Clinical and Biological Effects of an Agonist Anti-CD40 Antibody: A Cancer Research UK Phase I Study

Johnson, P., Challis, R., Chowdhury, F., Gao, Y., Harvey, M., Geldart, T., Kerr, P., Chan, C., Smith, A., Steven, N., Edwards, C., Ashton-key, M., Hodges, E., Tutt, A., Ottensmeier, C., Glennie, M. and Williams, A. (2015) Clinical and Biological Effects of an Agonist Anti-CD40 Antibody: A Cancer Research UK Phase I Study. Clinical Cancer Research, 21 (6), 1321-1328. (doi:10.1158/1078-0432.CCR-14-2355). (PMID:25589626)

Abstract

Purpose: This phase I study aimed to establish the biologic effects and MTD of the agonistic IgG1 chimeric anti-CD40 antibody ChiLob7/4 in patients (pts) with a range of CD40-expressing solid tumors and diffuse large B-cell lymphoma, resistant to conventional therapy. Potential mechanisms of action for agonistic anti-CD40 include direct cytotoxic effects on tumor cells and conditioning of antigen-presenting cells.

Experimental Design: ChiLob7/4 was given by IV infusion weekly for 4 doses at a range from 0.5 to 240 mg/dose. Validated ELISAs were used to quantify ChiLob7/4 in serum and test for anti-chimeric MAb (HACA) responses. Pharmacodynamic assessments included quantitation of T-cell, natural killer–cell, and B-cell numbers and activation in blood by flow cytometry and a panel of cytokines in plasma by Luminex technology. Planned dose escalation was in cohorts of 3 patients until MTD or biologic effect, defined as reduction of peripheral blood CD19+ B cells to 10% or less of baseline.

Results: Twenty-nine courses of treatment were given to 28 subjects. The MTD was 200 mg × 4, with dose-limiting toxicity of liver transaminase elevations at 240 mg. At 200 mg (range between 2.1 mg/kg and 3.3 mg/kg based on patient body weight), the trough level pretreatment was above 25 μg/mL. Grade 1-2 infusion reactions were seen above the dose of 16 mg, but could be prevented with single-dose corticosteroid premedication. HACA responses were seen after doses between 1.6 mg and 50 mg, but not above this. 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 50 mg upward. MIP-1β and IL12 plasma concentrations rose after doses above 16 mg. Fifteen of 29 treatments were accompanied by disease stabilization for a median 6 months, the longest for 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. Clin Cancer Res; 21(6); 1321–8. ©2015 AACR.



Translational Relevance

CD40 is expressed on antigen-presenting cells (APC) and some malignancies. On APC, ligation results in upregulation of costimulatory molecules, potentially bypassing the need for T-cell help in an antitumor immune response. Anti-CD40 antibodies produce substantial responses and durable anticancer immunity in animal models, an effect mediated by cytotoxic T cells. The IgG1 chimeric antibody ChiLob7/4 was developed as an agonist for CD40, and this first-in-man dose-escalation study describes its pharmacokinetic and pharmacodynamic characteristics. An MTD of 200 mg weekly × 4 was established, yielding concentrations that showed physiologic activity including depletion and activation of peripheral blood B and NK cells, increases in MIP-1β and IL12 levels, and disease stabilization in half of those treated. The treatment was well tolerated, with infusion reactions readily controlled by single-dose corticosteroid premedication. Dose-limiting toxicity was a reversible hepatic transaminitis. This study provides the basis for exploring the activity of ChiLob7/4 in combination studies with chemotherapy, tumor antigen vaccines, and other immunomodulatory antibodies.

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Contributors

Author: P. Johnson

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