Elimination of residual metastatic prostate cancer after surgery and adjunctive cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade immunotherapy

Cancer relapse after surgery is a common occurrence, most frequently result ing from the outgrowth of minimal residual disease in the form of metastase s. We examined the effectiveness of cytotoxic T lymphocyte-associated antig en 4 (CTLA-4) blockade as an adjunctive immunotherapy to reduce metastatic relapse after primary prostate tumor resection, For these studies, we devel oped a murine model in which overt metastatic outgrowth of TRAMP-C2 (C2) pr ostate cancer ensues after complete primary tumor resection. Metastatic rel apse in this model occurs reliably and principally within the draining lymp h nodes in close proximity to the primary tumor, arising from established m etastases present at the time of surgery. Using this model, we demonstrate that adjunctive CTLA-4 blockade administered immediately after primary tumo r resection reduces metastatic relapse from 97.4 to 44%, Consistent with th is, lymph nodes obtained 2 weeks after treatment reveal marked destruction or complete elimination of C2 metastases in 60% of mice receiving adjunctiv e anti-CTLA-4 whereas 100% of control antibody-treated mice demonstrate pro gressive CZ lymph node replacement. Our study demonstrates the potential of adjunctive CTLA-4 blockade immunotherapy to reduce cancer relapse emanatin g from minimal residual metastatic disease and may have broader implication s for improving the capability of immunotherapy by combining such forms of therapy with other cytoreductive measures including surgery.