Clinical and biological effects of an agonist anti-CD40 antibody. A Cancer Research UK phase I study
Mené sur 28 patients atteints d'une tumeur solide ou d'un lymphome diffus à grandes cellules B exprimant l'antigène CD40, cet essai de phase I analyse l'évolution de divers paramètres biologiques et cliniques suite à l'administration d'un anticorps anti CD40
Purpose: This study was of biological effects and maximum tolerated dose (MTD) of agonistic anti-CD40 antibody, ChiLob7/4, in patients (pts) with CD40-expressing solid tumors and diffuse large B-cell lymphoma (DLBL). Potential mechanisms of action include direct cytotoxic effects on tumor cells and conditioning of antigen-presenting cells. Experimental Design: ChiLob7/4 was given by 4 weekly IV doses from 0.5 to 240mg/dose. ELISA's were used to quantify ChiLob7/4 levels and anti-chimeric Ab (HACA) responses. Pharmacodynamic assessments included quantitation of T-, NK-, and B-cell numbers in blood by flow cytometry and a cytokine panel Luminex®. Planned dose escalation was in cohorts of 3 pts until MTD or biological effect, defined as reduction of peripheral blood CD19+ B-cells to 10% of baseline. Results: Twenty-eight subjects received 29 courses. MTD was 200mg x 4, with limiting toxicity of liver transaminitis at 240mg. At 200mg the trough level pre-treatment was >25μg/ml. Grade 1-2 infusion reactions were seen above 16mg, preventable with single dose corticosteroid premedication. HACA responses were seen after doses between 1.6mg and 50mg, but not higher. There were dose-dependent falls in blood B-cell numbers accompanied by reduced expression of CD21, and transient reductions in NK cell numbers with increased CD54 expression from 50mg. MIP-1β and IL12 plasma concentrations rose after 16mg. Fifteen of 29 treatments were accompanied by disease stabilisation for median 6 months, the longest 37 months. Conclusions: ChiLob7/4 can activate B- and NK-cells at doses that can be administered safely, and should be tested in combination with other antibodies and chemotherapy agents.