Potential Application of Chimeric Antigen Receptor (CAR)-T Cell Therapy in Renal Cell Tumors

Abstract

Currently, renal cell carcinoma is characterized by encouraging benefits from immunotherapy that have led to significant results in treatment outcome. The approval of nivolumab primarily as second-line monotherapy and, more recently, the approval of new combination therapies as first-line treatment have confirmed the importance of immunotherapy in this type of tumor. In this context, the chimeric antigen receptor (CAR)-T represents a further step forward in the field of immunotherapy. Initially tested on hematological malignancies, this new therapeutic approach is also becoming a topic of great interest for solid tumors. Although the treatment has several advantages over previous T-cell receptor-dependent immunotherapy, it is facing some obstacles in solid tumors such as a hostile tumor microenvironment and on-tumor/off-tumor toxicities. Several strategies are under investigation to overcome these problems, but the approval of CART cell therapy is still some way off. In renal cancer, the significant advantages obtained from immune checkpoint inhibitors represent a good starting point, but the potential nephrological toxicity of CART cell therapy represents an important risk. In this review, we provide the rationale and preliminary results of CART cell therapy in renal cell malignancies.

Chimeric Antigen Receptor T-Cells: An Overview of Concepts, Applications, Limitations, and Proposed Solutions

“…For many years, surgical intervention was the most effective treatment for RCC, known for its chemoresistance. Later, other treatments such as cytokine and tyrosine kinase inhibitors (TKIs) were approved, and when RCC showed possible immunological sensitivity, other immunotherapies were approved as well ( Schepisi et al, 2020 ). CAR-T cell therapy of RCC targets carboxy-anhydrase-IX (CA-IX) as an antigen, which participates in the catalysis of carbon dioxide hydration ( Bagley and O’Rourke, 2020 ; Bagley and O’Rourke, 2020 ) and is considered a critical antigen in RCC; however, it is also found in other normal tissues of gastric mucosa epithelium, small intestine epithelium, duodenum, and the biliary tree where it is expressed moderately ( Yeku et al, 2017 ).…”

Next Wave of Targets in the Treatment of Advanced Renal Cell Carcinoma

“…CAR-T cell therapy represents a potential strategy to restore T-cell anti-tumor activity through a bioengineering process that results in the expression of a chimeric antigen receptor (CAR) on T cells. CARs interact with their target antigens on tumor cells with high specificity and they are not restricted by a major histocompatibility complex (MHC), allowing them to be active in tumors with low levels of MHC expression [ 78 ]. Several challenges of CAR-T cell therapy in solid tumors have been identified, including a hostile TME leading to the elimination of CAR-T cells, as well as the lack of receptor specificity [ 78 ].…”

“…CARs interact with their target antigens on tumor cells with high specificity and they are not restricted by a major histocompatibility complex (MHC), allowing them to be active in tumors with low levels of MHC expression [ 78 ]. Several challenges of CAR-T cell therapy in solid tumors have been identified, including a hostile TME leading to the elimination of CAR-T cells, as well as the lack of receptor specificity [ 78 ]. Furthermore, potentially severe side effects due to off-target, on-tumor toxicities represent a critical limiting factor in implementing CAR-T cell therapy for solid tumors.…”

Immunotherapy and Its Development for Gynecological (Ovarian, Endometrial and Cervical) Tumors: From Immune Checkpoint Inhibitors to Chimeric Antigen Receptor (CAR)-T Cell Therapy

“…Notwithstanding, CAR-T cell therapy has not shown the same results in solid tumors, despite the impressive results obtained with TIL-dependent immunotherapy. Several factors may be responsible for this [ 85 ], for example, immune-dependent cancer antigen selection, which potentially improves the proliferation of cancer cells not expressing molecular targets [ 86 ], reduced tumor trafficking [ 87 ], reduced CAR-T persistence in the patient [ 88 ], CAR-T destruction, which is dependent on the tumor microenvironment [ 89 ] and no evidence of cancer-specific antigens [ 90 ]. These conditions may lead to immune-related toxicity, including cytokine release syndrome, acute kidney injury, and tumor lysis syndrome, all of which can lead to severe nephropathy [ 91 , 92 ].…”