Prolonged subcutaneous administration of 852A, a novel systemic toll-like receptor 7 agonist, to activate innate immune responses in patients with advanced hematologic malignancies.
The toll-like receptor (TLR) 7 agonist 852A, a small-molecule imidazoquinoline, stimulates plasmacytoid dendritic cells to produce multiple cytokines. We conducted a Phase II study of 852A in patients with recurrent hematologic malignancies. The primary objective was assessing the activity of 852A administered subcutaneously twice weekly for 12 weeks. Secondary objectives were assessing the safety of 852A and its ability to activate the immune system with prolonged dosing. Patients with relapsed hematologic malignancies of any age with adequate organ function were eligible. Patients initiated dosing at 0.6 mg/m(2) twice weekly and escalated by 0.2 mg/m(2) after every two doses as tolerated to a target dose of 1.2 mg/m(2) . Patients with responses or stable disease were eligible for additional cycles. Seventeen patients (15 males) entered the study: 6 with AML, 5 ALL, 4 NHL, 1 Hodgkin's lymphoma, and 1 multiple myeloma. The mean age was 41 years (12-71 years). The median number of prior chemotherapy regimens was 5 (range = 1-14). Thirteen patients completed all 24 injections. Grade 3-4 toxicities included nausea, dyspnea, fever, myalgia, malaise, and cough. Responses included one complete response (ALL), one partial response (AML), two stable disease (AML and NHL), and 9 progressive disease. This is the first in-human hematologic malignancy trial of a subcutaneously (SC) delivered TLR7 agonist using a prolonged dosing schedule. 852A was safely administered up to 1.2 mg/m(2) twice weekly with evidence of sustained tolerability and clinical activity in hematologic malignancies. Systemic TLR agonists for the treatment of hematologic malignancies warrant further study.
Department of Pediatrics, Division of Hematology-Oncology, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA. weige007@umn.edu
Brenda J
BJ
Weigel
Sarah
S
Cooley
Todd
T
DeFor
Daniel J
DJ
Weisdorf
Angela
A
Panoskaltsis-Mortari
Wei
W
Chen
Bruce R
BR
Blazar
Jeffrey S
JS
Miller
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000634:Aminoquinolines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D005260:Female; D019337:Hematologic Neoplasms / Q000188:drug therapy*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007279:Injections, Subcutaneous; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008297:Male; D008875:Middle Aged; D011804:Quinolines; D012074:Remission Induction; D016879:Salvage Therapy; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000819:agonists*; D055815:Young Adult
D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; C523097:N-(4-(4-amino-2-ethyl-1H-imidazo(4,5c)quinolin-1-yl)butyl)methanesulfonamide; D011804:Quinolines; D013449:Sulfonamides; D051199:Toll-Like Receptor 7