastatic nodules. The combination did not cause cumulative toxicity. Together, our findings offer a preclinical proof that by acting on the tumor stroma paclitaxel potentiates the antitumor activity elicited by a targeted delivery of IL2, thereby supporting the use of immunochemotherapy in the treatment of metastatic melanoma.
UR - http://www.scopus.com/inward/record.url?scp=84859402603&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84859402603&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-11-1919
DO - 10.1158/0008-5472.CAN-11-1919
M3 - Article
C2 - 22392081
AN - SCOPUS:84859402603
VL - 72
SP - 1814
EP - 1824
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 7
ER -