Genetically tailored cancer treatments train the immune system to target mutations unique to each patient.
Vaccines genetically tailored to the specific mutations of patients’ cancer cells have proven effective in small clinical trials. Research groups conducing separate studies in the US and Germany published promising results, generating cautious optimism that the approach could be a game-changer for cancer treatment. Like vaccines used against infectious diseases, the treatment works by using components of the target disease—in this case cancer cells—to stimulate an immune response. The specific makeup of each vaccine is tailored to the patient and their cancer cells’ unique genetic mutations. We spoke with Ugur Sahin, lead researcher of one of the studies, to learn more:
ResearchGate: Why does cancer treatment need to be personalized?
Ugur Sahin: Every human being is unique, and so is each cancer. Conventional treatments do not account for this, but instead go for the minimal common denominator.
RG: What’s the greatest challenge in developing personalized vaccines?
Sahin: One of the greatest challenges is selecting the right cancer-specific molecules that induce a strong immune response against the tumor when used in a vaccine. Another is to bring them to lymph tissue, which is the place where the immune system is trained. One also has to ensure that the tumor microenvironment is permissive for immune effectors to act against the tumor. Getting these challenges right will significantly move the personalized vaccination field forward.
RG: How did you address them?
Sahin: We address these three challenges by selecting cancer mutations (single amino acid exchanges) which are exclusive to cancer cells and not found in healthy ones. We deliver these mutations encoded by a synthetic RNA vaccine directly into the lymph nodes to inform immune effector cells what to act against. Moreover, RNA has an activating activity on the tumor microenvironment.
“Every human being is unique, and so is each cancer.”
RG: How did you personalize the vaccines in your study?
Sahin: The entire genetic information of each patient’s tumor was determined by deep sequencing and compared to the genome of healthy cells to determine cancer-cell specific mutations. Out of these, we selected the ten mutations for each patient with the highest likelihood of activating immune cells (T cells) to efficiently kill tumor cells. Then, a synthetic RNA vaccine that encodes these mutations was manufactured and injected into the patient’s lymph nodes.
RG: How did the vaccines work?
Sahin: We inject the vaccine into the patient’s lymph nodes, where so called dendritic cells, the coaches of the immune system, are resident. These take up the RNA and present each mutation to immune effector cells, so called T cells. This programs the T cells to find those cells in the body that carry the mutation, which would be only the cancer cells.
Such T cells against cancer cell mutations do arise spontaneously, but this process is inefficient. With the vaccine, we were able to induce immune responses in each and every patient, and against multiple mutations per patient.
RG: How effective were the vaccines?
Sahin: All 13 patients had a history of multiple relapses of their cancer before being enrolled, and eight of the 13 patients were in a tumor-free episode when they started personalized vaccination. They remained tumor-free for the whole follow-up period (up to 23 months).
The other five patients developed metastases before we could start personalized vaccination. Two of them had objective clinical responses, meaning measurable tumor mass shrinkage. One of these two had a complete response, meaning they became tumor-free under vaccination. The other had a partial response, meaning substantial shrinkage of the tumor.
“The beauty of this approach is that it is universally applicable, as long as the tumor has mutations.”
RG: Why test this on patients with melanoma? Would it work with other types of cancer?
Sahin: The beauty of this approach is that it is universally applicable, as long as the tumor has mutations, which virtually all tumors have. Melanoma is a cancer that has, on average, a high rate of mutations. We were able to induce immune responses in all the melanoma patients we treated very efficiently, including those patients who had a relatively low number of mutations. So we don’t expect that a low number of mutations—as is seen in some high medical need cancer types—is a hurdle.
RG: Where does this study fit into personalized cancer vaccine research more broadly?
Sahin: Personalized cancer vaccines are in their beginning. Our study is the first one to use mutations. There is a second study by US colleagues who have used another format: peptides for personalization.
RG: What’s the next step in this research?
Sahin: We’ll be investigating a new formulation, so the next trials will be Phase I trials again. However, the next trials will recruit more patients and will also focus on clinical response. Moreover, we want to include other potent compounds, like so-called checkpoint inhibitors. We will need trials with bigger cohorts, control arms, and longer follow-up periods.
Featured image courtesy of Martin Trotter.
