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The clinical utility of cytotoxic T lymphocyte antigen 4abrogation by human antibodiesJeffrey S. Webera,b The recent cloning and identification of a variety of T lymphocyte antigen 4 antibodies by the use of regulatory and counter-regulatory molecules on T cells and corticosteroids does not eliminate clinical benefit.
antigen presenting cells has led to the development of antibodies and other molecules that either stimulate or abrogate these immune functions. Patients withautoimmune disease, graft rejection and cancer might benefit from the ability to manipulate immune regulatory Keywords: autoimmunity, human antibody, immune regulation, T cell pathways. The first demonstration of clinical benefit by modulation of immune regulation in cancer involves the Departments of aMedicine bMolecular Microbiology and Immunology, Keck use of human antibodies against cytotoxic T lymphocyte School of Medicine, University of Southern California, Los Angeles, California, antigen 4. Murine preclinical studies suggested that cytotoxic T lymphocyte antigen-4 abrogation would provide Correspondence and requests for reprints to Professor Jeffrey Weber, MD, PhD, clinical benefit after an antitumor vaccination. Early trials of Departments of Medicine, Molecular Microbiology and Immunology, Keck School this antibody in patients with melanoma have shown of Medicine, University of Southern California/Norris Cancer Center 1441Eastlake Avenue, Suite 3440, Los Angeles, CA 90033, USA antitumor activity with and without vaccines that is Tel: + 1 323 865 3962; fax: + 1 323 865 0061; e-mail: [email protected] associated with a state of autoimmunity. Surprisingly, the reversal of the state of autoimmunity induced by cytotoxic Received 14 June 2006 Accepted 20 June 2006 T cell activation, can be detected within several hours The explosion of information on the identity of immune and reaches a maximum after 2–3 days [1,2]. After T cell regulatory molecules that provide both inhibitory and activation, most CTLA-4 is found in intracellular vesicles stimulatory signals to T cells has laid the groundwork for localized in apposition to an area of the cytoplasm close to testing novel antibodies and small molecules that the site of T cell receptor engagement known as the abrogate their signals. Cytotoxic T lymphocyte antigen immunologic synapse. Once localized beneath the T cell– 4 (CTLA-4), programmed death 1 (PD-1) and B and T antigen presenting cell interface, CTLA-4 then trans- lymphocyte antigen (BTLA) have been shown to be locates to the T cell surface where it carries out its counter-regulatory molecules that attenuate T cell inhibitory function, and has a fairly short half-life because activity and are implicated in the induction of tolerance of lysosomal targeting. CTLA-4 can compete for B7 co- [1–5]. The goal for the clinical use of antibodies that stimulatory binding, inhibit interleukin (IL)-2 production abrogate T cell regulatory activity is to break tolerance to as well as kinase cascades and down-regulate key self-antigens and augment T cell activity against self- components of the cell cycle machinery like cyclin- tumor antigens to achieve regression of established tumor dependent kinase 4 (Cdk-4), Cdk-6 and cyclin D3 that or prevent recurrence in patients with high risk of relapse are required for cell cycle progression [3].
of their cancer after surgery. In the ensuing review, wewill briefly describe the biochemistry of regulatory andcounter-regulatory molecules on T cells, summarize some Preclinical and in-vitro experiments show the important preclinical murine and in-vitro data that focus importance of cytotoxic T lymphocyte antigen on an important molecule, CTLA-4, and give a detailed description of the clinical experience with two humanCTLA-4 antibodies. The generation of autoimmunity as a The regulatory role of CTLA-4 was shown by the new paradigm for cancer treatment will be discussed.
generation of CTLA-4 knock-out mice which demon-strated that mice would die within 3–4 weeks ofmyocarditis and pancreatitis, with massive infiltration of Identification and characterization of the lymphocytes into normal nodal and other tissue [6].
activity of cytotoxic T lymphocyte antigen 4, These data established the idea that CTLA-4 had an important inhibitory effect on T cell immunity. It is felt CTLA-4 is a regulatory molecule found on T cells that is a that CTLA-4 may set a T-cell signaling threshold, homologue of CD28. Its expression is up-regulated after and that its abrogation may facilitate the expansion of Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
self-reactive T cells, of considerable value during the immune activation and subsequent tumor regression may generation of tumor-specific immunity.
have lowered the threshold of costimulatory signalsneeded for activation and differentiation of CD8 + Tcells to a level that did not require CD4 + T cell- A variety of antibodies against CTLA-4 that abrogate its mediated help via CD40 ligand. Alternatively, CTLA-4 function have been tested to determine whether blockade may have expanded a critical number of tumor- antitumor immunity can be augmented in their presence.
