Purpose: IL15 induces the activation and proliferation of natural killer (NK) and memory CD8þ T cells and has preclinical antitumor activity. Given the superior activity and favorable kinetics of ALT-803 (IL15N72D:IL15RaSu/IgG1 Fc complex) over recombinant human IL15 (rhIL15) in animal models, we performed this first-in-human phase I trial of ALT-803 in patients with advanced solid tumors. Patients and Methods: Patients with incurable advanced melanoma, renal cell, non–small cell lung, and head and neck cancer were treated with ALT-803 0.3 to 6 mg/kg weekly intravenously or 6 to 20 mg/kg weekly subcutaneously for 4 consecutive weeks, every 6 weeks. Immune correlates included pharmacokinetics, immunogenicity, and lymphocyte expansion and function. Clinical endpoints were toxicity and antitumor activity. Results: Twenty-four patients were enrolled; 11 received intravenous and 13 received subcutaneous ALT-803. Of these patients, nine had melanoma, six renal, three head and neck, and six lung cancer. Although total lymphocyte and CD8þ T-cell expansion were modest, NK cell numbers rose significantly. Neither anti–ALT-803 antibodies nor clinical activity were observed. Overall, ALT-803 was well tolerated, with adverse effects including fatigue and nausea most commonly with intravenous administration, whereas painful injection site wheal was reported most commonly with subcutaneous ALT-803. Conclusions: Subcutaneous ALT-803 produced the expected NK cell expansion and was well tolerated with minimal cytokine toxicities and a strong local inflammatory reaction at injection sites in patients with advanced cancer. These data, together with compelling evidence of synergy in preclinical and clinical studies, provide the rationale for combining ALT-803 with other anticancer agents.
Bibliographical noteFunding Information:
The authors would like to thank the study participants and acknowledge the contributions of the following individuals to this work: Minjun Apodaca, ASCP, and Leonard D'Amico, PhD, 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; and Angela Riggins and Michael Watling for their help in preparation of the manuscript figures. This work was supported by Cancer Immunotherapy Trials Network (CITN): NIH 1U01 CA154967-01 (ClinicalTrials.gov NCT01727076); Melanoma Research Alliance Academic Industry Award, Altor BioScience.
© 2018 American Association for Cancer Research.