A Dose-Escalation Study of Aerosolized Sargramostim in the Treatment of Metastatic Melanoma

Abstract

Objectives-Early testing of aerosolized sargramostim therapy demonstrated anecdotal clinical responses in patients with metastatic melanoma associated with emergence of systemic anti-tumor immunity. In order to improve the clinical and immunological efficacy of therapy without compromising patient safety, we performed a further dose escalation trial in patients with metastatic melanoma.Methods-We conducted a dose-escalation clinical trial of HLA-A2 + patients with metastatic melanoma to the lung treated with aerosolized GM-CSF (500-2000ug/dose, with increments of 250ug/dose/cohort) twice/day on days 1-7 & 15-21 every 28 days until progression or severe toxicity to find a dose where majority of patients develop anti-tumor immunity. Five patients were treated per each dose level. Clinical, immune, and safety parameters were examined.Results-The study accrued 40 patients. Toxicity was acceptable. All doses levels were exhausted without identifying a dose of GM-CSF at which majority of patients (≥ 3 of 5) demonstrated significant up-regulation of anti-tumor immunity. Three of 16 patients that were tetramer positive for at least one melanoma antigen (e.g. MART-1) pre-treatment developed an immune response (IR) to different tumor antigens. Two of 9 patients who were tetramer negative to all melanoma antigens pre-treatment developed an IR against gp100. The greatest changes in anti-tumor immunity occurred at the highest dose levels.Conclusions-A dose of aerosolized GM-CSF capable of inducing anti-tumor immunity in the majority of patients was not reached. All tested doses were well tolerated. The greatest increase in anti-tumor T cell immune responses was achieved at the highest doses of GM-CSF.

Inhaled Granulocyte/Macrophage–Colony Stimulating Factor as Therapy for Pulmonary Alveolar Proteinosis

“…GM-CSF inhalation therapy did not increase serum levels of GM-CSF autoantibody, which is of importance to the autoimmune basis of the disorder in patients with the common autoimmune form of the syndrome (2). Our results are supported by other studies indicating the safety of inhaled GM-CSF therapy in humans (28,29). A small decrease in neutrophil counts was observed during treatment but counts remained within the normal range.…”

Inhaled Granulocyte-Macrophage Colony Stimulating Factor for First Pulmonary Recurrence of Osteosarcoma: Effects on Disease-Free Survival and Immunomodulation. A Report From the Children's Oncology Group

“…Overall survival was similar to that described in multiple previous studies (1-6, 8, 9.). Our study again provided proof of principle that inhalation therapy for malignancy is a feasible and non-toxic route of administration of GM-CSF, which has shown some activity in other human tumor models (27). Doses of GM-CSF of 1750 μg twice daily however have not been previously administered to pediatric and adolescent patients.…”

“…However, no GM-CSF dose was capable of inducing antitumor immunity in the majority of patients. However, 5 patients developed an immune response to one or more melanoma specific antigens (27). …”

Latest Approved Therapies for Metastatic Melanoma: What Comes Next?

“…Indeed, a previous investigation (NCCTG study) has consisted to perform a dose-escalation clinical trial with aerosolized sargramostim in HLA-A2 patients with metastatic melanoma to the lung ( n = 40). The data showed that the toxicity was acceptable for all tested doses and the greatest increase in antitumor T-cell immune responses was achieved at the highest doses [77]. Then, a hypothesis-generating study was conducted to evaluate the safety and efficacy of prolonged administration of sargramostim as surgical adjuvant therapy in patients with melanoma at high risk of recurrence ( n = 98) [78].…”