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Clinical Trial
. 2006 Jul-Aug;29(4):455-63.
doi: 10.1097/01.cji.0000208259.73167.58.

Intrapatient dose escalation of anti-CTLA-4 antibody in patients with metastatic melanoma

Affiliations
Clinical Trial

Intrapatient dose escalation of anti-CTLA-4 antibody in patients with metastatic melanoma

Ajay V Maker et al. J Immunother. 2006 Jul-Aug.

Abstract

We previously reported our experience in treating 56 patients with metastatic melanoma using a human anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody. Durable tumor regressions were seen that correlated with the induction of autoimmune toxicities. In this study, we treated 46 additional patients using an intrapatient dose escalation schema to test whether higher doses of anti-CTLA-4 antibody would induce increased autoimmunity and concomitant tumor regression. Twenty-three patients started anti-CTLA-4 antibody administration at 3 mg/kg and 23 patients started treatment at 5 mg/kg, receiving doses every 3 weeks. Patients were dose-escalated every other dose to a maximum of 9 mg/kg or until objective clinical responses or grade III/IV autoimmune toxicity were seen. Escalating doses of antibody resulted in proportionally higher plasma concentrations. Sixteen patients (35%) experienced a grade III/IV autoimmune toxicity. Five patients (11%) achieved an objective clinical response. Two of the responses are ongoing at 13 and 16 months, respectively. Flow cytometric analysis of peripheral blood revealed significant increases in both T-cell surface markers of activation and memory phenotype. Thus, higher serum levels and prolonged administration of anti-CTLA-4 antibody resulted in a trend toward a greater incidence of grade III/IV autoimmune toxicity than previously reported, but did not seem to increase objective response rates.

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Figures

FIGURE 1
FIGURE 1
Patient 7 experienced complete regression of a large peri-portal lesion after receiving 9 mg/kg of anti–CTLA-4 antibody. He remains a responder at over 11 months.
FIGURE 2
FIGURE 2
Patient 10 experienced complete regression of an intramuscular lesion after receiving 9 mg/kg of anti–CTLA-4 antibody. He was a responder for 9 months until the growth of new lung lesions.
FIGURE 3
FIGURE 3
Patient 18 experienced autoimmune nephritis after receiving 3 doses (3, 3, and 5 mg/kg) of anti–CTLA-4 antibody. The renal stroma was edematous and infiltrated with plasma cells, eosinophils, and T lymphocytes. The tubule epithelium was abnormal with scant cytoplasm (upper panel, magnification 200 ×). A CD3 stain revealed lymphocytic invasion into the tubules, similar to acute transplant rejection (lower panel, magnification 600 ×).
FIGURE 4
FIGURE 4
Patient 1 experienced enlargement of his pituitary gland and symptoms of hypopituitarism after receiving a maximal dose of 9 mg/kg of anti–CTLA-4 antibody. Eight of 46 patients (17%) experienced autoimmune hypophysitis.

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