|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2005.07.012 on October 3 2005 © 2005 American Society of Clinical Oncology.
CTLA-4 Blockade: Autoimmunity As TreatmentDepartment of Medicine, Division of Hematology and Oncology, University of California, San Francisco, San Francisco, CA The immune system can recognize and respond to an incredible diversity of targets or antigens. With the evolution of this adaptive capability, the immune system has also co-evolved multiple layers of regulation to prevent autoimmunity, unwanted responses to self-antigens. Unfortunately, many tumor antigens represent self-antigens, and therefore tumors are usually not effectively eliminated by the immune system. Several different mechanisms are in place to maintain this tolerance to self-antigens. In the case of T-cell immunity, one important layer of regulation is the interplay between enhancement and inhibition of T-cell responses by costimulatory molecules. It is thought that, in most cases, signals from the T-cell receptor (TCR) alone are insufficient to result in optimal immune responses,1 and a second, costimulatory signal is required to overcome a threshold for T cells to respond. This enhancement of TCR signals is provided primarily by CD28 on the T cells, which can be triggered by B7 expressed on the antigen-bearing cells.2-7 Once activated, T cells express a second receptor, cytotoxic T lymphocyte–associated antigen 4 (CTLA-4), that can also bind the same B7 molecules. In contrast to CD28, CTLA-4 actually inhibits T-cell responses, thereby applying the brakes to an ongoing immune response.8-13 Evidence that this receptor is, in fact, crucial to the maintenance of tolerance was demonstrated by CTLA-4 knockout mice that develop a lethal lymphoproliferative disease with infiltration of multiple organs by activated T cells.14,15 In contrast, transient blockade of CTLA-4 triggering with antibody can lead to enhancement of T-cell responses but also can induce autoimmunity that can include encephalomyelitis, colitis and diabetes in some mouse models.16-18 Nevertheless, these observations have led to therapeutic approaches targeting this inhibitory pathway for tumor immunotherapy. Allison et al19 have demonstrated that CTLA-4 blockade can lead to tumor rejection of established tumors in mouse models. Moreover, CTLA-4 blockade in conjunction with a tumor vaccine can further enhance antitumor responses, albeit also with the induction of autoimmunity.20-22 This autoimmunity is thought to result from an unmasking of or activation of pre-existing autoreactive T cells. With these provocative findings, multiple antibodies blocking human CTLA-4 have been developed and have entered clinical trials. In this issue of the Journal of Clinical Oncology, Ribas et al23 report on a phase I trial of a human anti–CTLA-4 monoclonal, CP-675,206 (Pfizer, Groton-New London, CT) in patients with solid tumors, the majority of whom had melanoma. Thirty-nine patients received a single planned intravenous infusion of CP-675,206 in an escalating dose design. As would be predicted by the preclinical models, toxicities seen were primarily autoimmune and included dermatitis, colitis, and hypophysitis. Grade III/IV autoimmune toxicities were seen at the higher doses and resolved without specific treatment. Although this was a phase I trial, two of 34 melanoma patients experienced complete responses (6%) and two others (6%) experienced partial responses. These responses were also seen in patients who received the higher doses of antibody. Importantly, these clinical effects were also observed in patients without prior vaccination, consistent with the notion that CTLA-4 blockade can activate pre-existing autoreactive T cells. Moreover, these effects were seen after a single dose of CP-675,206. Although a subset of patients actually went on to receive additional doses, none of these redosed patients were converted from clinical nonresponders into responders. This report adds to a growing body of clinical experience with CTLA-4 blockade resulting in clinical responses in melanoma. Other studies used another fully human CTLA-4 blocking antibody MDX-010 (Medarex, Princeton, NJ).24-26 Hodi et al24 administered a single dose of MDX-010 to nine melanoma and ovarian carcinoma patients who had received tumor vaccines. Although they described no objective clinical responses, they did observe significant tumor necrosis in three of seven melanoma patients. In addition, four of nine patients had induction of autoantibodies and five of seven melanoma patients developed autoimmunity against their melanocytes. Phan et al26 observed objective clinical responses in three (21%) of 14 patients with metastatic melanoma who received MDX-010 with gp100 peptide vaccine every 3 weeks. However, they also observed grade III/IV autoimmune toxicity in 6 patients (43%) including dermatitis, enterocolitis, and hypophysitis. Similarly, Sanderson et al25 reported on 19 melanoma patients immunized with melanoma peptides and treated with escalating doses of MDX-010. These authors also observed enterocolitis and/or autoimmune symptoms in 11 patients (58%). Nevertheless, these trials are consistent with the potential autoimmune toxicities and clinical responses seen with CP-675,206. While the clinical experience with CTLA-4 blockade is still limited, the frequency of treatment-induced autoimmunity appears to be more frequent in patients with melanoma than in other malignancies such as ovarian or prostate cancer.27 To what extent this reflects inherent differences among the patients is unclear. That it is possible to identify autoreactive T cells that recognize melanosomal antigens in melanoma patients, even without vaccination,28 attests to the potential immunogenicity of this disease and would account for the dermatitis and vitiligo seen. Nevertheless, autoimmunity affecting other organs such as the gastrointestinal and neuroendocrine systems has also been observed in these clinical trials. Although the nature of recognition is not known in these cases, it has been speculated that induced T cells may possess chemokine receptors that may direct these T cells to migrate to different tissues such