A Comprehensive Preclinical Model Evaluating the Recombinant PRAME Antigen Combined With the AS15 Immunostimulant to Fight Against PRAME-expressing Tumors.
The PRAME tumor antigen is a potential target for immunotherapy. We assessed the immunogenicity, the antitumor activity, and the safety and the tolerability of a recombinant PRAME protein (recPRAME) combined with the AS15 immunostimulant (recPRAME+ AS15) in preclinical studies in mice and Cynomolgus monkeys. Four groups of 12 CB6F1 mice received 4 injections of phosphate-buffered saline (PBS), recPRAME, AS15, or recPRAME+AS15. Immunized mice were injected with tumor cells expressing PRAME (CT26-PRAME) 2 weeks or 2 months after the last injection. The mean tumor surface was measured twice a week. Two groups of 10 monkeys received 7 injections of saline or recPRAME+ AS15. T-cell responses were measured by flow cytometry using intracellular cytokine staining (ICS). In CB6F1 mice, repeated injections of recPRAME+ AS15 induced high PRAME-specific antibody titers and mostly CD4+ T cells producing cytokines. This immune response was long-lasting in these animals and was associated with protection against a challenge with PRAME-expressing tumor cells (CT26-PRAME) applied either 2 weeks or 2 months after the last injection; these data indicate the induction of an immune memory. In HLA-A02.01/HLA-DR1 transgenic mice, recPRAME+ AS15 induced both CD4+ and CD8+ T-cell responses, indicating that this antigen can be processed by the human leukocyte antigen and is potentially immunogenic in humans. In addition, a repeated-dose toxicity study in monkeys showed that 7 biweekly injections of recPRAME+ AS15 were well tolerated, and induced PRAME-specific antibodies and T cells. In conclusion, these preclinical data indicate that repeated injections of the PRAME cancer immunotherapeutic are immunogenic and have an acceptable safety profile.
GSK Vaccines, Rixensart, Belgium.
Catherine
C
Gérard
Nathalie
N
Baudson
Thierry
T
Ory
Lawrence
L
Segal
Jamila
J
Louahed
D000276:Adjuvants, Immunologic / Q000627:therapeutic use* / Q000633:toxicity; D000818:Animals; D000906:Antibodies / Q000097:blood; D000951:Antigens, Neoplasm / Q000627:therapeutic use* / Q000633:toxicity; D045744:Cell Line, Tumor; D004359:Drug Therapy, Combination; D005260:Female; D007167:Immunotherapy; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology; D011994:Recombinant Proteins / Q000627:therapeutic use / Q000633:toxicity; D013601:T-Lymphocytes / Q000276:immunology
D000276:Adjuvants, Immunologic; D000906:Antibodies; D000951:Antigens, Neoplasm; C404944:PRAME protein, human; D011994:Recombinant Proteins