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Originally published as JCO Early Release 10.1200/JCO.2005.09.923 on December 21 2004 © 2005 American Society of Clinical Oncology.
CTLA-4 Blockade: Unveiling Immune RegulationDepartment of Medical Oncology, Dana-Farber Cancer Institute; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA To maintain tissue homeostasis under the duress of infection or injury, the immune system is endowed with a diverse repertoire of soluble and cellular effectors. The innate response, composed of granulocytes, macrophages, dendritic cells, natural killer cells, and complement, is rapidly triggered into action, detecting tissue disturbance through a set of germline-encoded pattern recognition receptors. The adaptive reaction, consisting of antibody-producing B cells and T lymphocytes, is slower to develop, but manifests exquisite specificity and memory. These attributes reflect the requirement for expansion of rare clones harboring somatically rearranged immunoglobulin molecules or T-cell receptors specific for foreign proteins or processed peptides presented by major histocompatibility complex (MHC) molecules. These innate and adaptive responses are carefully orchestrated through soluble and membrane-bound regulators, resulting in the deployment of the most suitable effectors for containing the disorder, while minimizing tissue damage. Cancer cells similarly provoke immune recognition. In one pathway, innate effectors detect tumor cells directly.1 Natural killer cells and phagocytes express NKG2D molecules that function as receptors for stress-related genes such as MICA and MICB, which are induced as a consequence of cellular transformation. Natural killer cells further scan for the loss of MHC class I molecules on the surface of tumor cells. Dendritic cells use a variety of scavenger receptors to result in the phagocytosis of dying tumor cells. The adaptive response exploits an indirect pathway, termed cross-priming, to recognize cancer cells.2 In this mechanism, dendritic cells capture tumor cell debris, migrate to regional lymph nodes, and stimulate CD4+ and CD8+ T cells with tumor specificity. Primed T cells thereby acquire the capacity to detect tumor cells directly in a MHC-restricted fashion. CD4+ T cells also contribute to B-cell antibody production. Antitumor innate and adaptive responses are frequently detected in cancer-bearing hosts, but their biologic importance remains incompletely understood. In some cases, endogenous reactions may function to attenuate disease progression. In multiple cancer types, clinicopathologic studies of early-stage lesions demonstrate that dense intratumoral lymphocyte infiltrates are strongly correlated with reduced frequencies of metastasis and improved patient survival.3 Moreover, in advanced ovarian carcinoma, lymphocyte infiltrates also predict for complete responses and prolonged survival following cytotoxic therapy.4 Consistent with this protective role, several strains of immune-deficient mice display enhanced susceptibility to spontaneous and carcinogen-induced tumors.5 Nonetheless, other compelling data indicate that tumor cells sometimes exploit host responses to promote disease progression.6 Unresolved inflammation may facilitate tumor development by modulating tumor cell growth, apoptosis, invasion, and metastasis. Together, these divergent outcomes underscore a dual role for immunity in carcinogenesis.7 This improved understanding of endogenous host reactions provides a useful framework for characterizing specific defects that underlie the failure of tumor immunity. One critical mechanism involves inefficient tumor antigen presentation. Cancer cells typically lack the expression of important costimulatory molecules, such as B7 family members, that are necessary to directly prime potent T-lymphocyte responses, and dendritic cells infiltrating established tumors generally display limited maturation.8 Under these conditions, induced tumor-reactive T cells manifest impaired function. To overcome these defects, investigators have devised many vaccination strategies that improve dendritic cell-mediated tumor antigen presentation.9 In one approach, dendritic cells are expanded ex vivo from hematopoietic progenitors, loaded with cancer antigens, and inoculated into tumor-bearing hosts. In a second scheme, dendritic cells are stimulated in vivo with cytokines, microbial products, or adjuvants. These diverse immunization strategies incorporate whole tumor cells, which provide a large array of potential targets, or defined antigens, including mutated proteins, aberrantly expressed gene products, and normal differentiation antigens. Among the latter group, the melanosomal pigmentation proteins gp100, MART-1, and tyrosinase are perhaps the most intensively studied. Multiple early-stage clinical trials have established the ability of these vaccination schemes to enhance immunity and accomplish some tumor destruction.10 However, most immunized patients succumb to progressive disease, indicating that defects other than impaired antigen presentation remain to be addressed. In this context, emerging evidence implicates a critical role for immune regulatory circuits in attenuating antitumor immunity. These pathways primarily function to maintain tolerance to normal tissues, but since cancers arise from self, antitumor immune responses are similarly subject to regulation. One key player in the tolerance networks is cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4).11 The development of a lethal lymphoproliferative disorder in young CTLA-4–deficient mice illuminates the pivotal role of this gene product in immune homeostasis. CTLA-4 may operate in two major ways. First, the triggering of CTLA-4 on activated T cells induces cell cycle arrest and diminishes cytokine production, thereby restraining effector T-cell function. Second, regulatory T cells, a distinct cell population dedicated to controlling effector T cells in trans, constitutively express CTLA-4. As depleting regulatory T cells in mice provokes various autoimmune diseases,12 CTLA-4 likely contributes to their immunomodulatory