Anti-CTLA-4 antibody therapy: immune monitoring during clinical development of a novel immunotherapy

Abstract

Cytotoxic T-lymphocyte-associated antigen (CTLA-4), also known as CD152, is a co-inhibitory molecule that functions to regulate T-cell activation. Antibodies that block the interaction of CTLA-4 with its ligands B7.1 and B7.2 can enhance immune responses, including antitumor immunity. Two CTLA-4-blocking antibodies are presently under clinical investigation: ipilimumab and tremelimumab. CTLA-4 blockade has shown promise in treatment of patients with metastatic melanoma, with a recently completed randomized, double-blind phase III trial demonstrating a benefit in overall survival (OS) in the treated population. However, this approach appears to benefit only a subset of patients. Understanding the mechanism(s) of action of CTLA-4 blockade and identifying prognostic immunologic correlates of clinical endpoints to monitor are presently areas of intense investigation. Several immunologic endpoints have been proposed to correlate with clinical activity. This review will focus on the endpoints of immune monitoring described in studies to date and discuss future areas of additional work needed.

Figure 1. CTLA-4 is a negative regulator of T cell activation

Conventional T cells are activated by engagement of MHC (signal 1) and B7 (signal 2). Upon activation, T cells express CTLA-4 on the cell surface. CTLA-4 engagement with B7 inhibits T cell activation. Antibody blockade of CTLA-4 interaction with B7 prevents this inhibitory signal.

Figure 2. Grade III/IV irAEs correlated with clinical response or clinical benefit

The five studies evaluated each independently demonstrate a correlation between irAEs and either clinical response (CR+PR) (Attia 2005, Maker 2005, Downey 2007) or clinical benefit (CR+PR+SD) (Weber 2009 and Ku 2010). Several of the studies combined ipilimumab treatment with a second therapy (Attia 2005, Maker 2005, Downey 2007), limiting direct comparison. In Weber 2009, patients were treated with ipilimumab combined with a placebo or with budesonide; only the patients treated with ipilimumab monotherapy are analyzed here.

Figure 3. ALC≥1000 correlates with clinical benefit

In a study by Ku et al., all of the patients with clinical benefit (CR+PR+SD) at 24 weeks had an ALC ≥1000 at week 7 of the study. Conversely, none of the patients with an ALC<1000 at week 7 had clinical benefit. The entire study includes a total of 51 patients, 41 patients were evaluable for ALC at week 7 and clinical benefit at week 24.