Purpose: Preclinical data established IL15 as a homeostatic factor and powerful stimulator of NK and CD8þ T-cell function, the basis for clinical testing. Experimental Design: A first-in-human outpatient phase I dose escalation trial of subcutaneous (SC) rhIL15 was conducted in refractory solid tumor cancer patients. Therapy consisted of daily (Monday–Friday) subcutaneous injections of rhIL15 for two consecutive weeks (10 total doses/cycle). Clinical response was assessed by RECIST. Pharmacokinetics of rhIL15 and immune biomarkers were evaluated. Results: Nineteen patients were treated with rhIL15 at dose levels of 0.25, 0.5, 1, 2, and 3 mcg/kg/day. Fourteen patients completed 2 cycles of therapy that was well tolerated. One serious adverse event (SAE), grade 2 pancreatitis, required overnight hospitalization. Enrollment was halted after a patient receiving 3 mcg/kg/day developed a dose-limiting SAE of grade 3 cardiac chest pain associated with hypotension and increased troponin. No objective responses were observed; however, several patients had disease stabilization including a renal cell carcinoma patient who continued protocol treatment for 2 years. The treatment induced profound expansion of circulating NK cells, especially among the CD56bright subset. A proportional but less dramatic increase was found among circulating CD8þ T cells with maximal 3-fold expansion for the 2 and 3 mcg/kg patients. Conclusions: SC rhIL15 treatment was well tolerated, producing substantial increases in circulating NK and CD8þ T cells. This protocol establishes a safe outpatient SC rhIL15 regimen of 2 mcg/kg/day dosing amenable to self-injection and with otential as a combination immunotherapeutic agent.
Bibliographical noteFunding Information:
Cancer Immunotherapy Trials Network (CITN) was supported by NIH 1U01 CA154967-01 (Clinical Trials.gov NCT01727076). This study was also partially supported by the Intramural Research Program of the National Cancer Institute and P01 CA111412 and NCI R35 CA197292 (to J.S. Miller). The authors would like to acknowledge the contributions of the following individuals to this work: Minjun Apodaca, ASCP, and other members of the CITN Central Laboratory for their technical contributions, Stephen C. De Rosa MD and Tiffany Hensley-McBain of the HIV Vaccine Trials Network for their help in establishing the flow cytometric methods, the Fred Hutchinson Cancer Research Center Flow Cytometry Facility for their support in conducting testing, Valarie McCullar from the Miller laboratory at the University of Minnesota for functional assay testing, and Angela Riggins for her help in preparation of the manuscript figures.