Limits...
Phase I/II open-label study of the biologic effects of the interleukin-2 immunocytokine EMD 273063 (hu14.18-IL2) in patients with metastatic malignant melanoma.

Ribas A, Kirkwood JM, Atkins MB, Whiteside TL, Gooding W, Kovar A, Gillies SD, Kashala O, Morse MA - J Transl Med (2009)

Bottom Line: Treatment was generally well tolerated and there were no study drug-related grade 4 adverse events.Grade 3 events were mainly those associated with IL2, most commonly rigors (3 patients) and pyrexia (2 patients).EMD 273063 demonstrated biologic activity with increased immune-related cytokines and intratumoral changes in some patients consistent with the suspected mechanism of action of this immunocytokine.

View Article: PubMed Central - HTML - PubMed

Affiliation: University of California, 11-934 Factor Building, UCLA Medical Center, Los Angeles, CA 90095-1782, USA. aribas@mednet.ucla.edu

ABSTRACT

Background: To explore the biological activity of EMD 273063 (hu14.18-IL2), a humanized anti-GD2 monoclonal antibody fused to interleukin-2 (IL2), in patients with unresectable, stage IV cutaneous melanoma as measured by induction of immune activation at the tumor site and in peripheral blood.

Methods: Nine patients were treated with 4 mg/m2 per day of EMD 273063 given as a 4-h intravenous infusion on days 1, 2, and 3 every four weeks (one cycle). Peripheral blood was analyzed for T cell and natural killer cell phenotype and frequency, as well as levels of soluble IL2 receptor (sIL2R), IL10, IL6, tumor necrosis factor alpha and neopterin. Biopsies of tumor metastasis were performed prior to therapy and at day 10 of the first 2 cycles to study lymphocyte accumulation by immunohistochemistry.

Results: Treatment was generally well tolerated and there were no study drug-related grade 4 adverse events. Grade 3 events were mainly those associated with IL2, most commonly rigors (3 patients) and pyrexia (2 patients). Best response on therapy was stable disease in 2 patients. There were no objective tumor regressions by standard response criteria. Systemic immune activation was demonstrated by increases in serum levels of sIL2R, IL10, and neopterin. There was evidence of increased tumor infiltration by T cells, but not NK cells, in most post-dosing biopsies, suggesting recruitment of immune cells to the tumor site.

Conclusion: EMD 273063 demonstrated biologic activity with increased immune-related cytokines and intratumoral changes in some patients consistent with the suspected mechanism of action of this immunocytokine.

Show MeSH

Related in: MedlinePlus

Serum cytokine concentrations and immunohistochemical analysis of tumor biopsies. C = cycle. D = day. A, B, C: Serum concentrations of sIL2R (A), neopterin (B) and IL10 (C) before, during, and after infusions of EMD 273063. Serum samples were drawn before the first infusion (C1D1), during the first cycle infusion (C1D2 and C1D3) and then immediately before (C2D1) and during the second cycle of EMD 273063 (C2D2, C2D3). Depicted are the serum concentrations for each patient tested by ELISA. D: Immunohistochemical analysis of a pre-dosing and cycle 1 post-dosing tumor biopsies from patient 4104, who had disease stabilization over two cycles. Paraffin-fixed melanoma tumor specimens stained by immunohistochemistry for GD2, S100, and CD8 positive prior to and after exposure to EMD 273063.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2724499&req=5

Figure 2: Serum cytokine concentrations and immunohistochemical analysis of tumor biopsies. C = cycle. D = day. A, B, C: Serum concentrations of sIL2R (A), neopterin (B) and IL10 (C) before, during, and after infusions of EMD 273063. Serum samples were drawn before the first infusion (C1D1), during the first cycle infusion (C1D2 and C1D3) and then immediately before (C2D1) and during the second cycle of EMD 273063 (C2D2, C2D3). Depicted are the serum concentrations for each patient tested by ELISA. D: Immunohistochemical analysis of a pre-dosing and cycle 1 post-dosing tumor biopsies from patient 4104, who had disease stabilization over two cycles. Paraffin-fixed melanoma tumor specimens stained by immunohistochemistry for GD2, S100, and CD8 positive prior to and after exposure to EMD 273063.

Mentions: Exploration of biologic changes in post-dosing serum samples compared with baseline results demonstrated 3 parameters with statistically significant treatment-associated increases in the omnibus test: sIL2R (adjusted p < 0.0001), neopterin (adjusted p < 0.0003) and IL10 (adjusted p = 0.0345) (Figure 2A, B, C and Table 3). There were no changes in serum levels of S100 and IL6. There were also no significant changes in the frequency of CD4+ and CD8+ T cell subsets, NK cell number, NK activity, and ADCC between pre- and post-dosing blood cell samples. There was no difference between the 2 patients (0004–4101, 0004–4104) with stable disease who received 4 cycles of therapy and the 7 patients who progressed early with respect to changes in any of the parameters examined.


