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 Topalian, Kimberly B. Suri, Catherine Levy, Tamika Allen, Sharon Mavroukakis, Israel Lowy, Donald E. White, Steven A. Rosenberg

Research output: Contribution to journalArticle

Abstract

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 blockade of CTLA4 might have antitumor activity and a clinical experience with the blocking antibody ipilimumab in patients with metastatic melanoma did show durable tumor regressions in some patients. Therefore, a phase II study of ipilimumab was conducted in patients with metastatic renal cell cancer with a primary end point of response by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Two sequential cohorts received either 3 mg/kg followed by 1 mg/kg or all doses at 3 mg/kg every 3 weeks (with no intention of comparing cohort response rates). Major toxicities were enteritis and endocrine deficiencies of presumed autoimmune origin. One of 21 patients receiving the lower dose had a partial response. Five of 40 patients at the higher dose had partial responses (95% confidence interval for cohort response rate 4% to 27%) and responses were seen in patients who had previously not responded to IL-2. Thirty-three percent of patients experienced a grade III or IV immune-mediated toxicity. There was a highly significant association between autoimmune events (AEs) and tumor regression (response rate=30% with AE, 0% without AE). CTLA4 blockade with ipilimumab induces cancer regression in some patients with metastatic clear cell renal cancer, even if they have not responded to other immunotherapies. These regressions are highly associated with other immune-mediated events of presumed autoimmune origin by mechanisms as yet undefined.

Original languageEnglish (US)
Pages (from-to)825-830
Number of pages6
JournalJournal of Immunotherapy
Volume30
Issue number8
DOIs
StatePublished - Nov 2007

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Enteritis
Renal Cell Carcinoma
Anti-Idiotypic Antibodies
Peripheral Tolerance
Neoplasms
Blocking Antibodies
ipilimumab
Hypophysitis
Neoplasm Antigens
Immunotherapy
Interleukin-2
Melanoma
Confidence Intervals
T-Lymphocytes

Keywords

  • Costimulation
  • CTLA-4
  • Immunotherapy
  • Ipilimumab
  • Renal cancer

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Immunology

Cite this

Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. / Yang, James C.; Hughes, Marybeth; Kammula, Udai; Royal, Richard; Sherry, Richard M.; Topalian, Suzanne; Suri, Kimberly B.; Levy, Catherine; Allen, Tamika; Mavroukakis, Sharon; Lowy, Israel; White, Donald E.; Rosenberg, Steven A.

In: Journal of Immunotherapy, Vol. 30, No. 8, 11.2007, p. 825-830.

Research output: Contribution to journalArticle

Yang, JC, Hughes, M, Kammula, U, Royal, R, Sherry, RM, Topalian, S, Suri, KB, Levy, C, Allen, T, Mavroukakis, S, Lowy, I, White, DE & Rosenberg, SA 2007, 'Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis', Journal of Immunotherapy, vol. 30, no. 8, pp. 825-830. https://doi.org/10.1097/CJI.0b013e318156e47e
Yang, James C. ; Hughes, Marybeth ; Kammula, Udai ; Royal, Richard ; Sherry, Richard M. ; Topalian, Suzanne ; Suri, Kimberly B. ; Levy, Catherine ; Allen, Tamika ; Mavroukakis, Sharon ; Lowy, Israel ; White, Donald E. ; Rosenberg, Steven A. / Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. In: Journal of Immunotherapy. 2007 ; Vol. 30, No. 8. pp. 825-830.
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