Principles and use of anti-CTLA4 antibody in human cancer immunotherapy

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Cytotoxic T lymphocyte antigen-4 has become recognized as one of the key negative regulators of adaptive immune responses, having a central role in the maintenance of peripheral tolerance and in shaping the repertoire of emergent T cell responses. Concurrent recognition of the potential importance of inhibitory immune regulators in limiting antitumor responses, either as a result of chronic antigenic stimulation or the self-nature of many tumor-selective target antigens, has led to the development of cytotoxic T lymphocyte antigen-4-blocking antibodies as therapeutic anticancer agents. Following extensive preclinical modeling, these agents have entered clinical trials, where they are showing encouraging activity in heavily pretreated patients with advanced-stage disease, particularly with melanoma or renal carcinoma. Finding ways to dissociate antitumor activity from adverse immune events should enable actualization of their therapeutic potential in the coming years.

Introduction

The acceptance of the concept of immunosurveillance and evolution of the model of immunoediting incorporating contributions of both innate and adaptive immunity [1], combined with provocative correlative data from human cancers that suggest prolonged survival and/or reduced metastases in patients with greater levels of intratumor infiltration with T cells [2, 3, 4, 5], have heightened enthusiasm for clinical application of immunotherapies. Numerous vaccination approaches targeting the enhancement of the early events in adaptive immunity have been attempted. However, although the identification of tumor antigens recognized by T cells from melanoma and other cancers has enabled antigen-specific immunotherapy in preclinical murine models, ongoing clinical trials incorporating vaccination with peptides or peptide-pulsed dendritic cells (DCs) have not produced compelling evidence of therapeutic benefit. Although T cell responses directed towards the peptides used for immunization can be detected, they have proven too weak and transient to eradicate tumors. In addition, the recognition that there are few truly tumor-specific targets and that the majority of exploitable targets in most malignancies are self- or altered-self-antigens, either over- or aberrantly expressed by the tumor cells, has led to an increasing realization that to effectively mobilize T cells reactive to these specificities, it might be necessary to break multiple mechanisms of peripheral tolerance. This realization has been paralleled by an increased understanding of the roles of both T cell intrinsic cell autonomous regulatory elements and of non-cell-autonomous mediators (regulatory T cells) in the induction of peripheral tolerance. Blockade or inhibition of the negative regulators of immune responses provides a mechanism to enhance endogenous antitumor responses and to enhance the responses to other therapeutic maneuvers that might be limited by immunological checkpoint regulation (Figure 1).

This review summarizes our current understanding of CTLA-4 function in T cell responses in vitro and in preclinical murine models. The initial clinical experience with antibodies to CTLA-4 in human trials is reviewed along with a perspective on adverse events observed with CTLA-4 blockade.

Section snippets

CTLA-4: the archetypal inhibitory checkpoint

Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a member of the CD28–B7 immunoglobulin superfamily of immune regulatory molecules [6]. It shares its two ligands (B7.1, B7.2) with its co-stimulatory counterpart CD28. Together, these four molecules are acknowledged as perhaps the most important cofactors functioning at the tip of an immunological cascade, providing signals that are crucial in T cell activation and tolerance. B7.2 is expressed at a low level in nonactivated DCs and can be rapidly

Preclinical studies of CTLA-4 blockade

Numerous preclinical studies in murine models of malignancy have provided confirmatory evidence of the ability of anti-CTLA to enhance endogenous immune responses to immunogenic tumors, and to synergize with multiple other therapies in more poorly immunogenic tumors. Anti-CTLA-4 monotherapy induces rejection of several types of established transplantable tumors in mice, including colon carcinoma, fibrosarcoma, prostatic carcinoma, lymphoma and renal carcinoma [28, 29, 30, 31, 32]. Antitumor

Clinical trials of CTLA-4 blockade

Two human anti-CTLA-4 antibodies, developed using transgenic mouse technologies, have now entered into clinical trials (MDX-010 and CP-675,206) [40, 41, 42••, 43, 44•] (Table 1). They have been predominantly tested in metastatic melanoma and in renal carcinoma, although they have also been used in prostatic, ovarian, breast and colonic carcinomas. Although such studies are currently in their infancy (Phase I and early Phase II), several preliminary observations can be made. In heavily

Adverse immune events

Treatment with anti-CTLA-4 antibodies is frequently accompanied by adverse immune events (AIE). The most common side effect in the initial study of MDX-010 was development of an asymptomatic, grade 1 reticular and erythematous rash on the trunk and extremities, particularly in the patients with melanoma [41]. Histological examination revealed perivascular lymphoid aggregates of both CD4+ and CD8+ T cells juxtaposed with dying melanocytes, suggesting a loss of tolerance to melanocyte

Conclusions and future directions

Current results in heavily pretreated patients with advanced-stage disease provide optimism for the successful development of CTLA-4 blockade as a potent immunological adjuvant. Whether the association of clinical responses with AIE is an inherent part of effective checkpoint blockade, or whether they can be dissociated, remains an area for future study. Anecdotal reports of patients experiencing antitumor responses with minimal toxicity suggest that achieving the proper balance of immune

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

Karl S Peggs is a Visiting Fellow funded by the Leukaemia Research Fund, London, UK; Sergio A Quezada is a Fellow of the Cancer Research Institute, USA. James P Allison holds the David H Koch Chair in Immunologic Studies at the Memorial Sloan-Kettering Cancer Center.

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