Phase I/II open-label study of the biologic effects of the interleukin-2 immunocytokine EMD 273063 (hu14.18-IL2) in patients with metastatic malignant melanoma.

Ribas A, Kirkwood JM, Atkins MB, Whiteside TL, Gooding W, Kovar A, Gillies SD, Kashala O, Morse MA - J Transl Med (2009)

Serum cytokine concentrations and immunohistochemical analysis of tumor biopsies. C = cycle. D = day. A, B, C: Serum concentrations of sIL2R (A), neopterin (B) and IL10 (C) before, during, and after infusions of EMD 273063. Serum samples were drawn before the first infusion (C1D1), during the first cycle infusion (C1D2 and C1D3) and then immediately before (C2D1) and during the second cycle of EMD 273063 (C2D2, C2D3). Depicted are the serum concentrations for each patient tested by ELISA. D: Immunohistochemical analysis of a pre-dosing and cycle 1 post-dosing tumor biopsies from patient 4104, who had disease stabilization over two cycles. Paraffin-fixed melanoma tumor specimens stained by immunohistochemistry for GD2, S100, and CD8 positive prior to and after exposure to EMD 273063.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2724499&req=5

Figure 2: Serum cytokine concentrations and immunohistochemical analysis of tumor biopsies. C = cycle. D = day. A, B, C: Serum concentrations of sIL2R (A), neopterin (B) and IL10 (C) before, during, and after infusions of EMD 273063. Serum samples were drawn before the first infusion (C1D1), during the first cycle infusion (C1D2 and C1D3) and then immediately before (C2D1) and during the second cycle of EMD 273063 (C2D2, C2D3). Depicted are the serum concentrations for each patient tested by ELISA. D: Immunohistochemical analysis of a pre-dosing and cycle 1 post-dosing tumor biopsies from patient 4104, who had disease stabilization over two cycles. Paraffin-fixed melanoma tumor specimens stained by immunohistochemistry for GD2, S100, and CD8 positive prior to and after exposure to EMD 273063.
Mentions: Exploration of biologic changes in post-dosing serum samples compared with baseline results demonstrated 3 parameters with statistically significant treatment-associated increases in the omnibus test: sIL2R (adjusted p < 0.0001), neopterin (adjusted p < 0.0003) and IL10 (adjusted p = 0.0345) (Figure 2A, B, C and Table 3). There were no changes in serum levels of S100 and IL6. There were also no significant changes in the frequency of CD4+ and CD8+ T cell subsets, NK cell number, NK activity, and ADCC between pre- and post-dosing blood cell samples. There was no difference between the 2 patients (0004–4101, 0004–4104) with stable disease who received 4 cycles of therapy and the 7 patients who progressed early with respect to changes in any of the parameters examined.

Bottom Line: Treatment was generally well tolerated and there were no study drug-related grade 4 adverse events.Grade 3 events were mainly those associated with IL2, most commonly rigors (3 patients) and pyrexia (2 patients).EMD 273063 demonstrated biologic activity with increased immune-related cytokines and intratumoral changes in some patients consistent with the suspected mechanism of action of this immunocytokine.

View Article: PubMed Central - HTML - PubMed

Affiliation: University of California, 11-934 Factor Building, UCLA Medical Center, Los Angeles, CA 90095-1782, USA. aribas@mednet.ucla.edu

ABSTRACT

Background: To explore the biological activity of EMD 273063 (hu14.18-IL2), a humanized anti-GD2 monoclonal antibody fused to interleukin-2 (IL2), in patients with unresectable, stage IV cutaneous melanoma as measured by induction of immune activation at the tumor site and in peripheral blood.

Methods: Nine patients were treated with 4 mg/m2 per day of EMD 273063 given as a 4-h intravenous infusion on days 1, 2, and 3 every four weeks (one cycle). Peripheral blood was analyzed for T cell and natural killer cell phenotype and frequency, as well as levels of soluble IL2 receptor (sIL2R), IL10, IL6, tumor necrosis factor alpha and neopterin. Biopsies of tumor metastasis were performed prior to therapy and at day 10 of the first 2 cycles to study lymphocyte accumulation by immunohistochemistry.

Results: Treatment was generally well tolerated and there were no study drug-related grade 4 adverse events. Grade 3 events were mainly those associated with IL2, most commonly rigors (3 patients) and pyrexia (2 patients). Best response on therapy was stable disease in 2 patients. There were no objective tumor regressions by standard response criteria. Systemic immune activation was demonstrated by increases in serum levels of sIL2R, IL10, and neopterin. There was evidence of increased tumor infiltration by T cells, but not NK cells, in most post-dosing biopsies, suggesting recruitment of immune cells to the tumor site.

Conclusion: EMD 273063 demonstrated biologic activity with increased immune-related cytokines and intratumoral changes in some patients consistent with the suspected mechanism of action of this immunocytokine.

Show MeSH
Related in: MedlinePlus