High-Dose Recombinant Interleukin 2 Therapy for Patients With Metastatic Melanoma: Analysis of 270 Patients Treated Between 1985 and 1993

Atkins, Michael B.; Lotze, Michael T.; Dutcher, Janice P.; Fisher, Richard I.; Weiss, Geoffrey R.; Margolin, Kim; Abrams, Janet; Sznol, Mario; Parkinson, David; Hawkins, Michael; Paradise, Carolyn; Kunkel, Lori; Rosenberg, Steven A.

doi:10.1200/jco.1999.17.7.2105

Cited by 1,930 publications

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“…[13][14][15] Altogether, numerous clinical studies performed during the last decade showed that almost invariably 'cancer vaccines' yielded a modest clinical response rate (as measured by rigorous RECIST criteria) of no more than 5-10%. 16 Strikingly, though, most responses were quite durable 16 and in line with observations from studies using non-specific immune modulators such as recombinant interleukin-2 17 and anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibodies. 18,19 Previously, in an attempt to improve on the in vivo generation and amplification of TAA-specific T cells, we clinically evaluated the intra-lymph node administration of two individual plasmids encompassing either MART-1/Melan-A or tyrosinase antigen fragments in stage-III and IV melanoma patients with measurable disease.…”

Section: Introductionsupporting

confidence: 71%

Multivalent immunity targeting tumor-associated antigens by intra-lymph node DNA-prime, peptide-boost vaccination

et al. 2010

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Active immunotherapy of cancer has yet to yield effective therapies in the clinic. To evaluate the translatability of DNA-based vaccines we analyzed the profile of T-cell immunity by plasmid vaccination in a murine model, using transcriptome microarray analysis and flow cytometry. DNA vaccination resulted in specific T cells expressing low levels of co-inhibitory molecules (most notably PD-1), strikingly different from the expression profile elicited by peptide immunization. In addition, the T-cell response primed through this dual-antigen-expressing plasmid (MART-1/Melan-A and tyrosinase) translated into a substantial proliferation capacity and functional conversion to antitumor effector cells after tyrosinase and MART-1/Melan-A peptide analog boost. Furthermore, peptide boost rescued the immune response against the subdominant tyrosinase epitope. This immunization approach could be adapted to elicit potent immunity against multiple tumor antigens, resulting in a broader immune response that was more effective in targeting human tumor cells. Finally, this study sheds light on a novel mechanism of immune homeostasis through synchronous regulation of co-inhibitory molecules on T cells, highly relevant to heterologous prime boost approaches involving DNA vaccines as priming agents.

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Section: Introductionsupporting

confidence: 71%

Multivalent immunity targeting tumor-associated antigens by intra-lymph node DNA-prime, peptide-boost vaccination

et al. 2010

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“…Interpretation of the results was complicated by the fact that 13/14 responders also received high doses of interleukin-2, a drug known to have antitumor effects. 27 Marchand et al 28 observed regression of metastases in 7/25 patients treated with subcutaneous injections of an aqueous solution of a synthetic peptide derived from a protein encoded by the melanomaassociated gene MAGE-3 and presented in the context of HLA-A1. Nestle et al 29 treated 16 metastatic melanoma patients with a novel immunotherapy: autologous dendritic cells pulsed with either synthetic peptides or lysates of autologous melanoma tissue and then injected directly into the regional lymph node.…”

Section: Discussionmentioning

confidence: 99%

Treatment of metastatic melanoma with autologous, hapten‐modified melanoma vaccine: Regression of pulmonary metastases