reactive T cells needed to mediate tumor rejection. One Experiments with a variety of transplantable murine possibility is that effector CD8 + T cells may be tumors showed that treatment with antibodies that block generated in situations in which CD4 + T cells are CTLA-4 resulted in tumor regression, even a week after absent or ineffective. CTLA-4 antibody was also found to tumors are established, with long-lasting immunity to re- be effective in mediating regression together with a GM- challenge. CTLA-4 blockade enhanced immune re- CSF-transduced cell vaccine in a spontaneously arising sponses to weakly immunogenic tumors [7,8]. CTLA-4 prostate cancer model [14], and could eliminate recur- blocking antibody as a single agent, however, was not rence in a model of resected cancer with the same effective in causing regression of poorly immunogenic, spontaneously arising tumor at risk of relapse [15].
fast growing tumors such as B16 melanoma. The failure of Abrogation of CTLA-4 was also found to augment the CTLA-4-abrogating antibodies against poorly immuno- effects of suboptimal doses of chemotherapy in a genic tumors led to its combination with other antitumor transplanted murine tumor model [16], further support- therapies. Irradiated tumor cell vaccines genetically ing the antitumor role of CTLA-4 antibodies and engineered to produce granulocyte-macrophage colony- suggesting a possible additive or even synergistic role stimulating factor (GM-CSF) can induce prophylactic immunity to B16 melanoma by cross-priming [9]. TheGM-CSF/B16 vaccine does not, however, impact onpreexisting established tumors. When the cell vaccine In the prior experiments in mice, CD4 + T cells were not was combined with anti-CTLA-4 antibody, B16 tumors required for tumor rejection after combined vaccination completely regressed when vaccination was initiated and CTLA-4 abrogation [17], but tumor rejection and 4 days after tumor initiation and tumor size significantly depigmentation were actually enhanced in their absence.
decreased even when vaccination was delayed for 1 week This suggested that T regulatory cells might play a role in modulating responses to self-differentiation antigens.
Consistent with this hypothesis, depletion of CD25 +cells before vaccine and CTLA-4 abrogation therapy Regression of B16 melanoma after immunization with a increased its effectiveness, allowing the rejection of larger GM-CSF-transduced tumor cell vaccine with anti-CTLA- tumor burdens [18]. This increase in antitumor efficacy 4 antibody was accompanied by vitiligo characterized by was associated with an increase in the number of the presence of inflammatory cells and disappearance of melanoma antigen-specific T cells. These findings melanocytes in affected areas of the skin [11]. Depig- suggested that T regulatory cells may have interfered mentation was not observed in mice immunized with a with the induction of antitumor immunity and should be GM-CSF/B16 vaccine alone. This depigmentation sug- factored into the development of tumor immunotherapy gested that the antitumor response was at least in part treatments that include CTLA-4 abrogation. CTLA-4, directed against differentiation-related self-antigens, and however, did not appear to mediate suppression by T suggested that CTLA-4 blockade induced breaking of regulatory cells, and T regulatory cells and CTLA-4 may peripheral T cell tolerance [12]. Generation of prophy- represent two independent mechanisms involved in lactic responses by the GM-CSF-transduced cell vaccine did not depend on CD8 + T cell activity, but did requireCD4 + T cells in the above experiments. This suggestedthat cross-priming resulted in the induction of CD4 + T Clinical experience with two different cyto- cells with specificity for major histocompatibility complex class II-restricted peptides derived from the B16 tumor cells which themselves were known to be class II Single dose phase I trials of two different anti-CTLA-4 negative, and that tumor was eliminated by other effector antibodies have been conducted. Patients with metastatic cells [13]. In contrast, rejection of established tumors by melanoma and ovarian cancer were treated with single the GM-CSF–B16 vaccine in combination with anti- doses of MDX-010 or Ipilimumab from Medarex at doses CTLA-4 was independent of CD4 + T cells. CD8 + T from 1 to 3 mg/kg [19,20]. Two patients of 17 treated had cells and cells expressing NK1.1 were required for a partial response, and both the responders had melanoma rejection of established tumor, as were perforin and and had previously been vaccinated with a gene- Fas–Fas ligand. These data indicate that CTLA-4 transduced cell vaccine. Interestingly, of the six patients blockade directly induced cytotoxic CD8 + T lympho- with ovarian cancer, there were no objective responders, cytes in the absence of T cell help. The mechanism of but all six had evidence of tumor necrosis after resection Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
CTLA-4 abrogation by human antibodies Weber of accessible lesions. One patient developed rash, and one without autoimmunity, similar to that seen in the trials pruritis, neither of which was dose limiting after a single of Ipilimumab alone or with vaccine. Three of six dose dose. The antibody was then tested at a fixed dose of limiting toxicities were observed at the 15 mg/kg dose, so 3 mg/kg every 3 weeks with a multi-peptide gp100 the dose chosen for a phase II testing was 10 mg/kg.
