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(Anti-CTLA4 Antibody) Causes Regression of Metastatic Renal Cell Cancer Associated with Enteritis and Hypophysitis James C

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(Anti-CTLA4 Antibody) Causes Regression of Metastatic Renal Cell Cancer Associated with Enteritis and Hypophysitis James C CLINICAL STUDY Ipilimumab (Anti-CTLA4 Antibody) Causes Regression of Metastatic Renal Cell Cancer Associated With Enteritis and Hypophysitis James C. Yang,* Marybeth Hughes,* Udai Kammula,* Richard Royal,* Richard M. Sherry,* Suzanne L. Topalian,* Kimberly B. Suri,* Catherine Levy,* Tamika Allen,* Sharon Mavroukakis,* Israel Lowy,w Donald E. White,* and Steven A. Rosenberg* (J Immunother 2007;30:825–830) Summary: The inhibitory receptor CTLA4 has a key role in peripheral tolerance of T cells for both normal and tumor- associated antigens. Murine experiments suggested that block- ade of CTLA4 might have antitumor activity and a clinical t has become clear that T-cell responses are under the experience with the blocking antibody ipilimumab in patients Icontrol of both activating and inhibitory coreceptors.1,2 with metastatic melanoma did show durable tumor regressions The interaction of the T-cell receptor with its cognate in some patients. Therefore, a phase II study of ipilimumab was epitope, presented by the correct major histocompatibility conducted in patients with metastatic renal cell cancer with a complex molecule (‘‘signal one’’) is only one component primary end point of response by Response Evaluation Criteria of the complex signaling required to optimally activate a in Solid Tumors (RECIST) criteria. Two sequential cohorts T cell to proliferate, differentiate, and exhibit effector received either 3 mg/kg followed by 1 mg/kg or all doses at functions.3 The critical role of inhibitory signaling in 3 mg/kg every 3 weeks (with no intention of comparing cohort preventing, limiting, or terminating T-cell responses has response rates). Major toxicities were enteritis and endocrine recently become apparent.4 T-regulatory cells (T-regs) deficiencies of presumed autoimmune origin. One of 21 patients and inhibitory receptors such as CTLA4 and PD-1 are receiving the lower dose had a partial response. Five of 40 major regulators of the T-cell response and play patients at the higher dose had partial responses (95% significant roles in tolerance to ‘‘self.’’5 It is now known confidence interval for cohort response rate 4% to 27%) and that the tumor-bearing host can mount T-cell responses responses were seen in patients who had previously not to numerous tumor-associated antigens that can either be responded to IL-2. Thirty-three percent of patients experienced tissue differentiation antigens, overexpressed normal self a grade III or IV immune-mediated toxicity. There was a highly proteins, or tumor-associated mutated proteins.6 Despite significant association between autoimmune events (AEs) and the presence of numerous immunogenic targets on both tumor regression (response rate = 30% with AE, 0% without murine and human tumors, these tumors can still grow in AE). CTLA4 blockade with ipilimumab induces cancer regres- immunocompetent hosts. The failure to reject such sion in some patients with metastatic clear cell renal cancer, even tumors can result from inadequate stimulation (‘‘ignor- if they have not responded to other immunotherapies. These ance’’) or immunologic tolerance, yet the relative regressions are highly associated with other immune-mediated contribution of these 2 mechanisms in human cancer events of presumed autoimmune origin by mechanisms as yet remains controversial. undefined. CTLA4 (CD152) is an inducible receptor expressed by T cells which ligates the B7-family of molecules Key Words: renal cancer, immunotherapy, CTLA-4, ipilimumab, (primarily CD80 and CD86) on antigen-presenting cells.7 costimulation When triggered, it inhibits T-cell proliferation and function. Mice genetically deficient in CTLA4 develop lymphoproliferative disease and autoimmunity.8 In pre- Received for publication March 21, 2007; accepted June 11, 2007. clinical models, CTLA4 blockade also augments anti- From the *Surgery Branch, Center for Cancer Research, National tumor immunity.9,10 These findings led to the w Cancer Institute, Bethesda, MD; and Medarex Corp, Princeton, NJ. development of antibodies that block CTLA4 for use in Financial Disclosure: Dr Israel Lowry is an employee of Medarex Corp and as such receives salary and holds stock options from Medarex. cancer immunotherapy. Initial studies in patients with The remaining authors have declared there are no financial conflicts melanoma showed that one such antibody, ipilimumab of interest related to this work. (previously MDX-010; Medarex Inc), could cause objec- Current address: Suzanne L. Topalian, Johns Hopkins School of tive durable tumor regressions.11 Objective responses of Medicine, Baltimore, MD. Reprints: Dr James