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

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 þ 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 mg/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 Bcell numbers accompanied by reduced expression of CD21, and transient reductions in NK cell numbers with increased CD54 expression from 50 mg upward. MIP-1b 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.

Influence of immunoglobulin isotype on therapeutic antibody function

“…Moreover, human IgG2 agonistic anti-TNFR mAbs also do not require FcgR interaction for agonistic activity 60 ( Figure 1B). ChiLob 7/4, a CD40 mAb that has recently completed a phase 1 clinical trial, 66 is agonistic in human CD40 transgenic mice as IgG2 in the absence of FcgR expression and even as a F(ab9) 2 fragment. 60 FcgRindependent activity has also been demonstrated for another IgG2 CD40 mAb in a clinical trial: CP870-893.…”

T Cells Modified with CD70 as an Alternative Cellular Vaccine for Antitumor Immunity

“…Furthermore, administration of peptidebased booster containing anti-CD40 Abs after CD70-T priming was substantially effective in producing potent secondary expansion of primed CD8 T cells. Of those, good manufacturing practice (GMP)-grade poly-IC is commercially available and costimulatory agonistic antibodies including anti-CD40 have been developed, which have undergone clinical studies in some cancer patients [32][33][34][35]. More importantly, numerous human T-cell epitopes have been identified for decades, and recent progress on application of neo-antigen-derived peptide vaccines to cancer patients is rising [36][37][38] because GMP-grade peptides containing T-cell epitopes are relatively easy to synthesize cost-effectively.…”

Improving Adoptive T Cell Therapy: The Particular Role of T Cell Costimulation, Cytokines, and Post-Transfer Vaccination

“…Important to note is that CD40 triggering in malignant cells is able to promote tumor cell proliferation leading to tumor progression (147, 148). Likely depending on one or more of the above-described mechanisms, targeting of CD40 has already been proven a promising strategy in several preclinical models and clinical trials against solid cancer (120, 149–154). Also in preclinical models of ACT, agonistic CD40 antibodies promote tumor-specific T cell expansion and enhanced anti-tumor activity (155, 156).…”

“…Undoubtedly, the effects of agonistic antibody administration are often multifaceted thereby making it challenging to predict treatment outcome. Attempts to minimize the chance of antibody-induced toxicity could include pretreatment with corticosteroids and local administration of agonistic antibodies (151, 152, 154). …”