vaccine that included Montanide ISA 51, an oil-basedadjuvant, in patients with refractory metastatic melanoma Ipilimumab has also been combined with high dose IL-2 [21]. Fifty-six patients were treated with up to four doses and with Dacarbazine, both FDA approved agents for every 3 weeks. Seven responses were seen in that trial, melanoma [25,26]. A small randomized trial of Ipilimu- five partial responses (PR) and two complete responses mab alone or with Dacarbazine at 250 mg/mol/l2 on days (CR). Five of the responses were sustained beyond 25 1–5 given every 3 weeks was conducted with preliminary months and are ongoing. Of 14 there were 5 responders in results presented at the American Society for Clinical patients with grade III or more autoimmunity, compared Oncology meeting in 2005 [25]. For 35 patients who with two responses in 42 patients without autoimmune received the combination, there were six objective side effects, with a P < 0.008 for the association between responses for a 17% response rate, with a median survival autoimmunity and clinical response. The autoimmune of 14.2 months; for 37 patients who received Ipilimumab manifestation observed in that trial was named immune alone at 3 mg/kg every 3 weeks, the response rate was only 5% with a median survival of 11.2 months. Thefavorable survival results of the combination therapy have Ipilimumab has also been tested in several studies as an led to a large phase III randomized trial of Dacarbazine adjuvant for a multi-peptide gp100, Melan-A and with placebo compared with Dacarbazine plus Ipilimu- tyrosinase vaccine in patients with resected high-risk mab at 10 mg/kg for patients with previously untreated stages III and IV melanoma [22]. In the first trial, 19 patients received escalating doses of antibody from 0.3 to1 to 3 mg/kg every 4 weeks for six doses, then two more Ipilimumab was tested in an escalating dose trial with doses at a 3-month interval. In a follow-up trial, 25 IL-2 at the National Cancer Institute (NCI) standard additional patients received seven doses of Ipilimumab at dose of 720,000 IU/kg given intravenously every 8 h [26].
3 mg/kg every 8 weeks with the same vaccine given 12 Thirty-six patients were treated with Ipilimumab doses times in 12 months. Dose limiting toxicity consisting of from 0.3 to 3 mg/kg. Eight responses were found, with IBEs similar to those observed in the trial in metastatic three CR and five PR. Twenty-four patients received two disease was observed in three out of five patients at 3 mg/ cycles of IL-2 with antibody at 3 mg/kg four times. Five of kg every 4 weeks in the first trial, so the second trial was 24 patients had objective responses, all with autoimmune performed with antibody at 3 mg/kg but given every 8 side effects, and the IBE rate of five of 24 seemed no weeks to lessen the toxicity. For 22 patients with an IBE, different from prior trials of the antibody at that dose, there were five relapses, versus 14 of 22 without an IBE.
indicating that the IL-2 might have additive benefit For all 44 patients in the two trials, there was an clinically but no clear alteration in the IBE rate. This association between immune breakthrough events and combination deserves to be taken further in a phase II time to relapse, with P < 0.01. Immune responses to the three melanoma antigens were observed in most patientson both trials, but not clearly different from prior trials Clinical benefit correlates with autoimmune without CTLA-4 abrogation. A similar spectrum of side effects after cytotoxic T lymphocyte autoimmunity was seen as in the trials of Ipilimumab in unresectable stage IV melanoma. These data support and The extensive published experience with groups at NCI extend the idea that IBEs are associated with clinical and University of Southern California using Ipilimumab benefit after CTLA-4 abrogation, and suggest that the and data from a published phase I dose escalating trial of antitumor activity of Ipilimumab is clearly associated with Ticilimumab indicate that similar dose limiting auto- and may depend on the autoimmune effects [23].
immune phenomena that have been termed ‘immunebreakthrough events’ or IBEs have been observed with Anti-CTLA-4 antibody CP-675,206 from Pfizer (New the use of both antibodies [23,24]. The principal side London, Connecticut, USA), or Ticilimumab, has been effects of these antibodies have been diarrhea, colitis, tested in a single dose phase I trial at doses from 0.01 to hypophysitis and skin reactions. The spectrum of 15 mg/kg [24]. Thirty-nine patients were treated, of gastrointestinal side effects can range from several loose whom 34 had melanoma. Four objective responses were bowel movements daily to bloody diarrhea and colonic noted with two CR and two PR of 29 evaluable melanoma perforation. At the NCI, the incidence of colitis was patients (13%). All four responses were sustained for summarized in 193 patients with melanoma and renal more than 25 months. Three of 12 responses had cancer who received Ipilimumab alone or with a vaccine autoimmune side effects, compared with one of 18 [27]. Forty one of those patients, or nearly 21%, had Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
evidence of grade III or greater diarrhea or colitis. Thirty Mechanism of action of cytotoxic T lympho- six were colonoscoped, with findings of diffuse ulcera- tions and biopsy-proven colitis. The onset of symptoms The mechanism by which CTLA-4 abrogation induces occurred a median of 11 days after the last infusion of tumor regression and protects against relapse appears to antibody. Most patients recovered with the use of be linked to the ability to induce autoimmunity as intravenous and oral steroids in tapering doses, some- manifested by IBEs. An attractive hypothesis is that T times requiring long durations of 1–2 months. Often regulatory cells, which are CD4 + , CD25 + cells that uveitis and/or photophobia was associated with the express the marker FoxP3 and are CTLA-4 positive, may gastrointestinal findings, as was fevers [28]. Ulcerations be suppressed or eliminated by CTLA-4 abrogation, could be seen in the pharynx, stomach and small bowel as unleashing antitumor immune effectors and also causing well as the colon or rectum. Four patients in that cohort ‘bystander’ damage to the gastrointestinal tract and other were resistant to steroid tapers and received Remicade organs manifested as autoimmune colitis and other IBEs.
