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

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

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.
1078-0432
1321-1328
Johnson, P.
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Challis, R.
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Chowdhury, F.
928d9123-aed8-4ea5-87a6-297c5fe04742
Gao, Y.
eea234ba-f566-4f21-a65e-234b84cba285
Harvey, M.
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Geldart, T.
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Kerr, P.
e6f57cb3-ee20-4ec1-8288-297a67986e42
Chan, C.
90a4e769-0cfd-4d47-918c-aee88fe9e7af
Smith, A.
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Steven, N.
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Edwards, C.
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Ashton-key, M.
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Hodges, E.
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Tutt, A.
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Ottensmeier, C.
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Glennie, M.
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Williams, A.
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Johnson, P.
3f6068ce-171e-4c2c-aca9-dc9b6a37413f
Challis, R.
41a3af57-5279-4283-9082-ec2cc0579ec0
Chowdhury, F.
928d9123-aed8-4ea5-87a6-297c5fe04742
Gao, Y.
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Harvey, M.
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Geldart, T.
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Kerr, P.
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Chan, C.
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Smith, A.
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Steven, N.
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Edwards, C.
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Ashton-key, M.
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Hodges, E.
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Tutt, A.
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Ottensmeier, C.
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Glennie, M.
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Williams, A.
973ff46f-46f1-4d7c-b27d-0f53221e4c44

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)

Record type: Article

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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More information

Accepted/In Press date: 6 January 2015
e-pub ahead of print date: 6 January 2015
Published date: 14 March 2015
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 396339
URI: http://eprints.soton.ac.uk/id/eprint/396339
ISSN: 1078-0432
PURE UUID: 4d9159b9-ad51-4880-b563-2bb378f9e836
ORCID for P. Johnson: ORCID iD orcid.org/0000-0003-2306-4974

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Date deposited: 08 Jun 2016 13:08
Last modified: 26 Nov 2019 01:56

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Contributors

Author: P. Johnson ORCID iD
Author: R. Challis
Author: F. Chowdhury
Author: Y. Gao
Author: M. Harvey
Author: T. Geldart
Author: P. Kerr
Author: C. Chan
Author: A. Smith
Author: N. Steven
Author: C. Edwards
Author: M. Ashton-key
Author: E. Hodges
Author: A. Tutt
Author: C. Ottensmeier
Author: M. Glennie
Author: A. Williams

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