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CTLA-4 Blockade with Monoclonal Antibodies in Patients with Metastatic Cancer: Surgical Issues

¹ Division of Cutaneous Oncology, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA
² The Donald A. Adam Comprehensive Melanoma Research Center, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA
³ Department of Oncologic Sciences, University of South Florida College of Medicine, Tampa, FL, USA
⁴ Department of Surgery, University of South Florida College of Medicine, Tampa, FL, USA

Correspondence: Address correspondence and reprint requests to: Vernon K. Sondak, MD; E-mail: vernon.sondak{at}moffitt.org

Background: CTLA-4 (cytotoxic T lymphocyte–associated antigen 4) is a modulatory receptor on T cells involved in downregulating T cell activation. In animal models, CTLA-4 blockade abrogates tolerance to "self" antigens, resulting in the augmentation of antitumor immunity and induction of autoimmunity. CTLA-4 blockade by means of monoclonal antibodies (ipilimumab and tremelimumab) has been evaluated in multiple clinical trials in patients with metastatic cancer, mainly those with melanoma and renal cell cancer.

Methods: We examine available literature and ongoing clinical trials with ipilimumab and tremelimumab and review our own experience with patients treated with CTLA-4 blockade, with an emphasis on issues of direct relevance to surgical oncologists.

Results: CTLA-4 blockade can cause durable tumor regression in patients with metastatic melanoma and other solid tumors. Grade III/IV autoimmune toxicity has been frequently encountered in clinical trials and includes enterocolitis, dermatitis, hypophysitis, uveitis, and hepatitis. Enterocolitis is the most common immune-related adverse event and may cause severe diarrhea requiring intravenous hydration, high-dose corticosteroids, and blockade of tumor necrosis factor alpha with infliximab. Most patients respond to medical treatment, but up to 12% with grade III/IV enterocolitis develop perforation or bleeding that requires colectomy.

Conclusions: As more patients are enrolled onto clinical trials involving ipilimumab and tremelimumab, an increasing number of surgeons may be involved in the care of these patients who develop treatment-related complications. In this report, we review the rationale for CTLA-4 blockade and review selected clinical studies published so far with ipilimumab and tremelimumab. We offer guidelines on the management of patients who develop enterocolitis.