Year-end Sale % OFF 
Abstract
Advances in the treatment of metastatic clear cell renal cell carcinoma (ccRCC) have led to improved progression-free survival of many patients; however the therapies are toxic, rarely achieve durable long-term complete responses and are not curative. Herein we used a single bicistronic lentiviral vector to develop a new combination immunotherapy that consists of human anti-carbonic anhydrase IX (CAIX)-targeted chimeric antigen receptor (CAR) T cells engineered to secrete human anti-programmed death ligand 1 (PD-L1) antibodies at the tumor site. The local antibody delivery led to marked immune checkpoint blockade. Tumor growth diminished 5 times and tumor weight reduced 50–80% when compared with the anti-CAIX CAR T cells alone in a humanized mice model of ccRCC. The expression of PD-L1 and Ki67 in the tumors decreased and an increase in granzyme B levels was found in CAR T cells. The anti-PD-L1 IgG1 isotype, which is capable of mediating ADCC, was also able to recruit human NK cells to the tumor site in vivo. These armed second-generation CAR T cells empowered to secrete human anti-PD-L1 antibodies in the ccRCC milieu to combat T cell exhaustion is an innovation in this field that should provide renewed potential for CAR T cell immunotherapy of solid tumors where limited efficacy is currently seen.
Highlights
One of the new emerging mechanisms associated with the progression of clear cell renal cell carcinoma and other tumors is the immune checkpoint pathway, which consists of cellular interactions that prevent excessive activation of T cells under normal conditions
In order to develop a new chimeric antigen receptor (CAR) therapy for carbonic anhydrase IX (CAIX)+ RCC that could block T cell exhaustion (Figure 1A), we engineered a bicistronic lentiviral vector to express the anti-CAIX (G36) scFv linked to CD28 and CD3-ζ signaling domains (G36-CD28z CAR) in the first cassette and anti-programmed death ligand 1 (PD-L1) IgG1 or IgG4 in a second expression cassette after an IRES site (Figure 1B)
We focused our efforts on developing a single targeted CAR T cell immunotherapy that had the capacity to change the tumor microenvironment, which is known to contribute to immune escape of solid tumors
Summary
One of the new emerging mechanisms associated with the progression of clear cell renal cell carcinoma (ccRCC) and other tumors is the immune checkpoint pathway, which consists of cellular interactions that prevent excessive activation of T cells under normal conditions. Many tumors are able to stimulate the expression of immune checkpoint molecules, resulting in an exhausted phenotype of T cells that cannot restrain tumor progression [1]. Emerging clinical data highlight the importance of one inhibitory ligand and receptor pair as an immune checkpoint: the programmed death-ligand 1 (PD-L1; B7-H1 and CD274) and programmed death receptor-1 (PD-1; CD279), in preventing the killing of cancer cells by cytotoxic T-lymphocytes. PD-L1 is expressed constitutively on non-lymphoid tissues such as the heart, placenta, skeletal muscle and lung where it may serve to downregulate T cell receptor (TCR) signaling in PD-1+ cytotoxic T-lymphocytes to safeguard against www.impactjournals.com/oncotarget autoimmune mediated tissue damage [2]. The immune checkpoint inhibitors have the advantage of facilitating a memory response unlike the existing cytotoxic and targeted cancer therapies [7]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
