Clinical studies with lead anti-CD40 IS-Ab

Our lead anti-CD40 IS-Ab ChiLob7/4 has already been tested in a phase I study and was found well-tolerated when dosed repeatedly. These results form an excellent basis for further clinical immunogenicity/biomarker studies with this IS-Ab. In order to maximize the likelihood for achieving clinical efficacy, we selected clinical settings and regimens that closely resemble the pre-clinical experiments in which the most striking impact of anti-CD40 Abs has been obtained.

The first demonstration that IS-Abs could effectively be used in conjunction with chemotherapy came from pioneering work demonstrating that gemcitabine and agonist anti-CD40 IS-Abs display striking therapeutic synergy when administered to tumour-bearing mice. Subsequent pre- clinical research by others has lent further support  to the combined use of cytostatic regimens and immunostimulatory compounds for cancer therapy.

We will therefore perform a neo-adjuvant phase I, open label study in patients with resectable PDA. Weekly anti-CD40 Ab ChiLob7/4 will be added to standard dosing of gemcitabine. The primary aim of this study is to obtain first clinical proof of concept for the capacity of anti-CD40 IS-Abs to mobilize potent systemic and intra-tumor immunity, in particular when combined with gemcitabine. This trial will be preceded by a dose finding study for ChiLob7/4 when administered in conjunction with gemcitabine. The primary outcome measures will be (i) the effects of IS-Abs on the host immune response as determined by validated biomarker assays and (ii) the clinical safety and tolerability of these drugs. The key secondary outcome measure will be anti-tumor activity of the IS-Abs as witnessed by objective tumor responses.

Striking pre-clinical results with agonist anti-CD40 Ab were also obtained by using these IS-Ab to enhance the efficacy of cancer vaccines. Pre- clinical  studies  demonstrated  that  anti-CD40  IS-Abs  can  strongly  (>10-fold)  increase  the  potency  of synthetic peptide and mRNA vaccines. We have therefore chosen to test the combination of agonist anti- CD40 IS-Ab ChiLob7/4 with an mRNA vaccine encoding HPV16 -derived tumor antigens in recurrent human papillomavirus type (HPV)-positive head and neck squamous cell carcinoma (HNSCC). The mRNA vaccine that is produced by SME-partner BioNTech RNA Pharmaceuticals GmbH will be dosed repeatedly, either as single agent or in combination with weekly dosing of anti-CD40 Ab ChiLob7/4. We will undertake a phase I, open label dose finding study in patients who are in remission post treatment for HPV16+ disease. Once the optimal dose is established we will treat patients awaiting resection of newly diagnosed HPV16+ HNSCC or, in a parallel arm those with recurrent HPV16+. The HPV16 antigen-specific immune response will be evaluated before and after treatment in circulating blood and, where possible, in tumor biopsies. The primary outcome measures will be (i) the enhancement of HPV16 antigen-specific T-cell immunity by mRNA vaccine alone versus mRNA vaccine plus anti-CD40 Ab in blood and tumour biopsies as determined by GCLP-compliant assays and (ii) the safety and tolerability of the vaccine/IS-Ab combination. The key secondary outcome measure will be anti-tumor activity of the IS-Abs as witnessed by objective tumor responses.