Exciting Results with an mRNA Vaccine and Immunotherapy Combination in Melanoma Treatment

Made familiar to the world by the Covid-19 pandemic, mRNA vaccines have in fact been actively studied in cancer treatment since the early 2010s . During that period, scientists began to understand the potential of mRNA technology and developed the idea of using it to treat cancer. However, the number and success of studies of mRNA cancer vaccines have increased considerably in recent years, particularly during and after the COVID-19 pandemic.

How Do mRNA Cancer Vaccines Work?

The basic principle of mRNA cancer vaccines is to direct the immune system to develop a tailored response against cancer cells. These vaccines aim to target unique proteins found in cancer cells but absent from normal cells (neoantigens). The basic steps of mRNA cancer vaccination are:

1. Tumor samples are collected: Tumor biopsy samples taken from the patient are used to examine the genetic material in cancer cells.

2. Neoantigens are identified: The genetic material in the tumor samples is examined, and the specific neoantigens to target are identified. These neoantigens are patient-specific and may differ in each patient's cancer cells.

3. The mRNA sequence is designed: mRNA sequences are designed for the identified neoantigens. These mRNA molecules carry the information that immune cells (such as T cells) need to recognize and target cancer cells.

4. Vaccine production: The designed mRNA sequences are combined with nanoparticles to produce the vaccine. These nanoparticles help deliver mRNA safely into cells.

5. The vaccine is administered: The prepared mRNA cancer vaccine is injected into the patient. It helps immune cells recognize specific neoantigens present in cancer cells and develop a response against those cells.

6. Immune response: The immune system develops a response against the specific neoantigens it has learned to recognize through the vaccine. This response includes activation of T cells that target and destroy cancer cells.

In summary, mRNA cancer vaccines aim to provide effective cancer treatment by directing the immune system to recognize and target a patient's specific cancer cells.

Moderna's Cancer Vaccine

mRNA-4157/V940 is a cancer vaccine developed by Moderna. It consists of a single synthetic mRNA code designed and manufactured based on the unique mutation signature of a patient's tumor and contains up to 34 neoantigens. When used together with Keytruda (pembrolizumab) immunotherapy , this vaccine has received an FDA (US Food and Drug Administration) Breakthrough Therapy Designation for the adjuvant treatment of high-risk melanoma patients after complete resection (surgical removal).

The KEYNOTE-942 Study

According to the latest data from KEYNOTE-942, in patients with "high-risk melanoma," the combination of a patient-specific mRNA-based cancer vaccine (mRNA-4157/V940, Moderna) and the immune checkpoint inhibitor pembrolizumab significantly improved recurrence-free survival compared with pembrolizumab alone.

This recurrence-free survival benefit was associated with a 44% reduction in the risk of cancer recurrence or death in patients receiving the personalized vaccine and pembrolizumab.

This randomized phase 2b study is the first to show a positive result for a cancer vaccine in a randomized trial. According to the researchers, if confirmed in other studies, the approach holds promise for treating other immunotherapy-sensitive solid tumors (arising in tissues and organs).

Presented on April 16, 2023, this study was the most notable presentation at the American Association for Cancer Research (AACR) annual meeting.

This strategy may also be effective in other immunogenic cancers, particularly non-small cell lung cancer, kidney cancer, liver cancer, and gastroesophageal cancer.

These results can readily be called "exciting," particularly given the modest results of earlier cancer vaccine studies. Until now, cancer vaccines had been disappointing and had not made a meaningful impact in oncology.

The mRNA vaccine is individually prepared and encodes up to 34 patient-specific tumor neoantigens. It also strengthens the immune response.

In KEYNOTE-942, researchers randomly assigned patients with completely resected, high-risk cutaneous melanoma in a 2:1 ratio to receive intramuscular mRNA-4157 every 3 weeks for a total of 9 doses and intravenous pembrolizumab every 3 weeks for 18 cycles (107 patients), or pembrolizumab alone (50 patients). Mean follow-up was 101 weeks in the combination group and 105 weeks in the pembrolizumab group.

Grade 3 or higher adverse events occurred in 25% of patients in the combination group and 18% in the pembrolizumab group. Fatigue was the most common vaccine-related grade 3 event. No vaccine-related grade 4 adverse events or deaths were reported, and adding the vaccine to pembrolizumab did not increase the frequency of immune-mediated adverse events.

In the subgroup analysis, high tumor mutational burden was found to mean more neoantigens to target, which is useful when developing personalized neoantigen vaccines. The researchers determined tumor mutational burden by performing whole-exome and whole-transcriptome sequencing on tumor biopsy samples.

High tumor mutational burden was defined as 10 or more mutations per megabase.

Overall, combination treatment was more effective in patients with both high tumor mutational burden (HR, 0.642; 95% CI, 0.284 - 1.494) and low tumor mutational burden (HR, 0.586; 95% CI, 0.243 - 1.415).

The authors emphasized that the same applied to patients with high and low tumor inflammation scores, as well as PD-L1-positive and -negative patients. This suggests that the combination was similarly effective across all patient subgroups.

In conclusion, the positive results from KEYNOTE-942 are raising hopes for mRNA cancer vaccines. In particular, Moderna's mRNA-4157/V940 vaccine combined with pembrolizumab has shown a significant improvement in recurrence-free survival for patients with high-risk melanoma. Following unsuccessful clinical trials in the cancer vaccine field, these promising findings represent an important step both for melanoma patients and for scientists dedicated to developing cancer vaccines. Further studies aim to extend this success to other cancer types and establish an effective treatment strategy for a broad patient population. By offering an individualized and effective approach to cancer treatment, these advances could improve patients' quality of life and survival rates.