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Phase II trial of the regulatory T cell-depleting agent, denileukin diftitox, in patients with unresectable stage IV melanoma.

Telang S, Rasku MA, Clem AL, Carter K, Klarer AC, Badger WR, Milam RA, Rai SN, Pan J, Gragg H, Clem BF, McMasters KM, Miller DM, Chesney J - BMC Cancer (2011)

Bottom Line: We previously found that administration of an interleukin 2/diphtheria toxin conjugate (DAB/IL2; Denileukin Diftitox; ONTAK) to stage IV melanoma patients depleted CD4(+)CD25(HI)Foxp3(+) regulatory T cells and expanded melanoma-specific CD8(+) T cells.Importantly, 45.5% of the chemo/immuno-naïve sub-population (11/60 patients) experienced partial responses.One year survival was markedly higher in partial responders (80 ± 11.9%) relative to patients with progressive disease (23.7 ± 6.5%; p value < 0.001) and 40 ± 6.2% of the total DAB/IL2-treated population were alive at 1 year.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molecular Targets Program, James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA.

ABSTRACT

Background: We previously found that administration of an interleukin 2/diphtheria toxin conjugate (DAB/IL2; Denileukin Diftitox; ONTAK) to stage IV melanoma patients depleted CD4(+)CD25(HI)Foxp3(+) regulatory T cells and expanded melanoma-specific CD8(+) T cells. The goal of this study was to assess the clinical efficacy of DAB/IL2 in an expanded cohort of stage IV melanoma patients.

Methods: In a single-center, phase II trial, DAB/IL2 (12 μg/kg; 4 daily doses; 21 day cycles) was administered to 60 unresectable stage IV melanoma patients and response rates were assessed using a combination of 2-[(18)F]-fluoro-2-deoxy-glucose (FDG)-positron emission tomography (PET) and computed tomography (CT) imaging.

Results: After DAB/IL2 administration, 16.7% of the 60 patients had partial responses, 5% stable disease and 15% mixed responses. Importantly, 45.5% of the chemo/immuno-naïve sub-population (11/60 patients) experienced partial responses. One year survival was markedly higher in partial responders (80 ± 11.9%) relative to patients with progressive disease (23.7 ± 6.5%; p value < 0.001) and 40 ± 6.2% of the total DAB/IL2-treated population were alive at 1 year.

Conclusions: These data support the development of multi-center, randomized trials of DAB/IL2 as a monotherapy and in combination with other immunotherapeutic agents for the treatment of stage IV melanoma.

Trial registration: NCT00299689.

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Related in: MedlinePlus

Durable responses after DAB/IL2 administration. On the left, baseline anterior/posterior views of FDG-PET imaging reveal multiple FDG-avid melanoma metastases in three clinical examples: A, 78 year-old female; B, 47 year-old male; and C, 62 year-old male. After DAB/IL2 administration, we observed a clinically significant and durable reduction in tumor burden, including hepatic metastases, pulmonary nodules, metatastic lymph nodes and subcutaneous nodules in all three patient examples.
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Figure 2: Durable responses after DAB/IL2 administration. On the left, baseline anterior/posterior views of FDG-PET imaging reveal multiple FDG-avid melanoma metastases in three clinical examples: A, 78 year-old female; B, 47 year-old male; and C, 62 year-old male. After DAB/IL2 administration, we observed a clinically significant and durable reduction in tumor burden, including hepatic metastases, pulmonary nodules, metatastic lymph nodes and subcutaneous nodules in all three patient examples.

Mentions: We observed several examples of partial and mixed responses which are typical of immunotherapeutic agents. For example, an 82 year-old male developed multiple hepatic metastases (red box, second panel; Figure 1A) and a large duodenal mass (red arrow, first panel, Figure 1A) which caused significant nausea, vomiting and weight loss. After four cycles of DAB/IL2, he experienced the complete regression of his hepatic metastases confirmed by FDG-PET imaging and resolution of his symptoms but only a modest reduction in his duodenal mass (compare Baseline to +4 Months, Figure 1A; the increased 18 F-FDG uptake in the left kidney is due to hydronephrosis which is unrelated to melanoma). Next, an 83 year-old male received three cycles of DAB/IL2 and experienced marked regression of a large subcutaneous mass, a pelvic mass (Figure 1B, see bottom 2 horizontal red arrows just above the bladder [which normally contains tracer]) and a peritoneal mass (Figure 1B, right vertical arrow). Simultaneously, a large conglomeration of left axillary masses expanded (Figure 1B, dashed circle), paratracheal lymph nodes worsened (Figure 1B, upper arrows) and a peritoneal mass appeared and expanded with treatment (Figure 1B, left vertical arrow). This is a typical clinical example of a mixed response to DAB/IL2. A 78 year-old female experienced a dramatic reduction in metastases involving the liver, lung and bone that has persisted for 15 months with the exception of a single small right paratracheal lymph node (Figure 2A). A 47 year-old male who had previously progressed through high dose IL-2, biochemotherapy and several experimental agents also had a marked global reduction in hepatic, lung and subcutaneous metastatic burden (Figure 2B). As a final clinical example, a 62 year-old male who progressed after receiving anti-CTLA4 and experienced debilitating right upper quadrant pain, nausea/vomiting and fatigue associated with widespread hepatic metastases experienced a substantial partial response that was durable for at least 15 months (Figure 2C). These examples of partial but durable clinical responses to DAB/IL2 are suggestive of an immunotherapeutic mechanism of action for DAB/IL2.