as the gut.25 In the case of autoimmunity to endocrine glands, treatment may be unmasking pre-existing autoreactive or cross-reactive T cells that target these organs. Future clinical development of CTLA-4 blockade will undoubtedly focus upon enhancing clinical efficacy and perhaps reducing treatment-related adverse effects. If experience in mice gives any indication, coupling anti–CTLA-4 antibodies with a vaccine may help to direct immune responses toward target antigens, and such clinical trials have been reported, with more ongoing. In addition, there is also some indication that there may be a narrow window in which CTLA-4 blockade would be most effective, so timing of treatment may be an important factor.20,29,30 Regarding adverse effects, although Ribas et al23 observed grade III/ IV autoimmune toxicity attributable to the treatment, it is unclear whether these adverse effects should be deemed dose limiting, particularly when these toxicities are not life threatening and are self-limited (as in this trial) or require transient treatment with steroids (as in other CTLA-4 blockade trials). Ultimately, tumor immunotherapy must induce autoimmunity to cancer, and the challenge will be how we can control this toxicity, as we have learned to deal with adverse effects of currently used conventional treatments. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES 1. Mueller DL, Jenkins MK, Schwartz RH: Clonal expansion versus functional clonal inactivation: A costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy. Annu Rev Immunol 7:445-480, 1989[Medline] 2. Linsley PS, Brady W, Grosmaire L, et al: Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and Interleukin 2 mRNA accumulation. J Exp Med 173:721-730, 1991 3. Hathcock KS, Laszlo G, Dickler HB, et al: Identification of an alternative CTLA-4 ligand costimulatory for T cell activation. Science 262:905-907, 1993 4. Martin PJ, Ledbetter JA, Morishita Y, et al: A 44 kilodalton cell surface homodimer regulates interleukin 2 production by activated human T lymphocytes. J Immunol 136:3282-3287, 1986[Abstract] 5. Jenkins MK, Taylor PS, Norton SD, et al: CD28 delivers a costimulatory signal involved in antigen-specific IL-2 production by human T cells. J Immunol 147:2461-2466, 1991 6. Harding F, McArthur JG, Gross JA, et al: CD28 mediated signalling costimulates murine T cells and prevents the induction of anergy in T cell clones. Nature 356:607-609, 1992[CrossRef][Medline] 7. Lenschow DJ, Walunas TL, Bluestone JA: CD28/B7 system of T cell costimulation. Ann Rev Immunol. 14:233-258, 1996[CrossRef][Medline] 8. Brunet JF, Denizot F, Luciani MF, et al: A new member of the immunoglobulin superfamily—CTLA-4. Nature 328:267-270, 1987[CrossRef][Medline] 9. Linsley PS, Brady W, Urnes M, et al: CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med 174:561-569, 1991 10. Linsley PS, Greene JL, Brady W, et al: Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. Immunity 1:793-801, 1994[CrossRef][Medline] 11. Walunas TL, Lenschow DJ, Bakker CY, et al: CTLA-4 can function as a negative regulator of T cell activation. Immunity 1:405-413, 1994[CrossRef][Medline] 12. Krummel MF, Allison JP: CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med 182:459-465, 1995 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. Waterhouse P, Penninger JM, Timms E, et al: Lymphoproliferative disorders with early lethality in mice deficient in CTLA-4. Science 270:985-988, 1995 15. Tivol EA, Borriello F, Schweitzer AN, et al: Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3:541-547, 1995[CrossRef][Medline] 16. 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 17. Perrin PJ, Maldonado JH, Davis TA, et al: CTLA-4 blockade enhances clinical disease and cytokine production during experimental allergic encephalomyelitis. J Immunol 157:1333-1336, 1996[Abstract] 18. Luhder F, Hoglund P, Allison JP, et al: Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) regulates the unfolding of autoimmune diabetes. J Exp Med 187:427-432, 1998 19. Leach D, Krummel M, Allison JP: Enhancement of antitumor immunity by CTLA-4 blockade. Science 271:1734-1736, 1996[Abstract] 20. van Elsas A, Hurwitz AA, Allison JP: 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. J Exp Med 190:355-366, 1999 21. van Elsas A, Sutmuller RPM, Hurwitz AA, et al: Elucidating the autoimmune and anti-tumor effector mechanisms of a treatment based on cytotoxic T lymphocyte antigen-4 (CTLA-4) blockade in combination with a B16 melanoma vaccine: Comparison of prophylaxis and therapy. J Exp Med 194:481-489, 2001 22. Hurwitz AA, Foster BA, Kwon ED, et al: Combination immunotherapy of primary prostate cancer in a transgenic mouse model using CTLA-4 blockade. Cancer Res 60:2444-2448, 2000 23. Ribas A, Camacho LH, Lopez-Berestein G, et al: Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte associate antigen-4 monoclonal antibody CP-675,206. J Clin Oncol 23:8968-8977, 2005 24. 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 25. Sanderson K, Scotland R, Lee P, et al: Autoimmunity in a phase I trial of a fully human anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody with multiple melanoma peptides and Montanide ISA 51 for patients with resected stages III and IV melanoma. J Clin Oncol 23:741-750, 2005 26. Phan GQ, Sherry RM, Hwu P, 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 27. Davis TA, Tchekmedyian S, Korman A, et al: MDX-010 (human anti-CTLA4): a phase 1 trial in hormone refractory prostate carcinoma (HRPC). Proc Am Soc Clin Oncol 21:19a, 2002 (abstr 74) 28. Lee PP, Yee C, Savage PA, et al: Characterization of circulating T cells specific for tumor-associated antigens in melanoma patients. Nat Med 5:677-685, 1999[CrossRef][Medline] 29. Hurwitz AA, Yu TF, Leach DR, et al: CTLA-4 blockade synergizes with tumor-derived granulocyte-macrophage colony-stimulating factor for treatment of an experimental mammary carcinoma. Proc Natl Acad Sci U S A 95:10067-10071, 1998 30. Hurwitz AA, Foster BA, Kwon ED, et al: Combination immunotherapy of primary prostate cancer in a transgenic model using CTLA-4 blockade. Cancer Res 60:2444-2448, 2000 Related Article
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