et al. 2001

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Key words: melanoma; vaccine; immunotherapy; autologous; cyclophosphamideStudies performed and published over the past 30 years have made it clear that immunizing a tumor-bearing patient to his or her own tumor cells is exceedingly difficult. An appealing explanation for this difficulty is that tumor antigens are weakly immunogenic and often induce tolerance, i.e., paralysis of the immune response, rather than effective immunity. 1 Fortunately, advances in basic immunology have disclosed a number of ways of breaking immunologic tolerance. One way is the judicious use of cytotoxic drugs. In 1967, Maguire and Ettore 2 made the surprising discovery that administration of cyclophosphamide to animals prior to an immunization caused the cell-mediated immune response to be augmented rather than suppressed. We have shown that this phenomenon applies to cancer-bearing humans as well. Thus, the administration of low-dose (300 mg/m 2 ) cyclophosphamide prior to an immunization with autologous tumor cells greatly increased the development of cell-mediated immunity to those cells. 3 A second approach to circumventing tolerance is the use of haptens-small molecules that are incapable of inducing an immune response unless they are coupled to a larger molecule. Coupling of a hapten to a protein, i.e., hapten modification, often results in the induction of an immune response to the protein that would otherwise not be possible. For example, Weigle, 4 in a series of now classic experiments, immunized mice with hapten-modified thyroglobulin. This resulted in the induction of an immune response not only to the hapten-modified thyroglobulin, but also to unmodified, i.e., native, thyroglobulin and produced autoimmune thyroiditis. A similar phenomenon was observed more recently by Neurath et al. 5 They found that application of the hapten dinitrophenyl to the colonic mucosa of mice resulted in the development of an autoimmune colitis, similar to human ulcerative colitis. Initially, these mice developed cellular immunity to the haptenmodified mucosa. However, as the chemically modified mucosa cells were shed, a potent immune response to the normal, unmodified mucosa developed, which led to the autoimmune pathology.The immunologic basis of these interesting phenomena is now clear: there are T lymphocytes generated by immunization with hapten-modified cells that are reactive to both modified and unmodified cells. For example, class I MHC-restricted T-cell clones generated from mice immunized with TNP-modified syngeneic lymphocytes respond to MHC-associated, TNP-modified "self" peptides. Furthermore, some TNP-reactive clones respond to certain MHC-binding, unmodified peptides as well. 6 These observations in animal models provide a strong rationale for a human cancer vaccine consisting of autologous tumor cells modified with a hapten, DNP, preceded by the administration of low-dose cyclophosphamide. We have observed that administration of DNP vaccine to patients with metastatic melanoma induces a unique reaction-the development of inflamma...

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“…Early single-institutional and multi-institutional single-arm clinical trials of high-dose IL-2 in patients with metastatic melanoma revealed objective response rates of 16-17%, including a 6-7% complete response rate. 42,43 Further followup has shown 80-90% of complete responders remain alive 10-15 years later. 7 Durability and consistency of responses led to the FDA approval of IL-2 for metastatic melanoma in 1998.…”

Section: Literature Review and Analysismentioning

confidence: 99%

“…The mechanism of action for most immunotherapeutic agents remains incompletely understood, but these treatments are notable for their ability to produce a durable benefit in a subset of patients. 7,8 Ipilimumab has been associated with significant improvement in overall survival in the metastatic setting. 5,9 Immunotherapy requires special attention to several caveats.…”

Section: Introductionmentioning

confidence: 99%

“…Although therapeutic benefits can be durable, only a subset of patients respond. 7,8 In addition, unique adverse effects of immunotherapy, many of which relate to the induction of autoimmunity and pro-inflammatory-like states, 10 might limit eligibility or become challenges in clinical management. Recent studies suggest immunotherapy, particularly with ipilimu mab and related agents, might result in tumour regression over a prolonged time, based on the kinetics of establishing an effective host anti tumour immune response.…”

Section: Introductionmentioning

confidence: 99%

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The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma

et al. 2013

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| Immunotherapy is associated with durable clinical benefit in patients with melanoma. The goal of this article is to provide evidence-based consensus recommendations for the use of immunotherapy in the clinical management of patients with high-risk and advanced-stage melanoma in the USA. To achieve this goal, the Society for Immunotherapy of Cancer sponsored a panel of melanoma experts-including physicians, nurses, and patient advocates-to develop a consensus for the clinical application of tumour immunotherapy for patients with melanoma. The Institute of Medicine clinical practice guidelines were used as a basis for this consensus development. A systematic literature search was performed for high-impact studies in English between 1992 and 2012 and was supplemented as appropriate by the panel. This consensus report focuses on issues related to patient selection, toxicity management, clinical end points and sequencing or combination of therapy. The literature review and consensus panel voting and discussion were used to generate recommendations for the use of immunotherapy in patients with melanoma, and to assess and rate the strength of the supporting evidence. From the peer-reviewed literature the consensus panel identified a role for interferon-α2b, pegylated-interferon-α2b, interleukin-2 (IL-2) and ipilimumab in the clinical management of melanoma. Expert recommendations for how to incorporate these agents into the therapeutic approach to melanoma are provided in this consensus statement. Tumour immunotherapy is a useful therapeutic strategy in the management of patients with melanoma and evidence-based consensus recommendations for clinical integration are provided and will be updated as warranted.

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High-Dose Recombinant Interleukin 2 Therapy for Patients With Metastatic Melanoma: Analysis of 270 Patients Treated Between 1985 and 1993

Abstract: High-dose IL-2 treatment seems to benefit some patients with metastatic melanoma by producing durable CRs or PRs and should be considered for appropriately selected melanoma patients.

Cited by 1,930 publications

References 29 publications

Multivalent immunity targeting tumor-associated antigens by intra-lymph node DNA-prime, peptide-boost vaccination

Multivalent immunity targeting tumor-associated antigens by intra-lymph node DNA-prime, peptide-boost vaccination

Treatment of metastatic melanoma with autologous, hapten‐modified melanoma vaccine: Regression of pulmonary metastases

The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma

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