Preclinical Development of Ipilimumab and Nivolumab Combination Immunotherapy: Mouse Tumor Models, In Vitro Functional Studies, and Cynomolgus Macaque Toxicology.
The monoclonal antibodies ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) have shown remarkable antitumor activity in an increasing number of cancers. When combined, ipilimumab and nivolumab have demonstrated superior activity in patients with metastatic melanoma (CHECKMATE-067). Here we describe the preclinical development strategy that predicted these clinical results. Synergistic antitumor activity in mouse MC38 and CT26 colorectal tumor models was observed with concurrent, but not sequential CTLA-4 and PD-1 blockade. Significant antitumor activity was maintained using a fixed dose of anti-CTLA-4 antibody with decreasing doses of anti-PD-1 antibody in the MC38 model. Immunohistochemical and flow cytometric analyses confirmed that CD3+ T cells accumulated at the tumor margin and infiltrated the tumor mass in response to the combination therapy, resulting in favorable effector and regulatory T-cell ratios, increased pro-inflammatory cytokine secretion, and activation of tumor-specific T cells. Similarly, in vitro studies with combined ipilimumab and nivolumab showed enhanced cytokine secretion in superantigen stimulation of human peripheral blood lymphocytes and in mixed lymphocyte response assays. In a cynomolgus macaque toxicology study, dose-dependent immune-related gastrointestinal inflammation was observed with the combination therapy; this response had not been observed in previous single agent cynomolgus studies. Together, these in vitro assays and in vivo models comprise a preclinical strategy for the identification and development of highly effective antitumor combination immunotherapies.
Bristol-Myers Squibb, Redwood City, CA, United States of America.
Mark J
MJ
Selby
Bristol-Myers Squibb, Redwood City, CA, United States of America.
John J
JJ
Engelhardt
Bristol-Myers Squibb, Redwood City, CA, United States of America.
Robert J
RJ
Johnston
Bristol-Myers Squibb, Redwood City, CA, United States of America.
Li-Sheng
LS
Lu
Bristol-Myers Squibb, Redwood City, CA, United States of America.
Minhua
M
Han
Bristol-Myers Squibb, Redwood City, CA, United States of America.
Kent
K
Thudium
Bristol-Myers Squibb, Redwood City, CA, United States of America.
Dapeng
D
Yao
Bristol-Myers Squibb, Redwood City, CA, United States of America.
Michael
M
Quigley
Bristol-Myers Squibb, Redwood City, CA, United States of America.
Jose
J
Valle
Bristol-Myers Squibb, Redwood City, CA, United States of America.
Changyu
C
Wang
Bristol-Myers Squibb, Redwood City, CA, United States of America.
Bing
B
Chen
Bristol-Myers Squibb, Redwood City, CA, United States of America.
Pina M
PM
Cardarelli
Bristol-Myers Squibb, Redwood City, CA, United States of America.
Diann
D
Blanset
Bristol-Myers Squibb, Redwood City, CA, United States of America.
Alan J
AJ
Korman
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000628:therapy; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007167:Immunotherapy; D000074324:Ipilimumab; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D008252:Macaca fascicularis; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D000077594:Nivolumab; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism
D000911:Antibodies, Monoclonal; D060908:CTLA-4 Antigen; D000074324:Ipilimumab; D061026:Programmed Cell Death 1 Receptor; D000077594:Nivolumab