Manufacturing Process Development for an Epidermal Growth Factor-Based Cancer Vaccine

By incorporating disposable technologies and an improved purification scheme, scale-up and validation problems were resolved.


The Center for Molecular Immunology (Havana, Cuba) has been working on a novel cancer immunotherapy targeting the epidermal growth factor (EGF). The vaccine is composed of a chemical conjugate of EGF and a carrier protein (rP64k), designed to trigger an anti-EGF antibody response. Advanced clinical trials demanded further manufacturing process development to address scale-up and validation limitations in the initial process. The process development strategy focused on replacing the membrane dialysis purification step with a method that could be scaled up more easily; incorporating disposable technology to further facilitate scale-up and cleaning validation; and improving process and product characterization. The consistency of the new process was evaluated, and the equivalence of the vaccine preparations was assessed. The results of studies of molecular characterization, immunogenic activity, and clinical data are presented here.

Cancer vaccines were originally designed to target tumor-specific antigens: non-self antigens expressed only in tumor cells due to malignant mutations. It is now known that only a minority of cancer cells truly express no self antigens. Several studies have also been carried out on the immune recognition of non-mutated self antigens on tumor cells. The results of these studies support the feasibility of cancer vaccines targeting fully self antigens. 1,2

The epidermal growth factor receptor (EGF-R), a member of a family of membrane receptors with tyrosine kinase activity, is emerging as a new target candidate for anti-cancer therapy.3 Several agents targeting the EGF-R or its ligands are already in clinical testing, including small-molecule tyrosine kinase inhibitors,4 monoclonal antibodies,5,6 and cancer vaccines.7,8

Rationale for an EGF–Based Therapeutic Cancer Vaccine

A novel active immunotherapy approach, designed to provoke an anti-EGF antibody response, has been developed at the Center for Molecular Immunology (Havana, Cuba). The vaccine (under the commercial name CIMAvax-EGF) comprises the EGF coupled to an immunogenic carrier protein, administered together with an adjuvant.10–19

Figure 1. Scheme showing the mechanism of action of CIMAvax-EGF. Patients are immunized with a vaccine comprising an epidermal growth factor (EGF) linked to an immunogenic carrier protein and administered with an adjuvant. Vaccination provokes the formation of anti-EGF antibodies that bind to circulating EGF, blocking it from binding to its membrane receptor (EGF-R) and thus preventing the cell proliferation mechanisms initiated by EGF-EGF-R binding. In vaccinated patients, anti-EGF antibodies increase while EGF sera concentrations decrease over time.
It is known that tumor cell proliferation begins with binding between the EGF and its cell membrane receptor (EGF-R). The anti-EGF antibodies, induced by vaccination with CIMAvax EGF, bind to the EGF (self molecule) inhibiting its binding to the EGF-R, and thus preventing activation of cell proliferation mechanisms derived from this ligand–receptor interaction (Figure 1).

To validate the approach of vaccination with EGF in lung cancer therapy, clinical trials were designed to select the proper vaccine formulation (immunogenic carrier protein and adjuvant), as well as the proper scheme and therapeutic dose that would have a meaningful clinical effect.12–14,17–19

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