Enhancement of the T-cell armamentarium as a cell-based therapy for prostate cancer

Prostate cancer is frequently characterized by a large inflammatory infiltrate that includes T cells. Although T cells traffic to cancer lesions in large numbers, they are unable to generate a therapeutic response because of the immunosuppressive microenvironment. Therefore, arming T cells with a cytotoxic agent that is capable of killing cancer cells independent of these immunosuppressive signals is a rational approach to enhance their potency. Essentially, the T cells would serve as a cell-based vector, or "Trojan Horse," to selectively deliver a protoxin to disseminated prostate cancer lesions. The selective delivery of a protoxin using T cells represents an ideal method to maximize their therapeutic potency through a "field effect." Because systemically infused T cells are expected to traffic to sites of inflammation other than cancer, an additional level of specificity may be needed to prevent toxicity to nontarget tissues. Toward this goal, genetic engineering can be used to make protoxin expression dependent upon T-cell recognition of the prostate-specific membrane antigen by a chimeric antigen receptor. Furthermore, selective activation of the protoxin using a tissue- or tumor-specific protease, such as PSA, can promote further specificity. Thus, T-cell potency can be enhanced by targeted protoxin secretion and greater specificity achieved using combinatorial antigen recognition and protoxin activation.