activities as well. In contrast to the severe pathology of complete CTLA-4 deficiency, Allison et al discovered that transient, antibody-mediated blockade of CTLA-4 enhances antigen-specific T-cell responses with limited toxicities.13 The injection of anti-CTLA-4 antibodies stimulates the rejection of moderately immunogenic murine tumors, and this activity is potentiated with chemotherapy. Although CTLA-4 antibody blockade alone is less effective against poorly immunogenic tumors, combination therapy with vaccines mediates impressive therapeutic effects. In this issue of the Journal of Clinical Oncology, Weber et al14 report a phase I study that tests the administration of a fully human CTLA-4–blocking monoclonal antibody (MDX-010) combined with melanoma peptide vaccines. Nineteen patients with resected stage III or IV metastatic melanoma received repetitive doses of MDX-010 (in three dose level cohorts) together with gp100, MART-1, and tyrosinase peptides emulsified in an adjuvant, Montanide ISA 51. Consistent with an important role for CTLA-4 in maintaining immune homeostasis in humans, eight patients developed significant autoimmune toxicities. These included uveitis, rashes, and gastrointestinal reactions (diarrhea and abdominal pain). The uveitis and rashes might reflect T-cell responses against melanosomal antigens expressed in normal cells. T-cell infiltrates were also noted in the rectum of patients with diarrhea; while the antigenic specificities of these reactions remain to be determined, it is noteworthy that loss of CTLA-4 function precipitates inflammatory bowel disease in some murine models.15 To identify factors that might predispose to MDX-010 toxicity, the authors examined known genetic polymorphisms of CTLA-4; previous work linked specific genetic variants with an increased risk for multiple autoimmune diseases.16 Intriguingly, a CTLA-4 polymorphism conferring low-level expression seemed to be associated with a higher frequency of autoimmune toxicity in this melanoma cohort. This provocative finding should stimulate more detailed investigations of polymorphisms in larger numbers of treated patients. Another important result of the phase I trial was the suggestion that the incidence of tumor relapse might be reduced in patients manifesting autoimmune toxicity. An earlier trial of concurrent MDX-010 and melanoma peptide vaccination similarly raised this possibility.17 The coupling of tumor immunity and autoimmunity might reflect the use of normal differentiation proteins in the vaccination schemes and/or a comparable threshold for overcoming tolerance to both self and cancer antigens. However, it remains possible that tumor immunity might be dissociated from autoimmunity. Indeed, another study in which MDX-010 was administered to previously vaccinated melanoma and ovarian carcinoma patients revealed the induction of tumor necrosis and lymphocyte infiltrates in the absence of severe toxicity.18 Together, these three pilot trials underscore the need to determine the optimal MDX-010 dose and schedule and the most effective integration of CTLA-4 blockade with vaccination. Whereas achieving the proper balance of immune stimulation and inhibition of negative regulation poses a significant clinical challenge, therein lies the key to actualizing the considerable potential of active immunization against cancer. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. Acknowledgment Supported by National Institutes of Health grants CA74886, CA66996, and CA092625, and the Leukemia and Lymphoma Society. REFERENCES 1. Diefenbach A, Raulet D: The innate immune response to tumors and its role in the induction of T-cell immunity. Immunol Rev 188:9-21, 2002[CrossRef][Medline]
2. Huang AY, Golumbek P, Ahmadzadeh M, et al: Role of bone marrow-derived cells in presenting MHC class I-restricted tumor antigens. Science 264:961-965, 1994
3. Clark W, Elder D, Guerry D, et al: Model predicting survival in stage I melanoma based on tumor progression. J Natl Cancer Inst 81:1893-1904, 1989
4. Zhang L, Conejo-Garcia J, Katsaros D, et al: Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 348:203-213, 2003 5. Dunn GP, Old LJ, Schreiber RD: The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21:137-148, 2004[CrossRef][Medline] 6. Coussens L, Werb Z: Inflammation and cancer. Nature 420:860-867, 2002[CrossRef][Medline] 7. Dranoff G: Cytokines in cancer pathogenesis and cancer therapy. Nat Rev Cancer 4:11-22, 2004[CrossRef][Medline] 8. Banchereau J, Steinman R: Dendritic cells and the control of immunity. Nature 392:245-252, 1998[CrossRef][Medline] 9. Gilboa E: The promise of cancer vaccines. Nat Rev Cancer 4:401-411, 2004[CrossRef][Medline] 10. Pardoll DM: Spinning molecular immunology into successful immunotherapy. Nat Rev Immunol 2:227-238, 2002[CrossRef][Medline] 11. Salomon B, Bluestone JA: Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation. Annu Rev Immunol 19:225-252, 2001[CrossRef][Medline] 12. Hori S, Takahashi T, Sakaguchi S: Control of autoimmunity by naturally arising regulatory CD4+ T cells. Adv Immunol 81:331-371, 2003[Medline] 13. Chambers CA, Kuhns MS, Egen JG, et al: CTLA-4-mediated inhibition in regulation of T cell responses: Mechanisms and manipulation in tumor immunotherapy. Annu Rev Immunol 19:565-594, 2001[CrossRef][Medline]
14. Sanderson K, Scotland R, Lee P, et al: Autoimmunity in a phase I trial of a fully human anti-CTLA-4 monoclonal antibody with multiple peptides and Montanide ISA 51 for patients with resected stages III/IV melanoma. J Clin Oncol 23:741-750, 2005
15. Read S, Malmstrom V, Powrie F: Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp Med 192:295-302, 2000 16. Ueda H, Howson JM, Esposito L, et al: Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423:506-511, 2003[CrossRef][Medline]
17. Phan GQ, Yang JC, Sherry RM, et al: Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A 100:8372-8377, 2003
18. Hodi FS, Mihm MC, Soiffer RJ, et al: Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci U S A 100:4712-4717, 2003
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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