Synergy between chemotherapeutic agents and CTLA-4 blockade in preclinical tumor models

Maria Jure-Kunkel,John T Hunt,Gregg Masters,Emel Girit,Rachel Humphrey,Gennaro Dito,Francis Lee

doi:10.1007/s00262-013-1451-5

Abstract

Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) binding agent, has proven to be an effective monotherapy for metastatic melanoma and has shown antitumor activity in trials when administered with other therapeutic agents. We hypothesized that the combination of ipilimumab with chemotherapeutic agents, such as ixabepilone, paclitaxel, etoposide, and gemcitabine, may produce therapeutic synergy based on distinct but complementary mechanisms of action for each drug and unique cellular targets. This concept was investigated using a mouse homolog of ipilimumab in preclinical murine tumor models, including SA1N fibrosarcoma, EMT-6 mammary carcinoma, M109 lung carcinoma, and CT-26 colon carcinoma. Results of CTLA-4 blockade in combination with one of various chemotherapeutic agents demonstrate that synergy occurs in settings where either agent alone was not effective in inducing tumor regression. Furthermore, when combined with CTLA-4 blockade, ixabepilone, etoposide, and gemcitabine elicited prolonged antitumor effects in some murine models with induction of a memory immune response. Future investigations are warranted to determine which specific chemo-immunotherapy combinations, if any, will produce synergistic antitumor effects in the clinical setting.

Highlights

A complex and multifaceted interplay exists between the immune system and cancer
In the M109 lung carcinoma model (e), tumor-free mice previously treated with ixabepilone monotherapy or in combination with anti-mCTLA-4 monoclonal antibody (mAb) were rechallenged on Day 95 with live tumor cells
In the CT-26 colon carcinoma model (f), treatment of mice with anti-mCTLA-4 mAb and either ixabepilone or paclitaxel resulted in synergy between cytotoxic T-lymphocyte antigen4 (CTLA-4) blockade and these chemotherapeutic agents

Summary

Introduction

A complex and multifaceted interplay exists between the immune system and cancer. Innate and adaptive immune responses function to protect the host by attempting to mediate rejection of the tumor, and the immune system can facilitate tumor progression by secreting factors that support tumor growth and immune escape, suppressing effective antitumor immunity. During cancer progression, tumor cells can develop multiple strategies to evade immune detection and destruction [1, 2]; agents that modulate immune function are attractive therapeutic options to generate and expand robust and effective antitumor immune responses. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is one such receptor, and its role as a key negative regulator of T-cell responses gives it the potential as a target for therapy in multiple cancer types [3, 4]. One of the key events in the initiation of adaptive immunity is the antigen-specific activation of naıve T cells, a process which is controlled by a precise balance of stimulatory and inhibitory regulatory signals. Multiple signals are required for effective T-cell activation [5], Cancer Immunol Immunother (2013) 62:1533–1545 which is initiated by the engagement of the major histocompatibility antigen complex. CTLA-4, which has a higher affinity for binding B7 molecules than does CD28, curtails T-cell activation and proliferation by various mechanisms, including competitive inhibition of CD28, delocalization of protein kinase C-theta and CARMA1 from the immune synapse, transendocytosis of B7, and modulation of regulatory T-cell (Treg) function [7,8,9,10,11,12,13,14,15]

Methods

Results

Conclusion