Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis

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.

FIGURE 1

Patient with hepatic and multiple skeletal metastases from renal cell carcinoma who maintained a partial response for 17 months (baseline left, 2 y follow-up right). Tumor regressions illustrated continue 24 months after starting treatment, despite receiving high-dose dexamethasone for colitis at 4 months and showing progression in a solitary lymph node at 17 months.

FIGURE 2

A, Patient with obvious tumor progression at multiple sites after 2 doses of ipilimumab, who then experienced mild colitis after 2 additional doses and had marked tumor regression that continues at 21+ months. B, Another patient’s measured tumor burden in 7 pulmonary metastases is shown as a percent of their baseline size. Tumor remained stable during 4 doses of ipilimumab administered without symptoms, but regressed promptly after patient experienced a bout of biopsy-documented enteritis.