Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma

Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a critical immunoregulatory molecule (expressed on activated T cells and a subset of regulatory T cells) capable of down-regulating T cell activation. Blockade of CTLA-4 has been shown in animal models to improve the effectiveness of cancer immunotherapy. We thus treated 14 patients with metastatic melanoma by using serial i.v. administration of a fully human anti-CTLA-4 antibody (MDX-010) in conjunction with s.c. vaccination with two modified HLA-A*0201-restricted peptides from the gp100 melanoma-associated antigen, gp100:209–217(210M) and gp100:280–288(288V). This blockade of CTLA-4 induced grade III/IV autoimmune manifestations in six patients (43%), including dermatitis, enterocolitis, hepatitis, and hypophysitis, and mediated objective cancer regression in three patients (21%; two complete and one partial responses). This study establishes CTLA-4 as an important molecule regulating tolerance to “self” antigens in humans and suggests a role for CTLA-4 blockade in breaking tolerance to human cancer antigens for cancer immunotherapy.

[1]  R. Offringa,et al.  Elucidating the Autoimmune and Antitumor Effector Mechanisms of a Treatment Based on Cytotoxic T Lymphocyte Antigen-4 Blockade in Combination with a B16 Melanoma Vaccine , 2001, The Journal of experimental medicine.

[2]  J. Bluestone,et al.  CTLA-4 ligation blocks CD28-dependent T cell activation [published erratum appears in J Exp Med 1996 Jul 1;184(1):301] , 1996, The Journal of experimental medicine.

[3]  C. Thompson,et al.  T-cell regulation by CD28 and CTLA-4 , 2001, Nature Reviews Immunology.

[4]  E. Shevach,et al.  CD4+CD25+ T cells inhibit both the induction and effector function of autoreactive T cells and represent a unique lineage of immunoregulatory cells. , 1998, Journal of immunology.

[5]  P. Linsley,et al.  CTLA-4 is a second receptor for the B cell activation antigen B7 , 1991, The Journal of experimental medicine.

[6]  D. Mason,et al.  Human CD4+CD25+ thymocytes and peripheral T cells have immune suppressive activity in vitro , 2001, European journal of immunology.

[7]  M. Moser,et al.  Effect of interleukin‐10 on dendritic cell maturation and function , 1997, European journal of immunology.

[8]  F. Denizot,et al.  A new member of the immunoglobulin superfamily—CTLA-4 , 1987, Nature.

[9]  G. Freeman,et al.  Characterization of CTLA-4 structure and expression on human T cells. , 1993, Journal of immunology.

[10]  C. June,et al.  Cutting Edge: Regulatory T Cells from Lung Cancer Patients Directly Inhibit Autologous T Cell Proliferation1 , 2002, The Journal of Immunology.

[11]  Thomas Davis,et al.  Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[12]  C. June,et al.  CTLA-4 blockade enhances clinical disease and cytokine production during experimental allergic encephalomyelitis. , 1996, Journal of immunology.

[13]  Milton W. Taylor,et al.  Indoleamine 2,3-Dioxygenase Production by Human Dendritic Cells Results in the Inhibition of T Cell Proliferation , 2000, The Journal of Immunology.

[14]  Ethan M. Shevach,et al.  CD4+CD25+ Immunoregulatory T Cells Suppress Polyclonal T Cell Activation In Vitro by Inhibiting Interleukin 2 Production , 1998, The Journal of experimental medicine.

[15]  Fiona Powrie,et al.  Cytotoxic T Lymphocyte–Associated Antigen 4 Plays an Essential Role in the Function of Cd25+Cd4+ Regulatory Cells That Control Intestinal Inflammation , 2000, The Journal of experimental medicine.

[16]  J. Allison,et al.  CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells , 1996, The Journal of experimental medicine.

[17]  J. Allison,et al.  CTLA-4-Mediated inhibition of early events of T cell proliferation. , 1999, Journal of immunology.

[18]  S. Rosenberg,et al.  Immunization of patients with melanoma peptide vaccines: immunologic assessment using the ELISPOT assay. , 1998, The cancer journal from Scientific American.

[19]  J. Allison,et al.  Enhancement of Antitumor Immunity by CTLA-4 Blockade , 1996, Science.

[20]  P. Linsley,et al.  Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation , 1991, The Journal of experimental medicine.

[21]  B. Foster,et al.  Combination immunotherapy of primary prostate cancer in a transgenic mouse model using CTLA-4 blockade. , 2000, Cancer research.

[22]  G. Nabel,et al.  Regulation of the proinflammatory effects of Fas ligand (CD95L). , 1998, Science.

[23]  E. Wang,et al.  Functional analysis of antigen-specific T lymphocytes by serial measurement of gene expression in peripheral blood mononuclear cells and tumor specimens. , 1999, Journal of immunology.

[24]  Melvin Cohn,et al.  A Theory of Self-Nonself Discrimination , 1970, Science.

[25]  F. Marincola,et al.  Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma , 1998, Nature Medicine.

[26]  G. Pauli,et al.  Spontaneous apoptosis of dendritic cells is efficiently inhibited by TRAP (CD40‐ligand) and TNF‐α, but strongly enhanced by interleukin‐10 , 1995, European journal of immunology.

[27]  P. Linsley,et al.  CTLA-4 can function as a negative regulator of T cell activation. , 1994, Immunity.

[28]  R. Zinkernagel,et al.  Transforming growth factor-beta inhibits the generation of cytotoxic T cells in virus-infected mice. , 1989, Journal of immunology.

[29]  P. Linsley,et al.  Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. , 1994, Immunity.

[30]  A. Sharpe,et al.  CTLA‐4 regulates cell cycle progression during a primary immune response , 2002, European journal of immunology.

[31]  C. Benoist,et al.  Cytotoxic T Lymphocyte–associated Antigen 4 (CTLA-4) Regulates the Unfolding of Autoimmune Diabetes , 1998, The Journal of experimental medicine.

[32]  R. Schwartz,et al.  A cell culture model for T lymphocyte clonal anergy. , 1990, Science.

[33]  S. Rosenberg,et al.  Immunization of Patients with Metastatic Melanoma Using Both Class I- and Class II-Restricted Peptides from Melanoma-Associated Antigens , 2003, Journal of immunotherapy.

[34]  J. Allison,et al.  Combination Immunotherapy of B16 Melanoma Using Anti–Cytotoxic T Lymphocyte–Associated Antigen 4 (Ctla-4) and Granulocyte/Macrophage Colony-Stimulating Factor (Gm-Csf)-Producing Vaccines Induces Rejection of Subcutaneous and Metastatic Tumors Accompanied by Autoimmune Depigmentation , 1999, The Journal of experimental medicine.

[35]  J. Allison,et al.  Identification and distribution of the costimulatory receptor CD28 in the mouse. , 1992, Journal of immunology.

[36]  H. Griesser,et al.  Lymphoproliferative Disorders with Early Lethality in Mice Deficient in Ctla-4 , 1995, Science.