Phase I trial of granulocyte macrophage-colony stimulating factor and interleukin-4 as a combined immunotherapy for patients with cancer.
Antigen-presenting cells (APC), such as dendritic cells (DC), are the key component of many cancer immunotherapy strategies. However, DCs comprise a rare population of clinically obtainable cells and are compromised in function in cancer-bearing hosts. Clinical trials therefore rely upon DC generated ex vivo. The authors hypothesized that systemic administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) plus interleukin (IL)-4 might lead to the differentiation of DC from their precursors and enhance their number and function in vivo, as it does in vitro. Subjects with advanced malignancies were treated in this phase I, multiple cohort, dose-escalation trial combining GM-CSF (2.5 microgram/kg/d) plus IL-4 (0-6.0 microgram/kg/d). A cycle consisted of 14 days of cytokine therapy and 14 days of observation (cohorts A-D), or alternating 7-day treatment and observation periods (cohort E). Subjects were followed clinically to determine a maximally tolerated dose (MTD), and complimentary in vitro studies were performed to determine a biologically active dose (BAD). Twenty-one subjects received treatment on this outpatient-based protocol. Treatment was well tolerated and generally characterized by Grade 1 and 2 cytokine related toxicities. The MTD was determined to be GM-CSF 2.5 microgram/kg/d plus IL-4 6.0 microgram/kg/d (cohort E). Treatment in cohort D (GM-CSF 2.5 microgram/kg/d plus IL-4 4.0 microgram/kg/d) was well tolerated and resulted in a BAD. Systemic GM-CSF plus IL-4 provides a mechanism for increasing the number and function of APC in cancer patients. Future clinical applications of this strategy are numerous and include the potential as a strong vaccine adjuvant.
Gitlitz
Barbara J
BJ
Division of Hematology/Oncology, Jonsson Comprehensive Cancer Center, UCLA School of Medicine, Los Angeles, USA.
Figlin
Robert A
RA
Kiertscher
Sylvia M
SM
Moldawer
Nancy
N
Rosen
Frances
F
Roth
Michael D
MD
D000328:Adult; D000368:Aged; D015331:Cohort Studies; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D015847:Interleukin-4 / Q000008:administration & dosage*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000401:mortality / Q000473:pathology* / Q000628:therapy*; D011379:Prognosis; D018570:Risk Assessment; D016019:Survival Analysis; D016896:Treatment Outcome
D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor