Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis.
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.
Yang
James C
JC
Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. JamesYang@mail.nih.gov
Hughes
Marybeth
M
Kammula
Udai
U
Royal
Richard
R
Sherry
Richard M
RM
Topalian
Suzanne L
SL
Suri
Kimberly B
KB
Levy
Catherine
C
Allen
Tamika
T
Mavroukakis
Sharon
S
Lowy
Israel
I
White
Donald E
DE
Rosenberg
Steven A
SA
D000309:Adrenal Insufficiency / Q000139:chemically induced; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000556:secondary; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D003092:Colitis / Q000139:chemically induced; D004382:Duodenitis / Q000139:chemically induced; D004751:Enteritis / Q000139:chemically induced*; D005260:Female; D006801:Humans; D007018:Hypopituitarism / Q000139:chemically induced; D000074324:Ipilimumab; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000556:secondary; D008175:Lung Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000556:secondary; D008297:Male; D008582:Meningitis, Aseptic / Q000139:chemically induced; D008875:Middle Aged; D010900:Pituitary Diseases / Q000139:chemically induced*; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000074324:Ipilimumab