Co-expression of PD-L1 Antibodies Enhances the Anti-Tumor Efficacy
Chimeric antigen receptor T cell (CAR-T) therapy has shownsignificant efficacy in treating patients with refractory B-cellleukemia and lymphoma [1,2]. However, CAR-T therapy hasyielded less favorable results in treating patients with solidtumors such as pancreatic, ovarian or mesothelioma cancers[3-5]. One of the major obstacles in treating solid tumors withCAR-T is the scarcity of antigen that is uniformly expressed intumor cells such as CD19 in B cell hematologic malignancies[6,7]. Therefore, designing a CAR against an antigen that ishighly expressed in cancer cells but either has negligible orreduced expression in normal tissues to avoid off-tumor toxicityis extremely critical. Several CAR-T clinical trials in treating solidtumors demonstrated poor efficacy and severe toxicitiesincluding death because of the low expression of antigen in thenormal cells [7-13]. Moreover, the immunosuppressive tumormicroenvironment of solid tumors inhibits the T cell infiltrationand proliferation limiting the potential of CAR-T cellimmunotherapy [14,15].Mesothelin (MSLN) has emerged as one of the promising targetsfor CAR-T cell therapy for solid tumors because of itsoverexpression in cancer cells including pancreatic, ovarian andmesotheliomas but with a basal expression in normal tissues[16-18]. Mesothelin is encoded as a 71-kDa cell surfaceglycoprotein that is cleaved by a furin protease into an N-terminal 31 kDa soluble fragment megakaryocyte potentiating.
factor (MPF) and C-terminal 40 kDa membrane-boundmesothelin [16,18]. Although mesothelin is expressed in lung,heart, spleen, liver, kidney, and testis of adult tissues, thebiological function of mesothelin is not known . Miceharboring a null mutation in the mesothelin gene had aphenotype similar to the wild-type suggesting mesothelin wasnot required for growth and reproduction . However,mesothelin is believed to involve in cell adhesion in tumorprogression since it binds to the CA125/MuC16 facilitating themetastatic proliferation of ovarian cancer onto peritonealmesothelial cells [20,21].Programmed death 1 (PD-1) is expressed on B and T cells,macrophages and some of dendritic cells and upon activationregulates the tolerance and autoimmunity . PD-1-/- micedeveloped lupus-like autoimmune disease confirming the role ofPD-1 in maintaining tolerance and autoimmunity [23,24]. PD-L1, a ligand of PD-1, is expressed constitutively on cancer cellsand delivers pro-survival signals that favor tumor progression. PD-1 is capable of transmitting inhibitory signals whenengaged with PD-L1 expressed on tumor cells and thusinhibiting tumor-specific T-cell proliferation and cytokineproduction . Therefore, eliminating either PD-1 or PD-L1and blocking their interaction can result in the breakdown oftumor immune suppression.In this study, we generated a novel vector that co-expresseshuman MSLN-targeted CAR with secretory human anti-PD-L1antibodies to overcome tumor-mediated immunosuppression.We investigated its anti-tumor potential in pancreatic, ovarianand mesothelioma xenograft mouse models. The MSLN-targetedCAR-T cells secreting the anti-PD-L1 antibodies efficiently killedmesothelin-expressing cells in vitro as well as showed potent anti-tumor activity in a xenograft mouse model.
In conclusion, our results demonstrate that second-generationanti-mesothelin HN1CAR-T cells secreting anti-PD-L1 IgG-Fcantibodies enhanced anti-tumor efficacy and increased cytokine production. This CAR design may diminish CAR-T cellexhaustion and improve treatment for solid tumors. We proposethat CAR-T cells targeting tumor antigen as well as secretingantibody to block checkpoint signaling may circumvent theexhaustion of CAR-T cells. We foresee that a combination ofCAR and anti-PD1/PD-L1 into a single construct should beamong the next steps to explore to achieve higher anti-tumorefficacy in solid tumors.
Journal of Cancer Research and Immuno-Oncology
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