TY - JOUR
T1 - Clinical and biological effects of an agonist anti-CD40 antibody: a cancer research UK phase I study
AU - Johnson, Peter
AU - Challis, Ruth
AU - Chowdhury, Ferdousi
AU - Gao, Yifang
AU - Harvey, Melanie
AU - Geldart, Tom
AU - Kerr, Paul
AU - Chan, Claude
AU - Smith, Anna
AU - Steven, Neil
AU - Edwards, Ceri
AU - Ashton-Key, Margaret
AU - Hodges, Elisabeth
AU - Tutt, Alison
AU - Ottensmeier, Christian
AU - Glennie, Martin
AU - Williams, Anthony
PY - 2015/3/15
Y1 - 2015/3/15
N2 - 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, de fi ned 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 x 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.
AB - 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, de fi ned 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 x 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.
UR - http://www.scopus.com/inward/record.url?scp=84927615313&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-14-2355
DO - 10.1158/1078-0432.CCR-14-2355
M3 - Article
AN - SCOPUS:84927615313
SN - 1078-0432
VL - 21
SP - 1321
EP - 1328
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 6
ER -
