STUDY Skin Reactions in a Subset of Patients With Stage IV Melanoma Treated With Anti–Cytotoxic T-Lymphocyte Antigen 4 Monoclonal Antibody as a Single Agent Samer H. Jaber, BS; Edward W. Cowen, MD; Leah R. Haworth, RN; Susan L. Booher, RN, MS; David M. Berman, MD, PhD; Steven A. Rosenberg, MD, PhD; Sam T. Hwang, MD, PhD Objective: To describe the clinical and histologic mani- tions that were attributed to anti–CTLA-4 in 8 of them. festations of skin reactions incidentally noted in pa- Skin lesions consisted primarily of discrete, pruritic, ery- tients with stage IV melanoma who were treated with up thematous, minimally scaly papules that typically coa- to 9 mg/kg of a humanized monoclonal antibody reac- lesced into thin plaques on the trunk and extensor sur- tive against human cytotoxic T-lymphocyte antigen 4 faces of the extremities. Extensive alopecia was also noted (anti–CTLA-4) as a single agent every 3 weeks. in 1 patient. Histologically, a superficial, perivascular CD4ϩ-predominant T-cell infiltrate with eosinophils in Setting: Single-institution prospective study. the dermis, rare dyskeratotic cells, and mild epidermal spongiosis were present. An increase (compared with pre- Design: Patients treated with anti–CTLA-4 as a sole agent treatment values) in the peripheral blood eosinophil were prospectively referred for clinicopathologic charac- frequency was observed in patients at the time of skin terization of skin reactions occurring during treatment. eruptions (P=.006). Main Outcome Measures: Specific clinicopatho- Conclusions: Specific features of the skin eruption der- logic features were determined by means of a detailed his- matitis with increased tissue and peripheral blood eo- tory, a physical examination, conventional histologic sinophil levels in a subset of treated patients. Specific fea- analysis, antibody staining, and complete blood cell tures of skin eruption associated with anti–CTLA-4 counts. resemble those described for maculopapular reactions to medications. Results: Nine (14%) of 63 consecutive patients treated with anti–CTLA-4 as a sole agent developed skin erup- Arch Dermatol. 2006;142:166-172 VERCOMING TOLERANCE to arrest of T cells at the G1 phase of the of self-antigens signifi- cell cycle.3 In CTLA-4 knockout mice, a cantly limits the use of rapid, fatal lymphoproliferative disorder de- vaccine therapy for the velops,4 suggesting that CTLA-4 is also in- treatment of cancer.1 De- tegral to the maintenance of tolerance and Ospite multiple trials demonstrating that tu- prevention of autoimmunity. Moreover, mor vaccination results in the develop- CTLA-4 appears to be critical in regulat- ment of enhanced immunity, objective ing TH2vsTH1 differentiation in helper T responses are infrequent. Because most (TH) cells, because activated CTLA-4– known tumor antigens are normal “self- deficient T cells are strongly biased to- 5,6 proteins,” immune regulatory mecha- ward TH2 differentiation. nisms that prevent autoimmunity also pre- Given the integral role of CTLA-4 in the vent robust immune responses to cancer maintenance of tolerance, there has been and peptide vaccines. considerable interest in overcoming tol- erance in the treatment of cancer by block- Author Affiliations: See also page 175 ade of CTLA-4 function. As monotherapy Dermatology (Mr Jaber, in animal models, anti–CTLA-4 monoclo- Drs Cowen and Hwang, and Cytotoxic T-lymphocyte antigen 4 nal antibodies have been most effective in Ms Booher) and Surgery (CTLA-4) is an important costimulatory treating immunogenic tumors, with mini- Branches (Ms Haworth and molecule expressed by activated T cells and mal effects on large established tumors or Dr Rosenberg) and Laboratory 2 2,7 of Pathology (Dr Berman), a subset of regulatory T cells. Engage- weakly immunogenic tumors. Combin- Center for Cancer Research, ment of CTLA-4 inhibits T-cell activation ing anti–CTLA-4 therapy with concurrent National Cancer Institute, by blocking production of interleukin 2 and vaccination with tumor cells that secrete Bethesda, Md. interleukin 2 receptor expression, leading granulocyte-macrophagecolony-stimulating (REPRINTED) ARCH DERMATOL/ VOL 142, FEB 2006 WWW.ARCHDERMATOL.COM 166 ©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 factor substantially enhanced efficacy against poorly immu- nogenic tumors such as B16 melanoma.8 Table 1. Common Toxic Effects Criteria Version 2.0 Recently, results of 3 clinical trials involving the for Desquamation/Rash* use of anti–CTLA-4 in combination with peptide vac- cine for the treatment of cancer have been reported.9-11 Grade Description In total, 40 patients with metastatic melanoma and 2 I Macular or papular eruption or erythema without associated patients with metastatic ovarian