In situ CTLA-4 blockade mediates regression of local and distant tumors with minimal side effects
(English)Manuscript (preprint) (Other academic)
Preclinical and clinical studies describe powerful anti-tumor effects of systemic anti(a)CTLA-4 antibody therapy but also indicate that blocking immune regulatory checkpoints may precipitate severe autoimmune complications. In this study we compared conventional high-dose systemic aCTLA-4 with peritumoral low-dose injection in murine models of pancreatic (Panc02) and bladder (MB49) cancer. Tumor growth and autoimmune adverse events were monitored. Peritumoral aCTLA-4 therapy reduced tumor growth in an inverse dose-response manner, as 3x30mg was superior to 3x90mg. The local low-dose was compared with systemic administration of 200mg antibody and similar results were observed as to tumor regression and survival. Both local and systemic high-dose administrations lead to Treg accumulation in the tumor-draining lymph node. Lymphocytes from treated mice (irrespectively of treatment route) secreted IFNg upon tumor cell stimulation. Remarkably, local therapy was effective on both distant Panc02 tumors as well as the irrelevant tumor MB49, demonstrating its potential in treatment of metastatic disease. Systemic delivery of aCTLA-4 was associated with elevated autoantibody levels, splenomegaly and acute gastritis compared with local treatment. Taken together, in situ immunomodulation of tumors with aCTLA-4 can affect the regression and the cure of primary and distant tumors at reduced toxicity compared to systemic administration, and should be considered for patients with solid tumors.
CTLA-4, Immunotherapy, Local administration, Panc02, MB49, cancer, checkpoint blockade, antibody therapy, local CTLA-4 blockade
Immunology in the medical area
IdentifiersURN: urn:nbn:se:uu:diva-110727OAI: oai:DiVA.org:uu-110727DiVA: diva2:278083