Due to the relevance of CAIX as a tumor-associated antigen expressed in most cases of ccRCC and associated with low expression in non-tumor tissues and the design biases of the aforementioned clinical study, we continue to work on the development of other generations of humanized anti-CAIX CARs containing extracellular, transmembrane, and intracellular domains of CD28, which were superior to the first generation concerning the objective response observed in an orthotopic NSG mouse model of human ccRCC but still did not fulfil the expectations and require improvements and optimizations [26]. This evidence concerns the gene CD28 and nonpapillary renal cell carcinoma.