Cancer Immunotherapy: Individual mutations as new target structures

Interview with Prof. Ugur Sahin, founder and scientific managing director of TRON – Translational Oncology at the Mainz University Medical Center


Photo: Prof. Ugur Sahin

Prof. Ugur Sahin; ©private

A tumor is as unique as the person who is affected by it. For a long time, it was assumed this would make treatment more difficult since cancer drugs are not able to be one hundred percent effective in targeting the affected cells. In this interview with, Professor Ugur Sahin explains why it is precisely these individual mutations that make him hopeful for a new type of therapy.

Professor Sahin, how do you produce a personalized vaccine?

Ugur Sahin: All types of cancer originate in genetic variations, meaning mutations. We develop a vaccine that uses mutations as the target for immunotherapy. The particular challenge here is that every patient or rather every tumor carries different mutations. In the case of epithelial cancers such as breast, lung or colon cancer, there are generally anywhere between one hundred to one hundred thousand mutations. When you take a look at mutations of two randomly chosen patients, the overlap is less than five percent. There are therefore individual mutations in 95 percent of cases. This is why these types of mutations were long being ignored as therapeutic targets. Although there are drugs that are aimed at specific mutations, they only target the overlap percentage. That is why we deliberated how these individual mutations could be utilized in therapy.

Sahin: The therapeutic approach you developed consists of three steps. What are they?

Sahin: During the first step, the tumor is genetically analyzed via next-generation sequencing to determine all of the mutations. Here the tumor’s genetic makeup is compared to that of normal tissue, for instance, blood cells. This analysis lets you generate a list that includes all mutations. The second question is which mutations are suited for immunotherapy. We discovered that 20 percent of these mutations induce immune responses. Of course, this conversely means that 80 percent are not identified by the immune system. We also found out what types of immune responses are triggered by the mutations. Now we are able to predict the immune responses using computer algorithms. We have used a vaccine platform we have been developing over the past 15 years here in Mainz to produce mutation-specific, completely personalized vaccines within a few days.

Grafic: Syringe and DNA

Once the mutations have been determined, a personalized vaccine is being developed, which is injected to the patient in the inguinal lymph nodes; © /brijit vijayan

What principle is this platform based on?

Sahin: We use identified mutation – usually an amino acid exchange – and amino acid structures surrounding the mutation. There are approximately 27 amino acids we identify as the recombinant vaccine, the so-called epitope. We revert to ten epitopes and not just one in this case. We have inserted them into an RNA vaccine. We have synthetically produced this type of carrier RNA and used the information we were able to gather from next-generation sequencing and the mutations. We can produce synthetic mRNA within a few days using different methods. If you use the synthetic RNAs, which indicate the mutations and represent a kind of identikit picture of the tumor, to immunize, the immune cells, that is the body’s T cells are being activated based on this identikit picture. The T cells are essentially able to identify certain characteristics on the identikit picture. After they have proliferated, they leave the lymph node, enter the blood circulation and migrate into the tumor tissues. Here they are able to stop tumor growth and cause the tumor to regress.

What is the treatment process?

Sahin: We inject several times into both lymph nodes in the groin. A repeated activation of T cells is necessary. In a current ongoing clinical study, patients initially receive eight immunizations on a weekly basis. If patients tolerate this well and the cancer is stable, they are subsequently vaccinated at monthly to tri-monthly intervals until therapy can be paused after one year.

Are there any side effects?

Sahin: We have tested this procedure in animals during drug development. Now we were able to start a clinical trial in Mainz, Mannheim, and Vienna. So far, we have treated eight patients who exhibit a great level of tolerance. We expect to complete the study by the end of this year and will not have any concluding results on immunogenicity and tolerability until then.

Is this treatment expensive to produce?

Sahin: Production is currently still very expensive. Our study is co-financed by a company and the German Federal Ministry of Education and Research (German: Bundesministerium für Bildung und Forschung). Until the therapy is universally available in perhaps four to five years, we will continue to examine how we can reduce costs. This would be possible through automation or economies of scale for example. We feel confident that a completely personalized therapy doesn’t need to cost more than the currently available biological therapy.
Photo: Simone Ernst; Copyright: B. Frommann

©B. Frommann

The interview was conducted by Simone Ernst and translated by Elena O'Meara.