Advancements in Personalised Cancer Vaccines
For many years, personalised medicine in the fight against cancer has revolved around identifying specific alterations within tumours and selecting from existing medications to target them effectively. However, a groundbreaking experimental vaccine developed by Moderna in collaboration with Merck takes this concept to a new level. Rather than choosing a treatment from a predefined list, this innovative approach manufactures a unique vaccine tailored to each patient, based on the specific mutations found in their own tumour, as detailed in recent scientific discussions.
This week marked a significant milestone for this approach, as Intismeran autogene, a personalised messenger RNA (mRNA) vaccine, demonstrated its ability to significantly reduce the risk of melanoma recurrence when combined with pembrolizumab, an established immunotherapy for this type of skin cancer. This achievement marks the first instance of an mRNA-based oncological treatment yielding positive results in an advanced Phase 3 clinical trial.
Experts have expressed optimism regarding these results, suggesting they indicate the viability of personalised cancer vaccines in larger patient cohorts. Marco Gerlinger, an oncologist at St Bartholomew’s Hospital in London and a researcher involved with another cancer vaccine developed by BioNTech, noted the importance of this advancement, indicating that such treatments could potentially be tailored for various cancer types.
Potential Beyond Oncology
The implications of this development might extend beyond oncology. Sam Barrell, director of the British medical research organisation LifeArc, highlighted that demonstrating the feasibility of customised medications could boost confidence in similar strategies for treating rare diseases caused by specific genetic mutations.
Intismeran is not a traditional vaccine aimed at preventing infections; rather, it is a therapeutic vaccine specifically designed for individuals already diagnosed with skin cancer. Its primary objective is to diminish the likelihood of recurrence following the surgical removal of a tumour. According to the US National Cancer Institute, this type of vaccine harnesses the immune system to identify and eliminate cancerous cells, as opposed to preventive vaccines.
Creating Targeted Vaccines
The development of Intismeran involves obtaining a tumour sample, which is then sequenced to identify mutations that differentiate cancerous cells from healthy ones. Some of these alterations can generate abnormal protein fragments known as neoantigens, which serve as signals that the immune system can be trained to recognise. Consequently, a unique vaccine is formulated for each individual based on this genetic information.
The challenge lies in determining which mutations to include in the vaccine. Moderna employs artificial intelligence tools to identify the neoantigens most likely to elicit a robust immune response, as explained by Adnan Khattak, an oncologist and researcher involved in the study. This selection process determines the components of the vaccine tailored for each patient.
Intismeran comprises a synthetic mRNA molecule capable of encoding up to 34 neoantigens selected from the mutations identified in each patient’s tumour. These instructions are introduced into the body to produce the neoantigens, aiming to activate T cells that can recognise tumour cells bearing the same signals.
A Paradigm Shift in Precision Medicine
This approach represents a significant shift from conventional precision medicine methods. Traditionally, the strategy involved identifying a specific characteristic of the cancer—such as particular mutations—and searching for an already developed medication to target it. In this instance, however, a specific version of the treatment was created for each participant, reflecting the unique genetic landscape of their tumours.
It is noteworthy that two individuals diagnosed with the same type of melanoma may possess different mutations, resulting in distinct vaccines tailored to their specific needs. Previous data presented by Moderna indicates the extent of this variability; in a Phase 2 trial, over 99% of the selected neoantigens were unique among participants.
Significant Trial Outcomes
The latest trial, known as INTerpath-001, included 1,137 individuals with high-risk melanoma at stages IIB to IV, all of whom had undergone complete surgical tumour removal. Participants received Intismeran in conjunction with pembrolizumab (marketed as Keytruda) or were treated with pembrolizumab alone.
On August 19, Moderna announced that the combination effectively extended the period without melanoma recurrence and prevented metastasis to other areas of the body. Both companies considered these findings to be statistically significant and clinically relevant.
However, the exact reduction in the risk of relapse or metastasis during this Phase 3 trial remains to be determined. The companies plan to present comprehensive results in due course, and follow-up assessments will continue to ascertain if the treatment also enhances patient survival rates. Earlier Phase 2b results indicated a 49% reduction in the risk of recurrence or death and a 59% decrease in the risk of distant metastasis or death, but these figures cannot be directly applied to the new study.
Challenges Ahead for Individualised Vaccines
The very feature that sets Intismeran apart also presents one of its key challenges. Unlike mass-produced medications, each vaccine must be custom-designed following an analysis of the patient’s tumour. This entails sequencing the tumour, identifying mutations, selecting neoantigens, and manufacturing the corresponding mRNA. Currently, this process can take several months, which poses a potential issue for rapidly progressing cancers.
Moreover, it remains to be seen whether this model can transition from clinical trials to widespread patient application without compromising speed or quality. Moderna and Merck are already testing Intismeran in other contexts, including non-small cell lung cancer, bladder cancer, and kidney cancer, according to their clinical programme; however, success in melanoma does not guarantee similar outcomes across all tumour types.
At this stage, Intismeran remains experimental, and the complete results of the trial are still awaited. Nevertheless, the Phase 3 trial represents a large-scale test of a concept that, until recently, had primarily been demonstrated in smaller studies: the genetic information from an individual’s tumour can be utilised not only to select a treatment but also to create a bespoke therapy specifically for them.