The recent advances in cancer treatment with immune response checkpoint inhibitors demonstrated that immunotherapy may play a key role in cancer therapy. Immune response checkpoint inhibitors are very efficient in patients with tumors that are highly infiltrated with tumor specific T cells because they are immunogenic. In contrast their efficacy is much weaker or completely absent in non-immunogenic tumors that are not infiltrated with tumor specific T cells.  These tumor specific T cells can be triggered in non-immunogenic tumors by cancer vaccines. Cancer vaccines can, therefore, render non-immunogenic tumors sensitive to treatment with immune response check-point inhibitors.

The central problem in tumor vaccination is the choice of the optimal antigen to target.

Tumor antigens may be distinguished into two groups:

  • Tumor Associated Antigens (TAA) that are normal proteins expressed by several tumors but also by normal cells (self-antigens). To date all the vaccines tested in clinical studies targeted TAA but failed to show clinical efficacy. This is due to the fact that the immune system is tolerant to TAA because they are self-antigens (self-tolerance).
  • Tumor Specific Antigens (TSA) that are abnormal proteins harboring somatic mutations. These mutations can create T cell reactive epitopes (neo-epitopes or neo-antigens) that are recognized by the immune system as non-self and are not involved in the self-tolerance process. These neo-antigens may be very efficient tumor vaccines providing that they are immunogenic.

Although neo-antigens seem to be extremely promising for developing efficient cancer vaccines several issues should be addressed.

  1. Their use may be limited by the genetic heterogeneity of tumors. It is likely that neo-antigens are not expressed by all the lesions of the same tumor. Neo-antigen free lesions could therefore escape neo-antigen specific immune response.
  2. Their identification requires fully specialized research centers, is time consuming and may be very expensive. Vaccination with patient specific neo-antigen cannot be a standard treatment given worldwide.
  3. The current drug clinical development model cannot be applied to neo-antigen based vaccines. Neo-antigens are patient specific and can be used only for the treatment of the neo-antigen expressing patients. It will be virtually impossible to evaluate potential toxicity and efficacy of the patient-specific vaccines before their approval as cancer treatment.

The complexity of these challenges raises the following question:

Can we find neo-antigen like vaccines that share all the neo-antigen properties (escaping self-tolerance and immunogenicity) but ar not patient specific and could be a standard treatment given worldwide ?