Phase II Trial of Recombinant Tumor Necrosis Factor in Disseminated Malignant Melanoma

Feldman, Erik; Creagan, Edward T.; Schaid, D. J.; Ahmann, David L.

doi:10.1097/00000421-199206000-00015

Cited by 27 publications

(8 citation statements)

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“…IFN and TNF-␣ are known to cause transient changes in blood cell counts as a result of margination. 40,[43][44][45][46][47] A previous study by Merrigan et al, 30 using single doses (from 10 6 to 10 8 PFU/patient) of Newcastle disease virus, orders of magnitude below the doses tested in this trial, verified a dose-dependent induction of IFN in the serum of 17 patients along with fever and a transient leukopenia. In the present study, these transient hematologic changes were induced by the first dose of PV701.…”

Section: Discussionmentioning

confidence: 71%

Phase I Trial of Intravenous Administration of PV701, an Oncolytic Virus, in Patients With Advanced Solid Cancers

Pecora

Rizvi

Cohen

et al. 2002

JCO

343

330

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Section: Discussionmentioning

confidence: 71%

Phase I Trial of Intravenous Administration of PV701, an Oncolytic Virus, in Patients With Advanced Solid Cancers

Pecora

Rizvi

Cohen

et al. 2002

JCO

343

330

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“…This simultaneous release of a broad array of cytokines suggested a unique pattern of NK cell activation in response to IL-12 plus trastuzumab that could be induced in a subset of cancer patients. As single agents, neither interferon ␥ nor TNF-␣ have demonstrated significant antitumor activity in the Phase I/II setting (33,34). In the case of TNF-␣, significant toxicity has been encountered even in good risk patients.…”

Section: Discussionmentioning

confidence: 99%

A Phase I Study of Interleukin 12 with Trastuzumab in Patients with Human Epidermal Growth Factor Receptor-2-Overexpressing Malignancies

Parihar¹,

Nadella

Lewis³

et al. 2004

Clinical Cancer Research

105

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Purpose: On the basis of preclinical studies, we hypothesized that interleukin (IL)12 would potentiate the antitumor actions of an antihuman epidermal growth factor receptor-2 (HER2) monoclonal antibody (trastuzumab). We conducted a Phase I trial to determine the safety and optimal biological dose of IL-12 when given in combination with trastuzumab.Patients and Methods: Patients with metastatic HER2-positive malignancies received trastuzumab on day 1 of each weekly cycle. Beginning in week 3, patients also received intravenous injections of IL-12 on days 2 and 5. The IL-12 component was dose-escalated within cohorts of 3 patients (30, 100, 300, or 500 ng/kg). Correlative assays were conducted using serum samples and peripheral blood cells obtained during the course of therapy.Results: Fifteen patients were treated, including 12 with HER2 2؉ or 3؉ breast cancer. The regimen was well tolerated with IL-12-induced grade 1 nausea and grade 2 fatigue predominating. Evaluation of dose-limiting toxicity and biological end points suggested that the 300 ng/kg dose was both the maximally tolerated dose and the optimal biological dose of IL-12 for use in combination with trastuzumab. Two patients with HER2 3؉ breast cancer within the 500 ng/kg dose level experienced grade 1 asymptomatic decreases in left ventricular ejection fraction of 12% and 19% after 3 and 10 months of therapy, respectively. There was one complete response in a patient with HER2 3؉ breast cancer metastatic to the axillary, mediastinal, and supraclavicular nodes, and 2 patients with stabilization of bone disease lasting 10 months and >12 months, respectively. Correlative assays showed sustained production of interferon ( Conclusions: The addition of IL-12 to trastuzumab therapy did not appear to enhance the efficacy of this antibody treatment. Sustained production of IFN-␥ and other cytokines were observed in three patients: One who exhibited a complete response and two others who had stabilization of disease lasting over 6 months. Given the small sample size and heterogeneity of the patient population, the effects of IL-12 on the innate immune response to trastuzumab therapy should be further explored in the context of a larger clinical trial.

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“…Clinical trials by combinatory administration of TNF-α and other cytokines were tested [89]. Septic shock and thrombocytopenia were major limiting factors for its clinical application and no apparent antitumor effects were observed after systemic administration [90,91], although local application of TNF-α into metastatic foci may be beneficial [92].…”

Section: Mechanism Of Anti-tumor Effectmentioning

confidence: 99%

Cytokine Therapy for Cancer

Tagawa

2000

CPD

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Modulation of immune responses by the use of recombinant cytokines or cytokine genes is one of the strategies for cancer therapy. Although host immune responses are complex and many kinds of cells are involved, crucial steps for enhancing anti-tumor responses can be induced by a single or a few cytokines administered. However, cytokines may induce toxic reactions or produce no substantial effects, when the concentration is inappropriate. Administration of recombinant cytokine(s) has advantages in controlling the blood concentration and the biological activity that can be induced by the cytokine. Since cytokines are relatively unstable in vivo, cancer patients have to receive a large amount of the recombinant protein to maintain the required blood concentration for biological activity. Administration of the protein is thereby often toxic to the patients. In contrast, secretion of the cytokine from tumor or vehicle cells by gene transfer is another therapeutic maneuver. Previous preclinical studies have shown that cytokines which facilitate type 1 helper T (Th1) cells-mediated immune reactions but not Th2 cells-mediated reactions, when produced in tumors, are effective for anti-tumor responses. Several technical problems to express sufficient amounts of cytokines in appropriate target cells remain unresolved but the potential of cytokine gene therapy is being explored. Cytokine therapy trials also contributes to our present knowledge of how anti-tumor responses can be effectively produced in cancer patients, shedding the light on the generation of tumor-specific immunity in the patients.

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Phase II Trial of Recombinant Tumor Necrosis Factor in Disseminated Malignant Melanoma

Cited by 27 publications

References 0 publications

Phase I Trial of Intravenous Administration of PV701, an Oncolytic Virus, in Patients With Advanced Solid Cancers

Phase I Trial of Intravenous Administration of PV701, an Oncolytic Virus, in Patients With Advanced Solid Cancers

A Phase I Study of Interleukin 12 with Trastuzumab in Patients with Human Epidermal Growth Factor Receptor-2-Overexpressing Malignancies

Cytokine Therapy for Cancer

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