Should High-Dose Interleukin-2 Still Be the Preferred Treatment for Patients with Metastatic Melanoma?

Dillman, Robert O.; Barth, Neil M.; VanderMolen, Louis A.; Mahdavi, Khosrow; McClure, Stephanie E.

doi:10.1089/cbr.2012.1220

Cited by 21 publications

(17 citation statements)

References 35 publications

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“…The 20% 5-year survival rates from date of IL2 therapy in these studies suggested a benefit for a number of patients who had not obtained an objective response. 14,24 What is provocative about the current retrospective review is that patients, who received IL2 + ASI in the form of a TC or DC/TC vaccine, had a 5-year survival rate that was three times higher than patients who received only IL2, but the latter's 5-year survival rate of 13% is similar to the survival rate reported by various investigators for high-dose IL2 therapy. 15,[24][25][26] IL2 has been used as a standard therapy to treat melanoma ever since its regulatory approval for the treatment of metastatic renal cell cancer in 1992.…”

Section: Il2 Plus Active Specific Immunotherapy 55mentioning

confidence: 49%

“…Before availability of these agents, high-dose inpatient interleukin-2 (IL2) regimens were considered the treatment of choice in those patients who were physically fit enough for such therapy. 12,13 We documented a dramatic decline in the use of IL2 in the treatment of metastatic melanoma in recent years, 14 but also suggested that IL2 should still be the treatment of choice in patients who are medically fit enough for such treatment. This suggestion was based on the documentation of a surprisingly high 20% 5-year survival rate for 150 patients treated with inpatient IL2 regimens during 1987-2010, and the lack of long-term follow-up data for the newer therapies.…”

Section: Introductionmentioning

confidence: 99%

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High-Dose IL2 in Metastatic Melanoma: Better Survival in Patients Immunized with Antigens from Autologous Tumor Cell Lines

Dillman

DePriest

McClure

2014

Cancer Biotherapy and Radiopharmaceuticals

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Various published data show that in patients with metastatic melanoma, high-dose interleukin-2 (IL2) is associated with 5-year survival rates of 15% from treatment initiation. We previously reported a median survival of 15.6 months, and a 20% 5-year survival rate for 150 patients who were treated with inpatient IL2 (Cancer Biother Radiopharm 2012;27:337). In the current study, we sought to determine whether treatment with active specific immunotherapy (ASI) with patient-specific tumor stem cell vaccines derived from autologous tumor cell (TC) lines contributed to the survival result. Existing databases revealed that 32/149 IL2-treated patients also received ASI, while 117 did not. ASI was given within 12 months of IL2 therapy in 19/32 patients. Patients who received IL2 plus ASI had better overall survival (p<0.001) with longer median survival (39.5 vs. 12.0 months) and a higher 5-year survival rate (39% vs. 13%). Survival was better even after exclusion of 55 IL2-alone patients who died before 12 months of follow-up (p=0.12). In subset analyses, survival was longer for 25 patients who received ASI after IL2 than for 7 who received ASI before IL2 (5-year survival 46% vs. 14%, p<0.001) and for 16 patients who received a dendritic cell/TC-based ASI compared with 16 injected with irradiated TC (p=0.17). This retrospective study suggests that receipt of IL2 followed by a patient-specific melanoma stem cell vaccine is associated with better survival than IL2 alone.

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Section: Il2 Plus Active Specific Immunotherapy 55mentioning

confidence: 49%

Section: Introductionmentioning

confidence: 99%

High-Dose IL2 in Metastatic Melanoma: Better Survival in Patients Immunized with Antigens from Autologous Tumor Cell Lines

Dillman

DePriest

McClure

2014

Cancer Biotherapy and Radiopharmaceuticals

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“…However, in patients with metastatic melanoma, long term survival remains at less than 10% [2]. Traditional regimens including dacarbazine, temozolomide, high-dose interleukin-2 (IL-2), and paclitaxel with or without cisplatin or carboplatin have demonstrated only modest response rates (<20%) [3]. More recently, novel immunotherapeutic and targeted approaches have been developed and used in the treatment of metastatic melanoma, including ipilimumab, a monoclonal antibody directed against CTLA-4, and vemurafenib, a specific inhibitor of signaling by mutated BRAF [3], but both agents possess unique limitations.…”

Section: Introductionmentioning

confidence: 99%

“…Traditional regimens including dacarbazine, temozolomide, high-dose interleukin-2 (IL-2), and paclitaxel with or without cisplatin or carboplatin have demonstrated only modest response rates (<20%) [3]. More recently, novel immunotherapeutic and targeted approaches have been developed and used in the treatment of metastatic melanoma, including ipilimumab, a monoclonal antibody directed against CTLA-4, and vemurafenib, a specific inhibitor of signaling by mutated BRAF [3], but both agents possess unique limitations. Phase III trials with ipilimumab showed an overall response rate of less than 20% and revealed a serious potential for autoimmune toxicity, with immune-related events occurring in 60% of patients [4].…”

