Impact of combination therapy with anti-PD-1 blockade and a STAT3 inhibitor on the tumor-infiltrating lymphocyte status.

Impact of combination therapy with anti-PD-1 blockade and a STAT3 inhibitor on the tumor-infiltrating lymphocyte status.

Publication date: Oct 03, 2019

Recently, clinical studies using anti-immune checkpoint molecule antibodies have been successful in solid tumors, such as melanoma and non-small cell lung cancers. However, pancreatic cancers are still intractable and difficult to treat once recurrence or metastasis occurs; thus, novel combined use of immune checkpoint blockade (ICB) with molecular targeted drugs is considered a therapeutic option. Previously, we developed a novel humanized MHC-double knockout (dKO) NOG mouse model and demonstrated that an anti-PD-1 antibody or a STAT3 inhibitor showed anti-tumor effects through an immunological mechanism. In the current study, using a humanized mouse model, we aimed to develop a combination therapy with an anti-PD-1 antibody and a STAT3 inhibitor (STX-0119) for use in vivo against pancreatic cancer. In an in vitro investigation, STX-0119 showed weak to moderate cytotoxic activity against several pancreatic cancer cell lines, which exhibited activated pSTAT3 and weak PD-L1 expression. However, unexpectedly, an in vivo study indicated that the combination of the anti-PD-1 antibody with STX-0119 remarkably reduced the anti-tumor effect and TIL numbers despite the effective anti-tumor activity against pancreatic cancer produced individually by STX-0119 and the anti-PD-1 antibody. These results suggested that the combination of an anti-PD-1 antibody with specific signal inhibiting drugs should be carefully evaluated to avoid unexpected side effects, and such studies might contribute to the development of an effective combination regimen of ICB with cancer-targeting drugs such as tyrosine kinase inhibitors (TKIs).

Ashizawa, T., Iizuka, A., Maeda, C., Tanaka, E., Kondou, R., Miyata, H., Sugino, T., Kawata, T., Deguchi, S., Mitsuya, K., Hayashi, N., Asai, A., Ito, M., Yamaguchi, K., and Akiyama, Y. Impact of combination therapy with anti-PD-1 blockade and a STAT3 inhibitor on the tumor-infiltrating lymphocyte status. 24378. 2019 Immunol Lett.

Concepts Keywords
Antibodies Cancer immunotherapy
Antibody C-Met
Blockade Tumor-infiltrating lymphocytes
Cancer STAT3
Combination Therapy Immune checkpoint
Cytotoxic Checkpoint inhibitor
Immune Checkpoint Blockade Medicine
Inhibitor Branches of biology
Knockout Medical specialties
Lung Immune system
Melanoma However pancreatic cancers
Metastasis Antibodies
MHC
Molecule
Pancreatic Cancer
STAT3
Tumor
Tyrosine Kinase

Semantics

Type Source Name
drug DRUGBANK L-Tyrosine
disease DOID cancer
disease MESH development
gene UNIPROT TLR1
gene UNIPROT CD274
pathway BSID Pancreatic cancer
disease DOID pancreatic cancer
gene UNIPROT ST8SIA2
gene UNIPROT NOG
disease MESH metastasis
disease MESH recurrence
disease MESH pancreatic cancers
disease MESH lung cancers
pathway BSID Melanoma
disease DOID melanoma
disease MESH melanoma
disease MESH tumor
gene UNIPROT RPL17
gene UNIPROT IMPACT

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