Immunotherapy
In today’s clinical practice, however, cytotoxic therapy is not guided by tumor genetics.
In view of the commonly experienced severe side effects of the drugs and the frequently experienced treatment failures there is an urgent need for personalized therapeutic strategies based on the patient’s tumor genetics. That’s exactly the focus of precision oncology.
A deeper understanding of tumor genetics and immune regulatory pathways, the signaling cascades which serve to circumvent the immunosurveillance of the tumor in particular, have led to a renaissance of tumor immunotherapy.
Checkpoint inhibitors, for instance drugs such as nivolumab (anti-PD1-antibody), pembrolizumab (anti-PD1-antibody), atezolizumab (anti-PDL1-antibody), durvalumab (anti-PDL1-antibody) or ipilimumab (anti-CTLA4 antibody) block one of the emergency exits used by the tumor against successful immune defense. Nivolumab is the first PD-1 inhibitor that demonstrated better survival rates than docetaxel in comparative studies of patients with non-small cell lung cancer of various histologies (1, 2). Impressive results of this form of immunotherapy have also been reported for other tumor types (3, 4).
A completely different strategy for cancer immunotherapy has been based on active immunization by various types of cancer vaccines. Starting with the pioneering work of W. B. Coley more than a century ago who successfully developed a nonspecific bacterial-toxin based vaccine against sarcomas (5) a multitude of cancer vaccines have been developed.
NextGen Oncology is focused on the development of cancer vaccines based on tumor-specific peptides. Relevant clinical trials using a great variety of peptide-based vaccines have been recently reviewed (6).
The Figure below depicts molecular key differentiators enabling the immune defense system to recognize and eliminate tumor cells.
In order to design personalized specific peptide vaccines all of a tumor’s more than 20,000 genes that code proteins are examined for mutations by next-generation exome sequencing. All genetic mutations with impact on the amino acid sequence, structure and function of the proteins are then matched to an exome sequencing that has been simultaneously carried out on the blood. This leads to the identification of genetic markers that are absolutely specific to the tumor (mutated neoantigen peptides) and thus highly useful in developing a personalized vaccine. In a further step, NextGen Oncology assesses whether and if so, which part of the patient’s mutation-carrying section of protein can be presented to the immune system by the individual antigen-presenting system (HLA-Haplotype) of the patient.
Exactly this section is then rebuilt (mutated neoantigen peptide). A personalized cancer vaccine usually contains a group of up to ten of such absolutely specific peptides.
The main steps of our vaccine development process and vaccine application are illustrated in the Figure below.