Section: Introductionmentioning

confidence: 99%

Folate-conjugated immunoglobulin targets melanoma tumor cells for NK cell effector functions

Skinner¹,

McMichael²,

Jaime-Ramirez³

et al. 2016

Melanoma Research

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The folate receptor (FR) is over-expressed on the vascular side of cancerous cells including those of the breast, ovaries, testes, and cervix. We hypothesized that a folate-conjugated immunoglobulin (F-IgG) would bind to the FR that is over-expressed on melanoma tumor cells to target these cells for lysis by natural killer (NK) cells. Folate receptor expression was confirmed in the Mel-39 (human melanoma) cell line by flow cytometry and immunoblot analysis, using KB (human oral epithelial) and F01 (human melanoma) as a positive and negative control, respectively. FR-positive and negative cell lines were treated with F-IgG or control immunoglobulin G (C-IgG) in the presence or absence of cytokines in order to determine NK cell ability to lyse FR-positive cell lines. NK cell activation was significantly upregulated and lysis of Mel 39 tumor cells enhanced following treatment with F-IgG, as compared to C-IgG at all effector:target (E:T) ratios (p<0.01). This trend was further enhanced by NK cell stimulation with the activating cytokine interleukin-12 (IL-12). NK cell production of cytokines such as interferon-gamma (IFN-γ), macrophage inflammatory protein 1 alpha (MIP-1α), and regulated on activation normal T-cell expressed and secreted (RANTES) were also significantly increased in response to co-stimulation with IL-12 stimulation and F-IgG-coated Mel 39 target cells, as compared to controls (p<0.01). In contrast, F-IgG did not bind to the FR-negative cell line F01 and had no significant effect on NK cell lysis or cytokine production. This research indicates the potential use of F-IgG for its ability to induce an immune response from NK cells against FR-positive melanoma tumor cells which can be further enhanced by the addition of cytokines.

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“…A smaller subset of patients respond to immunotherapy, such as systemic interleukin-2 (IL-2) therapy, interferon (IFN)- α or immune-modulating antibodies such as anti-CTLA-4 (ipilimumab) and anti-PD1(L). In contrast to targeted therapy, ∼70% of complete responders to IL-2 treatment display long-term regression and, in many cases, can be considered cured, emphasising the role of IL-2 and immunotherapy in melanoma treatment (Smith et al , 2008; Hodi et al , 2010; Coventry and Ashdown, 2012; Dillman et al , 2012; Simeone and Ascierto, 2012; Lipson et al , 2013). …”

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confidence: 99%

Low-dose inhalation of interleukin-2 bio-chemotherapy for the treatment of pulmonary metastases in melanoma patients

et al. 2014

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Background:Interleukin-2 (IL-2) treatment for patients with metastatic melanoma has shown remarkable durable responses. Systemic administration of IL-2 may cause severe side effects, whereas local administration is considered to be a safe alternative. The lungs are common sites of metastases in melanoma patients causing considerable respiratory problems. We sought to evaluate the potential antitumoral effect of a low-dose inhalative IL-2 (lh-IL-2) regimen for patients with melanoma lung metastases. In addition, we explored the prophylactic potential of Ih-IL-2 after surgical removal of lung metastases in a study carried out in an outpatient setting.Methods:Twenty patients with American Joint Committee on Cancer stage-IV (M1b and M1c) melanoma were enrolled in this study and treated with 3 × 3 million IU inhalative IL-2 q.d. together with monthly dacarbazine bolus injections. Five patients received lh-IL-2 after surgical resection of lung metastases to prevent recurrence of the disease (prophylaxis group, N=5). All other patients were enrolled in the treatment group (N=15). Clinical evaluations were carried out monthly and radiological follow-up was performed every third month.Results:Nine patients in the treatment group had a clinical benefit with partial regression (27%) or stable disease (33%). Four patients had progression of lung metastases (26.7%) and two patients were not evaluable (13.3%). In the prophylaxis group, none of the patients developed new lung metastases during lh-IL-2 therapy. The median follow-up period was 7.8 months in the treatment group and 25.7 months in the prophylaxis group. In the majority of patients, treatment was well tolerated.Conclusions:Low-dose IL-2 inhalation might offer an effective and safe treatment option for lung metastases in melanoma patients. In addition, lh-IL-2 may have a prophylactic potential to prevent recurrence in the lungs after pulmonary melanoma metastasectomy. Administration can easily be performed in an outpatient setting, thus offering an attractive treatment option.

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Should High-Dose Interleukin-2 Still Be the Preferred Treatment for Patients with Metastatic Melanoma?

Cited by 21 publications

References 35 publications

High-Dose IL2 in Metastatic Melanoma: Better Survival in Patients Immunized with Antigens from Autologous Tumor Cell Lines

High-Dose IL2 in Metastatic Melanoma: Better Survival in Patients Immunized with Antigens from Autologous Tumor Cell Lines

Folate-conjugated immunoglobulin targets melanoma tumor cells for NK cell effector functions

Low-dose inhalation of interleukin-2 bio-chemotherapy for the treatment of pulmonary metastases in melanoma patients

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