Chimeric antigen receptor T cells secreting anti-PD-L1 antibodies more effectively regress renal cell carcinoma in a humanized mouse model

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.

T-cells “à la CAR-T(e)” – Genetically engineering T-cell response against cancer

“…To remedy to this, Caruana et al engineered T cells to secrete heparanase enabling the efficient degradation of ECM and targeting of neuroblastoma tumors in mouse [258]. Furthermore, it is feasible to engineer T cells to secrete checkpoint blockers [259][260][261] (Fig. 1) or HVEM [262] to lower the immunosuppressive pressure in the tumor vicinity.…”

Identification of Carbonic Anhydrase IX as a Novel Target for Endoscopic Molecular Imaging of Human Bladder Cancer

“…A novel human anti-CAIX monoclonal antibody has therapeutic potential in the unmet medical need of the specific elimination of highlyexpressed CAIX renal carcinoma cells [31]. In addition, the chimeric antibody girentuximab has been widely tested in clinical trials for administration both alone and in combination with multiple drugs, including radioisotopes, cytokines, and chimeric antigen receptor (CAR) T cell therapy [32,33]. If the CAIX antibody is found to be safe without toxic side-effects in vivo, it could be labeled with a fluorescent molecule for optical molecular imaging.…”

Cellular Immunotherapy in B-Cell Malignancy

“…Other groups have used constitutive expression of costimulatory molecules such as CD40L [68] and 4-1BB [69]. Secretion of PD-L1-blocking antibodies by CAR T cells [70], expression of a PD-1-dominant negative receptor binding to PD-L1 but not signaling to the T cell [71], and chimeric 'switch' receptors consisting of the extracellular domain of PD-1 and the signaling domain of CD28 [72] have been used to overcome an immunosuppressive micromilieu.…”