[Frontiers in Bioscience 14, 1761-1770, January 1, 2009]

Altering regulatory T cell function in cancer immunotherapy: a novel means to boost the efficacy of cancer vaccines

Jens Ruter1, Brian G. Barnett1, Ilona Kryczek1,2, Michael J. Brumlik1,3, Benjamin J. Daniel1,3, George Coukos4, Weiping Zou1,2, Tyler J. Curiel1,3

1Department of Medicine, Hematology and Medical Oncology, Tulane University School of Medicine, 1430 Tulane Avenue SL-78, New Orleans, LA 70112, 2Department of Surgery, University of Michigan, 1500 East Medical Center Drive, Room TC2101, Ann Arbor, Michigan 48109-0346, 3San Antonio Cancer Institute, University of Texas Health Sciences Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, 4Center for Research on Reproduction and Women's Health, University of Pennsylvania, 1355 BRB II/III, 421 Curie Boulevard, Philadelphia, PA 19104

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Depletion of regulatory T Cells
3.1. Anti-CD25 antibodies
3.2. Denileukin diftitox
3.3. Cytotoxic chemotherapy
3.3.1. Cyclophosphamide
3.3.2. Fludarabine
4. Blockade of regulatory T cell function
4.1. Anti-GITR antibody
4.2. TLR signaling
4.3. Anti-CTLA-4 antibodies
5. Blockade of regulatory T cell trafficking
5.1. Chemokine signaling
6. Blockade of regulatory T cell differentiation
6.1. Dendritic cell-regulatory T cell interactions
6.1.1. PDC-T cell interactions
6.1.2. MDC-T cell interactions
6.1.3. Vascular leukocyte-T cell interactions
6.2. Other Strategies
7. Combining depletion of regulatory T cells with tumor vaccines
7.1. Antigen specificity of Tregs
7.2. Expansion of Tregs by cancer vaccines
7.3. Timing of Treg depletion in relation to active vaccination
7.4. Pathologic consequences of Treg depletion
7.5. The regulatory cell population targeted for depletion
8. Summary and conclusions
9. References

1. ABSTRACT

Cancers express tumor associated antigens that should elicit immune attack, but spontaneous immune rejection of established cancer is rare. Recent data demonstrate that specific and active tumor-mediated mechanisms hinder host anti-tumor immunity. CD4+CD25+ T regulatory cells (Tregs) are important mediators of active immune evasion in cancer. Disrupting tumor-mediated mechanisms hindering host immunity is a novel approach to tumor immunotherapy. Treg depletion improves endogenous anti-tumor immunity and the efficacy of active immunotherapy in animal models for cancer, suggesting that inhibiting Treg function could also improve the limited successes of human cancer immunotherapy. We have identified five strategies to block Treg activity: depletion, interference with trafficking, inhibition of differentiation, blockade of function or raising the effector T cell threshold for suppression. Discovery of additional regulatory cell populations expands the potential targets for these approaches. The fusion toxin denileukin diftitox (Ontak) reduces Treg numbers and function in the blood of some patients with cancer. We discuss specific strategies to block Treg activity and present some of our preliminary data in this area. Combining Treg depletion with active vaccination and other approaches poses additional challenges that are discussed.