C. Yang, Rm 10/3-5952, 9000 Rockville Pike, measurable disease were only documented for patients Bethesda, MD 20892 (e-mail: [email protected]). with melanoma, although reductions of serum tumor Copyright r 2007 by Lippincott Williams & Wilkins markers was seen for some patients with ovarian or J Immunother Volume 30, Number 8, November/December 2007 825 Yang et al J Immunother Volume 30, Number 8, November/December 2007 prostate cancer.12 Many of these patients had received TABLE 1. Patient Characteristics concurrent or prior antitumor vaccines and based on murine models, it was hypothesized that these vaccines Cohort B may have also contributed to the responses seen. Like Cohort A Previous IL-2 No Previous IL-2 melanoma, renal cell cancer (RCC) is responsive to Patients (n = ) 21 26 14 immunotherapy with interleukin-2, yet few active vac- Median age (range) 59 (31-70) 52 (32-67) 59 (34-69) cines exist which target RCC-associated antigens. There- Sex (M/F) 17/4 16/10 12/2 ECOG PS fore, a phase II trial of single-agent ipilumimab in 015166 patients with metastatic renal cancer was undertaken to 1 6 10 8 investigate whether other immunoresponsive tumors Sites of metastases could respond to CTLA4 blockade and if this could Lung only 2 5 2 occur in the absence of any vaccination. Any liver and/or bone 6 8 4 Previous therapy Nephrectomy 21 26 13 MATERIALS AND METHODS IL-2 21 26 0 Chemotherapy 6 2 0 All treatment was administered under a Food and Drug Administration and Institutional Review Board- ECOG PS indicates Eastern Clinical Oncology Group performance status. approved clinical protocol after obtaining the written, informed consent of the participants. Ipilimumab was provided by the Medarex Corp (Princeton, NJ). Patients ipilimumab is described in detail elsewhere13). One of over 16 years of age with measurable metastatic clear cell these 3 patients also had extensive generalized rash and renal cancer and no systemic therapy within the past 3 multiarticular arthritis. In 2 of these patients, high-dose weeks were considered eligible (patients recently disconti- systemic dexamethasone followed by a rapid taper was nuing other therapies were required to show evidence of given to control diarrhea and the other patient responded disease progression before entry). Patients were excluded to steroid enemas. The patient who had colitis, rash, and if they had an Eastern Clinical Oncology Group arthritis and who received indomethacin and steroid performance status of Z2, significant abnormalities in enemas, had a partial response in multiple lung and hematologic or major organ laboratory parameters, adrenal metastases that was maintained for 18 months significant active viral or bacterial infections, prior before progressing with an isolated femoral bony CTLA4-directed therapies, a requirement of systemic metastasis. steroids or renal cancer of nonclear cell type. Patients Forty patients were enrolled in cohort B, 14 with no with preexisting autoimmune diseases were also excluded. prior IL-2 and 26 after prior IL-2 therapy. Their All patients were treated intravenously every 3 characteristics and treatment features are listed in weeks with one of 2 dosing regimens in sequential Table 1. Seventeen of these 40 patients (43%) incurred cohorts: cohort A—patients received a loading dose of clinically significant immune-mediated toxicities (14 grade 3 mg/kg with all subsequent doses given at 1 mg/kg. III, 2 grade IV, 1 grade V), thought to be of autoimmune Cohort B—patients received all doses at 3 mg/kg only. etiology. Thirteen had enteritis alone, 1 had hypophysitis, In cohort B, patients who had not had prior IL-2 could 1 had both of these manifestations, 1 patient (with tumor participate if they were ineligible for high-dose IL-2 or in his sole remaining adrenal gland) showed primary had limited or indolent disease documented. Evaluation adrenal insufficiency, and 1 patient had aseptic meningitis for response was by Response Evaluation Criteria in with cerebrospinal fluid lymphocytosis (Table 2). Solid Tumors (RECIST) criteria and radiologic studies As reported separately,13 gastrointestinal toxicity from were performed before every other dose with designated treatment evaluation points after every 4 doses. Owing to study design and size, no intention to compare cohorts for TABLE 2. Toxicities of Ipilimumab rates of response was intended. Response durations are No. Patients Doses of Ipilimumab Given measured from initial treatment to date of relapse. Repeat treatment courses (for up to 1 y) were instituted unless Cohort A* 21 Enteritis/colitis 3 5, 5, 6 limiting toxicity or objective tumor progression was Dermatitis 1 5 documented. Arthralgia 1 5 Cohort Bw Previous IL2 26 RESULTS Enteritis/colitis 8 1, 1, 1, 2, 4, 4, 4, 6 Twenty-one patients were enrolled in cohort A. All Hypopituitarism 2 4, 5 had had previous IL-2 therapy. Their characteristics and Aseptic meningitis 1 4 No previous
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