Combination of 4-1BB agonist and PD-1 antagonist promotes antitumor effector/memory CD8 T cells in a poorly immunogenic tumor model.
Immunotherapies targeting the programmed death 1 (PD-1) coinhibitory receptor have shown great promise for a subset of patients with cancer. However, robust and safe combination therapies are still needed to bring the benefit of cancer immunotherapy to broader patient populations. To search for an optimal strategy of combinatorial immunotherapy, we have compared the antitumor activity of the anti-4-1BB/anti-PD-1 combination with that of the anti-PD-1/anti-LAG-3 combination in the poorly immunogenic B16F10 melanoma model. Pronounced tumor inhibition occurred only in animals receiving anti-PD-1 and anti-4-1BB concomitantly, while combining anti-PD-1 with anti-LAG-3 led to a modest degree of tumor suppression. The activity of the anti-4-1BB/anti-PD-1 combination was dependent on IFNγ and CD8(+) T cells. Both 4-1BB and PD-1 proteins were elevated on the surface of CD8(+) T cells by anti-4-1BB/anti-PD-1 cotreatment. In the tumor microenvironment, an effective antitumor immune response was induced as indicated by the increased CD8(+)/Treg ratio and the enrichment of genes such as Cd3e, Cd8a, Ifng, and Eomes. In the spleen, the combination treatment shaped the immune system to an effector/memory phenotype and increased the overall activity of tumor-specific CD8(+) CTLs, reflecting a long-lasting systemic antitumor response. Furthermore, combination treatment in C57BL/6 mice showed no additional safety signals, and only minimally increased severity of the known toxicity relative to 4-1BB agonist alone. Therefore, in the absence of any cancer vaccine, anti-4-1BB/anti-PD-1 combination therapy is sufficient to elicit a robust antitumor effector/memory T-cell response in an aggressive tumor model and is therefore a candidate for combination trials in patients.
Rinat Laboratories, Pfizer Inc., South San Francisco, California. shihao.chen@pfizer.com john.lin@pfizer.com.
Shihao
S
Chen
Rinat Laboratories, Pfizer Inc., South San Francisco, California.
Li-Fen
LF
Lee
Oncology Research Unit, Pfizer Inc., San Diego, California.
Timothy S
TS
Fisher
Drug Safety R&D, Pfizer Inc., San Diego, California.
Bart
B
Jessen
Oncology Research Unit, Pfizer Inc., San Diego, California.
Mark
M
Elliott
Drug Safety R&D, Pfizer Inc., San Diego, California.
Winston
W
Evering
Rinat Laboratories, Pfizer Inc., South San Francisco, California.
Kathryn
K
Logronio
Rinat Laboratories, Pfizer Inc., South San Francisco, California.
Guang Huan
GH
Tu
Oncology Research Unit, Pfizer Inc., San Diego, California.
Konstantinos
K
Tsaparikos
Rinat Laboratories, Pfizer Inc., South San Francisco, California.
Xiaoai
X
Li
Oncology Research Unit, Pfizer Inc., San Diego, California.
Hui
H
Wang
Rinat Laboratories, Pfizer Inc., South San Francisco, California.
Chi
C
Ying
Rinat Laboratories, Pfizer Inc., South San Francisco, California.
Mengli
M
Xiong
Oncology Research Unit, Pfizer Inc., San Diego, California.
Todd
T
VanArsdale
Rinat Laboratories, Pfizer Inc., South San Francisco, California. shihao.chen@pfizer.com john.lin@pfizer.com.
John C
JC
Lin
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005260:Female; D007156:Immunologic Memory / Q000276:immunology; D016130:Immunophenotyping / Q000379:methods; D007167:Immunotherapy / Q000379:methods; D007371:Interferon-gamma / Q000276:immunology; D008099:Liver / Q000201:enzymology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D008810:Mice, Inbred C57BL; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D059016:Tumor Microenvironment / Q000276:immunology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000819:agonists*; D000093322:Lymphocyte Activation Gene 3 Protein
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D007371:Interferon-gamma; D000093322:Lymphocyte Activation Gene 3 Protein; C000720327:Lag3 protein, mouse