Tailor-made medicine
On October 24, at the European Society for Medical Oncology (ESMO) congress in Madrid, Merck and Moderna presented the results of a phase 3 trial with a therapeutic mRNA vaccine (remember the one for Covid?) made to measure for each of the patients who received it. The clinical trial, named INTerpath-001, has been conducted on people who underwent surgery for high-risk melanoma.
If we look twenty-six years back, when the draft of the human genome (June 2000) and the completed sequence (April 2003) were announced, the long-term promise was that of medicine tailored to fit, totally personalized: reading each person's genome and treating them accordingly. As always with this topic, the film Gattaca (1997) comes to mind, by director Andrew Niccol, starring a very young Ethan Hawke, Uma Thurman, and Jude Law.
Today, INTerpath-001 is a first taste of this personalized medicine. 1,137 patients participated in the study, randomized at a ratio of two to one. Everyone received standard immunotherapy, and two-thirds added a vaccine designed with the sequence of their own tumor: an mRNA that encodes up to 34 neoantigens. Neoantigens are proteins derived from mutations acquired by the tumor that the immune system can recognize as foreign. By sequencing the patients' tumors, the researchers were able to detect these mutations characteristic of each patient's tumor and introduce them into the vaccine's mRNA molecule, thereby helping to “train” the immune system to recognize and attack them.
According to the published results, with a median follow-up of 24.6 months, the combination of immunotherapy and vaccine reduced the risk of recurrence or death by 42% compared to immunotherapy alone. It should be noted that serious adverse effects were similar in both groups (14.2% versus 13.4%). Some patients did not respond to the vaccine and time will tell what the benefit is beyond two years, as overall survival cannot yet be analyzed. Furthermore, getting samples to the laboratory, sequencing them, and manufacturing the vaccine requires several weeks; therefore, its feasibility and logistics outside the controlled environment of clinical trials will also have to be assessed and studied. We will be keeping an eye on ongoing trials, such as those for patients with lung cancer, who are also receiving the new personalized mRNA vaccine.
Despite this first taste of personalized medicine, oncology today lives primarily in the era of precision medicine, where the drug is chosen according to the patient's tumor mutation. One of the most exciting examples right now is the KRAS protein. For decades it was considered impossible to block due to its characteristic structure and its broad involvement in cell biology, until in 2021 the FDA approved sotorasib, the first KRAS inhibitor for lung tumors with the G12C mutation.
Sequencing the tumor is now, therefore, a requirement for prescribing approved drugs, and it will be even more so: both for the vaccine, if it is confirmed and approved, and for other drugs that are on the way. The question for public health systems, including ours, is how and which patients will be able to have their tumor sequenced on a routine basis to aid in molecular diagnosis and decision-making regarding the treatment to follow.