Phase II trial of the regulatory T cell-depleting agent, denileukin diftitox, in patients with unresectable stage IV melanoma.

Telang S, Rasku MA, Clem AL, Carter K, Klarer AC, Badger WR, Milam RA, Rai SN, Pan J, Gragg H, Clem BF, McMasters KM, Miller DM, Chesney J - BMC Cancer (2011)

Durable responses after DAB/IL2 administration. On the left, baseline anterior/posterior views of FDG-PET imaging reveal multiple FDG-avid melanoma metastases in three clinical examples: A, 78 year-old female; B, 47 year-old male; and C, 62 year-old male. After DAB/IL2 administration, we observed a clinically significant and durable reduction in tumor burden, including hepatic metastases, pulmonary nodules, metatastic lymph nodes and subcutaneous nodules in all three patient examples.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3293785&req=5

Figure 2: Durable responses after DAB/IL2 administration. On the left, baseline anterior/posterior views of FDG-PET imaging reveal multiple FDG-avid melanoma metastases in three clinical examples: A, 78 year-old female; B, 47 year-old male; and C, 62 year-old male. After DAB/IL2 administration, we observed a clinically significant and durable reduction in tumor burden, including hepatic metastases, pulmonary nodules, metatastic lymph nodes and subcutaneous nodules in all three patient examples.
Mentions: We observed several examples of partial and mixed responses which are typical of immunotherapeutic agents. For example, an 82 year-old male developed multiple hepatic metastases (red box, second panel; Figure 1A) and a large duodenal mass (red arrow, first panel, Figure 1A) which caused significant nausea, vomiting and weight loss. After four cycles of DAB/IL2, he experienced the complete regression of his hepatic metastases confirmed by FDG-PET imaging and resolution of his symptoms but only a modest reduction in his duodenal mass (compare Baseline to +4 Months, Figure 1A; the increased 18 F-FDG uptake in the left kidney is due to hydronephrosis which is unrelated to melanoma). Next, an 83 year-old male received three cycles of DAB/IL2 and experienced marked regression of a large subcutaneous mass, a pelvic mass (Figure 1B, see bottom 2 horizontal red arrows just above the bladder [which normally contains tracer]) and a peritoneal mass (Figure 1B, right vertical arrow). Simultaneously, a large conglomeration of left axillary masses expanded (Figure 1B, dashed circle), paratracheal lymph nodes worsened (Figure 1B, upper arrows) and a peritoneal mass appeared and expanded with treatment (Figure 1B, left vertical arrow). This is a typical clinical example of a mixed response to DAB/IL2. A 78 year-old female experienced a dramatic reduction in metastases involving the liver, lung and bone that has persisted for 15 months with the exception of a single small right paratracheal lymph node (Figure 2A). A 47 year-old male who had previously progressed through high dose IL-2, biochemotherapy and several experimental agents also had a marked global reduction in hepatic, lung and subcutaneous metastatic burden (Figure 2B). As a final clinical example, a 62 year-old male who progressed after receiving anti-CTLA4 and experienced debilitating right upper quadrant pain, nausea/vomiting and fatigue associated with widespread hepatic metastases experienced a substantial partial response that was durable for at least 15 months (Figure 2C). These examples of partial but durable clinical responses to DAB/IL2 are suggestive of an immunotherapeutic mechanism of action for DAB/IL2.

Bottom Line: We previously found that administration of an interleukin 2/diphtheria toxin conjugate (DAB/IL2; Denileukin Diftitox; ONTAK) to stage IV melanoma patients depleted CD4(+)CD25(HI)Foxp3(+) regulatory T cells and expanded melanoma-specific CD8(+) T cells.Importantly, 45.5% of the chemo/immuno-naïve sub-population (11/60 patients) experienced partial responses.One year survival was markedly higher in partial responders (80 ± 11.9%) relative to patients with progressive disease (23.7 ± 6.5%; p value < 0.001) and 40 ± 6.2% of the total DAB/IL2-treated population were alive at 1 year.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molecular Targets Program, James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA.

ABSTRACT

Background: We previously found that administration of an interleukin 2/diphtheria toxin conjugate (DAB/IL2; Denileukin Diftitox; ONTAK) to stage IV melanoma patients depleted CD4(+)CD25(HI)Foxp3(+) regulatory T cells and expanded melanoma-specific CD8(+) T cells. The goal of this study was to assess the clinical efficacy of DAB/IL2 in an expanded cohort of stage IV melanoma patients.

Methods: In a single-center, phase II trial, DAB/IL2 (12 μg/kg; 4 daily doses; 21 day cycles) was administered to 60 unresectable stage IV melanoma patients and response rates were assessed using a combination of 2-[(18)F]-fluoro-2-deoxy-glucose (FDG)-positron emission tomography (PET) and computed tomography (CT) imaging.

Results: After DAB/IL2 administration, 16.7% of the 60 patients had partial responses, 5% stable disease and 15% mixed responses. Importantly, 45.5% of the chemo/immuno-naïve sub-population (11/60 patients) experienced partial responses. One year survival was markedly higher in partial responders (80 ± 11.9%) relative to patients with progressive disease (23.7 ± 6.5%; p value < 0.001) and 40 ± 6.2% of the total DAB/IL2-treated population were alive at 1 year.

Conclusions: These data support the development of multi-center, randomized trials of DAB/IL2 as a monotherapy and in combination with other immunotherapeutic agents for the treatment of stage IV melanoma.

Trial registration: NCT00299689.

Show MeSH
Related in: MedlinePlus