A new study is utilizing personalized immunotherapy to target specific tumor-associated genomic changes in an effort to combat tumors formed during cutaneous melanoma. The dendritic cell vaccine is tailored to recognize each patient’s tumor, which is thought to be the driving force underlying its ability to proficiently stimulate the immune system.
In previous immunotherapy schemes, vaccines were designed to target proteins that tumors expressed at high levels. Unfortunately, the proteins targeted were also expressed in normal cells, ultimately confusing the immune system as to which cells to attack (tumor vs. self). Therefore, these vaccines were not able to sufficiently stimulate the immune response to eliminate the tumor.
Instead of identifying and targeting proteins upregulated in patients’ tumors, researchers from Washington University School of Medicine are examining tumors for mutations that differentiate cancer cells from normal cells. They are interested in identifying missense mutations in the DNA that result in amino acid substitutions in proteins (herein referred to as altered peptides) of cancer cells, specifically. By designing a vaccine to target the altered peptides of a specific tumor, researchers hope to stimulate the patient’s immune system to attack cancer cells exclusively, thereby efficiently eliminating the tumor while leaving surrounding, healthy tissue intact.
In this study, three tumors were surgically excised and their genomes sequenced. Utilizing the exome sequencing results, predictive algorithms, and in silico binding analysis techniques, scientists were able to determine potential altered peptide candidates specific for each patients’ tumor, of which seven were selected for incorporation into each of the tailored vaccines.
The tailored vaccinations increased the efficiency of each patient’s T cell response in as quickly as two weeks, with the response peaking around 8-9 weeks. In addition, the researchers found that targeting several of the altered peptides of these tumors resulted in the activation of a subtype of T cells that would have otherwise remained unaware of the tumor, further enhancing the overall immune response. Another promising result is the ability of this vaccination method to circumnavigate the growing concern of clonal tumor evolution, common in therapeutic strategies that target dominant pathways, such as BRAF inhibitors.
While this dendritic cell vaccine is in its phase 1 clinical trial, therefore in its infancy, early results are promising. The researchers have shown that a vaccine aimed at altered peptides of a tumor population expands the ‘antigenic breadth’ and ‘clonal diversity’ of the patient’s immune system. Furthermore, this vaccination design strategy can be expounded upon to target tumors present in lung, bladder, and colorectal cancers. Lastly, the early results of this study serve as a ‘proof-of-principal’ regarding personalized immunotherapy and the power it can have on patient outcomes.