(Infliximab), a chimeric antitumor necrosis factor block- Little evidence exists to favor this hypothesis, however, ing antibody, with relief of symptoms. Four patients had because work by the NCI group has shown no evidence of perforations, of which three had renal cell carcinoma. The any effect of CTLA-4 antibodies on T cell regulatory mortality rate of those with gastrointestinal toxicity was activity in vitro or in vivo using peripheral blood cells from 5%. A striking association of gastrointestinal autoimmune patients receiving Ipilimumab [30]. No phenotypic manifestations with clinical response in metastatic changes in numbers of CD4 + CD25 + T regulatory cells disease, and with time to relapse in patients with high- were observed in either of the early trials of Ipilimumab risk resected melanoma was observed [21,22].
with vaccines [19–22]. Finally, the murine data do notsupport the idea that T regulatory activity is required for The same group from NCI also reported on the incidence the antitumor activity of CTLA-4 abrogating antibodies of hypophysitis with Ipilimumab, which was documented [31,32]. In contrast, objective responses in melanoma in eight of 163 cases, approximately 5% [29]. This patients who received Ticilimumab were associated with condition, which is rarely reported post-partum, pre- reductions in regulatory T cells and constitutive high sented with edema and heterogenous enhancement of levels of IL-10, detection of increased non-specific IL-2 the pituitary on magnetic resonance imaging, and low secretion and a positive correlation between CTLA-4 and adrenocorticotropic hormone and/or thyroid stimulating glucocorticoid-induced tumor necrosis factor receptor hormone as well as cortisol. Patients required replace- detected by reverse-transcriptase polymerase chain reac- ment with corticosteroids and/or mineralocorticoids as tion [33]. Non-responders had stable levels of T well as thyroid hormones depending on which axis of the regulatory cells and high IL-10 secretion, and a positive pituitary was affected. As with colitis, the incidence of correlation between CTLA-4 and PD-1. These data are hypophysitis as an IBE was associated with clinical consistent with the idea that CTLA-4 abrogation might response, of the eight patients described with hypo- alter T regulatory cell activity. An alternative idea is that physitis, five had a clinical response with P < 0.008 for CTLA-4 antibodies directly impact on the activity of the association. Long-term hormone replacement has effector cells, promoting both tumor-specific and non- been required in virtually all patients with this form specific T cells with low avidity for self-antigens. Some of the clues to favor this idea are the reproducible increasein activated CD4 + /HLA-DR + T cells observed withboth Ipilimumab and Ticilimumab treatment, and the Uveitis as an IBE has been found to be associated with evidence that trafficking molecules such as CCR4 are colitis. In a study of 40 patients with colitis, the incidence altered on T cells in patients treated with Ipilimumab of uveitis was significant, with inflammatory cells in the anterior chamber, and photophobia as common manifes-tations [28]. The condition was successfully treated in all cases with prolonged administration of steroid topical CTLA-4 abrogating antibodies are the first in a class of antibodies that alter T cell function by either abrogatinginhibitory influences or potentiating their activation. An The immediate use of high-dose intravenous steroids, attractive feature of these antibodies is the induction of followed by a tapering dose of oral prednisone, has been long-term, sustained clinical responses in those who are found to induce recovery in most cases of colitis and other refractory to prior therapy. The proportion of objective grade III or above toxicity. Budesonide or Entocort, an responders is modest, in the range of 10–20%, but an orally administered and poorly absorbed steroid, has unknown number of patients with stable disease have been used in patients with grade II diarrhea, and is apparently never progressed. It is not clear that optimal currently being tested in a placebo-controlled rando- dosing and scheduling of this interesting drug has been mized phase II trial with reduction of colitis and diarrhea achieved. It is certainly not clear what immunomodulators and cytotoxics would be best to combine with CTLA-4 Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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