Bortezomib improves adoptive carbonic anhydrase�IX‑specific chimeric antigen receptor‑modified NK92 cell therapy in mouse models of human renal cell carcinoma

Abstract

Adoptive chimeric antigen receptor (CAR) T or NK cells offer new options for cancer treatment. Clinical results indicate that CAR-modified T cell (CAR-T) therapy has curative therapeutic efficacy for hematological malignancies. However, the efficacy of the therapy in most solid tumors, including advanced renal cell carcinoma (RCC), remains highly limited. New regimens, including combination of CART cells with chemical drugs, must be studied to enhance the therapeutic efficacy of CART or NK cells for solid tumors. In the present study, a carbonic anhydrase IX (CAIX)-specific third-generation CAR was transduced into NK92 cells by lentiviral vectors. The immune effects, including cytokine release and cytotoxicity, of the CAR-NK92 cells against CAIX-positive RCC cells were evaluated in vitro. Combination therapeutic effects of bortezomib and CAR-NK92 cells were analyzed in a mouse model with human RCC xenografts. The results revealed that CAIX-specific CAR-NK92 cells specifically recognized in vitro cultured CAIX-positive RCC cells and released cytokines, including IFN-γ, perforin and granzyme B, and exhibited specific cytotoxicity. The cytotoxicity of the CAR-NK92 cells was enhanced after treating RCC cells with bortezomib in vitro. The suppressive efficacy of bortezomib combined with CAR-NK92 cells against established CAIX-positive tumor xenografts was more significant than that of the monotherapy with either CAR-NK92 cells or bortezomib. Therefore, bortezomib can enhance the effects of the CAR-NK92 cells against RCC in vitro and in vivo. This study provided an experimental basis for the novel clinical regimen of CAIX-specific CAR-modified NK or T cells for the treatment of RCC.

Renaissance of armored immune effector cells, CAR-NK cells, brings the higher hope for successful cancer therapy

“…In vitro consideration indicated that CAR-NK92 had a remarkable cytotoxic effect on target cells. Furthermore, a combination of bortezomib with CAR-NK92 cells showed greater suppressive efficacy against CAIX-positive tumor xenografts in comparison to the monotherapy with either CAR-NK92 cells or bortezomib [161].…”

“…Unchanged NK-92 cells failed to inhibit tumor progression [153,160]. Advanced renal cell carcinoma (RCC) is another solid tumor that has been evaluated with antigenspecific CAR-NK cells [161]. In this regard, a carbonic anhydrase IX (CAIX)-specific third-generation CAR-NK92 cells were utilized.…”

Making Potent CAR T Cells Using Genetic Engineering and Synergistic Agents

“…Many attempts have been made to enhance CAR T cell activity by using small molecules. Several studies have shown the synergy effects of small molecules, including tyrosine kinase inhibitors, cytotoxic agents, histone deacetylase inhibitors, proteasome inhibitors, and immune-modulators, with CAR T cells (Table 2) [191][192][193][194][195][196][197][198]. Afatinib, a tyrosine kinase inhibitor, increased CAR-NK cell infiltration into the tumor [192].…”

Overhauling CAR T Cells to Improve Efficacy, Safety and Cost

“…This point is key to ensure the safety of these off the shelf approaches based on cell lines, as is the case for NK-92 derived cell products. Importantly, recent reports showed that CAR-expressing NK-92 cells can be used in combination with drugs like bortezomib [ 90 ] or regorafenib [ 91 ] or in combination with oncolytic virus [ 92 ] to improve responses in solid tumor models. These results led to several clinical trials using CAR-expressing NK-92 cells for patients with CD33 + AML (acute myeloid leukemia, Identifier: NCT02944162), CD19 + ( Identifier: NCT02892695) or CD7 + ( Identifier: NCT02742727) leukemia/lymphoma and Her2 + glioblastoma ( Identifier: NCT03383978).…”