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 resulting from the outgrowth of minimal residual disease in the form of metastases. We examined the effectiveness of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade as an adjunctive immunotherapy to reduce metastatic relapse after primary prostate tumor resection, For these studies, we developed a murine model in which overt metastatic outgrowth of TRAMP-C2 (C2) prostate cancer ensues after complete primary tumor resection. Metastatic relapse in this model occurs reliably and principally within the draining lymph nodes in close proximity to the primary tumor, arising from established metastases present at the time of surgery. Using this model, we demonstrate that adjunctive CTLA-4 blockade administered immediately after primary tumor resection reduces metastatic relapse from 97.4 to 44%, Consistent with this, lymph nodes obtained 2 weeks after treatment reveal marked destruction or complete elimination of C2 metastases in 60% of mice receiving adjunctive anti-CTLA-4 whereas 100% of control antibody-treated mice demonstrate progressive CZ lymph node replacement. Our study demonstrates the potential of adjunctive CTLA-4 blockade immunotherapy to reduce cancer relapse emanating from minimal residual metastatic disease and may have broader implications for improving the capability of immunotherapy by combining such forms of therapy with other cytoreductive measures including surgery.

手术后癌症复发是一种常见现象，最常见的原因是微小残留病灶以转移的形式生长。我们研究了细胞毒性T淋巴细胞相关抗原4（CTLA - 4）阻断作为一种辅助免疫疗法在减少原发性前列腺肿瘤切除术后转移性复发方面的有效性。为了这些研究，我们建立了一个小鼠模型，在该模型中，完全切除原发性肿瘤后，TRAMP - C2（C2）前列腺癌会发生明显的转移性生长。在这个模型中，转移性复发可靠地发生，主要发生在靠近原发性肿瘤的引流淋巴结内，源于手术时已存在的转移灶。利用这个模型，我们证明在原发性肿瘤切除后立即进行辅助性CTLA - 4阻断可使转移性复发从97.4%降低到44%。与此一致的是，治疗2周后获取的淋巴结显示，在接受辅助性抗CTLA - 4的小鼠中，60%的小鼠C2转移灶明显破坏或完全消除，而在接受对照抗体治疗的小鼠中，100%的小鼠显示C2淋巴结进行性转移。我们的研究证明了辅助性CTLA - 4阻断免疫疗法在减少由微小残留转移性疾病引起的癌症复发方面的潜力，并且通过将这种治疗形式与包括手术在内的其他细胞减灭措施相结合，可能对提高免疫疗法的能力具有更广泛的意义。