Principles and use of anti-CTLA4 antibody in human cancer immunotherapy
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.
References (55)
- et al.
The immunobiology of cancer immunosurveillance and immunoediting
Immunity
(2004) - et al.
Lymphoproliferation in CTLA-4-deficient mice is mediated by costimulation-dependent activation of CD4+ T cells
Immunity
(1997) - et al.
The interaction properties of costimulatory molecules revisited
Immunity
(2002) - et al.
Molecular interactions mediating T cell antigen recognition
Annu Rev Immunol
(2003) - et al.
Tyrosine phosphorylation controls internalization of CTLA-4 by regulating its interaction with clathrin-associated adaptor complex AP-2
Immunity
(1997) - et al.
In vivo overexpression of CTLA-4 suppresses lymphoproliferative diseases and thymic negative selection
Eur J Immunol
(2005) - et al.
Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses
J Exp Med
(2001) - et al.
In vivo blockade of CTLA-4 enhances the priming of responsive T cells but fails to prevent the induction of tumor antigen-specific tolerance
Proc Natl Acad Sci USA
(1999) - et al.
Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer
Clin Cancer Res
(2005) - et al.
Study of tumor infiltrating lymphocytes and transforming growth factor-beta as prognostic factors in breast carcinoma
Int J Cancer
(1997)
Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer
N Engl J Med
Proliferative activity of intratumoral CD8(+) T-lymphocytes as a prognostic factor in human renal cell carcinoma: clinicopathologic demonstration of antitumor immunity
Cancer Res
CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer
Cancer Res
The B7 family revisited
Annu Rev Immunol
Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4
Science
Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4
Immunity
Crystal structure of the B7-1/CTLA-4 complex that inhibits human immune responses
Nature
B7-1 and B7-2 selectively recruit CTLA-4 and CD28 to the immunological synapse
Immunity
Structural analysis of CTLA-4 function in vivo
J Immunol
B7-independent inhibition of T cells by CTLA-4
J Immunol
Modulation of tryptophan catabolism by regulatory T cells
Nat Immunol
CTLA-4 (CD152) can inhibit T cell activation by two different mechanisms depending on its level of cell surface expression
J Immunol
Secondary but not primary T cell responses are enhanced in CTLA-4-deficient CD8+ T cells
Eur J Immunol
Cytotoxic T lymphocyte antigen-4 (CTLA-4) regulates primary and secondary peptide-specific CD4(+) T cell responses
Proc Natl Acad Sci USA
Pinpointing when T cell costimulatory receptor CTLA-4 must be engaged to dampen diabetogenic T cells
Proc Natl Acad Sci USA
CTLA-4: new insights into its biological function and use in tumor immunotherapy
Nat Immunol
Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength
Immunity
Cited by (402)
Cancer Immunotherapy
2024, Veterinary Clinics of North America - Small Animal PracticeImmune Checkpoint Blockade and Skin Toxicity Pathogenesis
2022, Journal of Investigative DermatologyA radiologist's guide to novel anticancer therapies in the era of precision medicine
2022, European Journal of Radiology OpenTherapeutic Strategies in BRAF V600 Wild-Type Cutaneous Melanoma
2024, American Journal of Clinical Dermatology