cancer were treated symptoms II As grade I but with pruritus or other associated symptoms with anti–CTLA-4 therapy in combination with or covering Ͻ50% of body surface area or localized after peptide vaccine therapy. In one of these trials, a desquamation or other lesions covering Ͻ50% single administration of anti–CTLA-4 in patients for of body surface area whom previous vaccine therapy had failed yielded his- III Symptomatic generalized erythroderma or macular, papular, Ն topathologic evidence of tumor cell death and lym- or vesicular eruption or desquamation covering 50% of body surface area phocytic invasion within some tumors but no objec- IV Generalized exfoliative dermatitis or ulcerative dermatitis tive clinical responses.10 In the other 2 trials in which repeated doses of anti–CTLA-4 were given in combi- *Toxic effects grading system described in Trotti et al.13 nation with peptide vaccine, a subset of patients with metastatic melanoma demonstrated major tumor regression with long tumor-free intervals.9,11 matitis bear clinical and histologic similarities to those Administration of anti–CTLA-4 was associated with reported for maculopapular drug exanthems (MPEs),15 multiple autoimmune toxic effects, including enteroco- which are the most common cutaneous adverse effects litis, hypophysitis, hepatitis, uveitis,12 vitiligo, in- of widely used medications such as aminopenicillins creased antinuclear antibody levels, elevated rheuma- and sulfonamide antimicrobial drugs. toid factor levels, and rashes.9-11 Recent experience at the National Cancer Institute (NCI) Clinical Center showed METHODS that 14 (25%) of 56 patients with stage IV melanoma treated with anti–CTLA-4 and vaccinated with HLA- A*0201–restricted gp100 peptides experienced grades III All patients gave informed consent in an institutional review board–approved protocol in the Surgery Branch of the NCI, to IV autoimmune reactions (ie, reversible [grade III] or Bethesda, Md. Anti–CTLA-4 (MDX-010; Medarex, Prince- irreversible/progressive [grade IV] toxic effects involv- ton, NJ),9 is a fully humanized antibody reactive with ing function of a major organ and requiring immuno- CTLA-4. The major inclusion criteria for patients entering suppressive treatment13), including rashes.14 Autoim- this study for experimental melanoma treatment included mune manifestations were more pronounced in patients being 16 years or older; having a life expectancy 6 months or with more dramatic objective disease responses,9,14 sug- longer, an Eastern Cooperative Oncology Group perfor- gesting that effective anticancer responses may be cor- mance status of 2 or less, and a diagnosis of stage IV mela- noma (except mucosal or ocular melanoma) that is clinically related with autoimmunity to self-antigens other than tu- Ͼ mor antigens. evaluable and measurable; and being postmenopausal ( 1 Rashes have been common adverse effects in recipi- year) or using reliable contraception (if female) or willing to use male contraception during the time of participation in ents of anti–CTLA-4 therapy administered after or in 9 the trial (if male). Major exclusion criteria included a history conjunction with vaccination. Phan et al observed that of malignancy within the previous 5 years (with exceptions rashes developed in 4 (29%) of 14 patients, with 3 of the for certain in situ cancers and basal and/or squamous cell 4 patients experiencing grades III to IV rashes based on carcinoma of the skin); presence of autoimmune disease, common toxic effects criteria version 2.0 (Table 1).13 active infection, or concurrent medical condition requiring Histologically, these showed epidermal spongiosis, use of systemic or topical corticosteroids or immunosup- papillary dermal edema, and a perivascular lympho- pressive agents; being pregnant or nursing; prior treatment cytic infiltrate with eosinophils. Hodi et al10 reported with anti–CTLA-4, or a history of systemic hypersensitivity that all patients (7/7) with metastatic melanoma and 1 to 1 of the investigational agents used in the trial. of 2 with ovarian cancer developed a skin eruption Patients were enrolled in an experimental immunotherapy pro- tocol that contained the following 3 treatment arms: (1) patients (grade I) after anti–CTLA-4 therapy. Last, Sanderson et 11 who were seronegative for human leukocyte antigen (HLA)- al reported that 7 (37%) of 19 patients developed a A*0201 were treated with anti–CTLA-4 alone; (2) patients grade I to II rash. who were seropositive for HLA-A*0201 were randomized to re- Although it has been documented that dermatitis ceive melanoma-associated peptides in conjunction with develops in a significant percentage of patients treated anti–CTLA-4; and (3) patients who were seropositive for