Short survival and easy recurrence are a major problem in the treatment of malignant tumors worldwide. To this end, scientists use the specific gene mutations of the patient's tumor cells to screen out a large number of tumor neoantigens that are not found in normal cells, and then design a "personalized neoantigen vaccine" for the patient's tumor to stimulate the patient's body to produce a specific immune response against the neoantigen, so that it can specifically recognize and attack cancer cells. Personalized neoantigen vaccines are also considered to be a new track for cancer immunotherapy worldwide, and MIT Technology Review selected it as one of the "Top 10 Breakthrough Technologies" in 2019. Recently, several preliminary clinical trials have shown that this "customized" cancer vaccine can significantly prolong the survival of cancer patients and effectively reduce the recurrence rate.
According to a clinical report presented at the American Association for Cancer Research (AACR) Annual Meeting held April 5-10, 2024, BioNTech, a global leader in mRNA vaccine development, and Genentech, a subsidiary of Roche, a global biopharmaceutical giant, jointly developed a personalized neoantigen pancreatic cancer mRNA vaccine with gratifying efficacy, and the recurrence-free survival of pancreatic cancer patients treated with this therapy has been extended to more than 3 years, which is twice as long as the results of clinical trials previously published in the journal Nature.
The doctor holds a model of the pancreas in his hand. Visual China|Figure
While this is only a continuation of the results of the Phase I clinical trial, this new development is undoubtedly encouraging. It is important to know that pancreatic cancer is known as the "king of cancer", mainly pancreatic ductal adenocarcinoma (PDAC), which occurs in the pancreatic ductal epithelium, and is the most malignant, fastest-growing and most difficult to treat among almost all cancers. Pancreatic cancer is generally detected at an advanced stage, and only 10%-20% of patients can be treated with surgery, but the recurrence rate after surgery is very high. If polypharmacy is not treated, about 90% of patients relapse 7 to 9 months after surgery, and the five-year overall survival rate is only 8% to 10%. Even with systemic chemotherapy after surgery, about 80% of patients can delay recurrence by about half a year, and the five-year overall survival rate only improves to about 20%. Radiotherapy, antibody-targeted therapy, and the latest CAR-T immunotherapy are all less effective in advanced pancreatic cancer.
The overall gene mutation rate of pancreatic cancer is relatively low, and it is difficult to find some antigen molecules with strong immunogenicity, which is one of the main reasons why targeted therapy and immunotherapy are difficult to play a role. However, scientists have recently used high-throughput sequencing and bioinformatics to discover that pancreatic cancer tumor cells have some new genetic mutations, which can produce neoantigens, which are unique proteins that only exist on the surface of cancer cells and can trigger the body's immune response, making them ideal targets for immunotherapy.
Although a single or a few antigens are weak and the number of immune T cells activated is limited, if these dozens of antigens are combined to activate more T cells, they can effectively target and kill tumor cells. To this end, BioNTech and Genentech researchers collaborated to screen for neoantigen-producing gene mutations from the tumor cells of each pancreatic cancer patient, make individual mRNA vaccines, and then combine about 20 individual mRNA vaccines according to the different gene mutation sites of each patient, customize the personalized neoantigen vaccine combination ("BNT122" or "RO7198457") belonging to that patient, and package them with nanolipid particles for intravenous injection. BioNTech has accumulated extensive experience in the development of mRNA vaccines for the novel coronavirus and is actively advancing mRNA vaccines to other fields such as cancer treatment.
According to a paper published online on the website Nature in May 2023, researchers at Memorial Sloan Kettering Cancer Center in the United States used this customized, personalized neoantigen mRNA vaccine to conduct a phase I clinical trial in pancreatic cancer patients. From December 2019 to August 2021, researchers enrolled a total of 34 patients with pancreatic cancer, of whom 28 patients underwent surgery and 19 patients subsequently received antibody-targeted therapy. Of the 19 patients who underwent surgery and antibody-targeted therapy, a total of 16 patients were treated with BNT122, a personalized neoantigen vaccine combination, and 15 of them also received multi-agent chemotherapy. Among the 16 patients treated with BNT122, the vast majority did not experience serious side effects related to mRNA vaccine injection, only one patient experienced grade 3 or above adverse reactions (fever and hypertension), and the other patients only had grade 1 or 2 adverse reactions, demonstrating that BNT122 was well tolerated and safe. More excitingly, a total of 8 patients developed an immune response to BNT122. BNT122 was found to activate a large number of T cells in these patients, including long-lived and multifunctional neoantigen-specific CD8+ T cells, which accounted for 10% of all blood T cells in these patients.
During the 18-month post-vaccination follow-up period, the median recurrence-free survival of patients who developed an immune response to the mRNA vaccine combination BNT122 was not yet reached, i.e., their recurrence-free survival was at least 18 months or more, compared with 13.4 months in the eight patients who did not respond. Results from the new Phase I clinical trial, presented at the 2024 Annual Meeting of the American Association for Cancer Research (AACR), showed that the median recurrence-free survival of eight patients with a good immune response to BNT122 has exceeded 3 years and may be further extended.
In addition, further testing revealed that BNT122 caused multiple CD8+ T cell expansions in 8 responding patients, 98% of which were not present in blood, tumors, or adjacent tissues prior to vaccination. More than 80% of newly expanded CD8+ T cells remain in the blood for a long time, averaging about 0.1% of all blood T cells. The researchers also isolated these newly expanded CD8+ T cells for immune response testing and found that CD8+ T cells isolated from 6 of the 8 patients were still immune to the corresponding neoantigen 3 years after vaccination.
New clinical trial data suggest that BNT122 can induce the production of a large number of long-lived CD8+ T cells with long-lasting immune function, which is one of the important reasons for prolonging recurrence-free survival in pancreatic cancer patients. This result has undoubtedly given the researchers great confidence, and they have now started a Phase II clinical trial in October 2023 to further validate the safety and efficacy of BNT122 in patients with pancreatic ductal adenocarcinoma in a larger patient population. The Phase II clinical trial is primarily recruiting patients in the U.S. and plans to open multiple centers globally. In addition to the treatment of pancreatic cancer, BNT122, a personalized neoantigen vaccine therapy jointly developed by BioNTech and Genentech, is also in Phase II clinical trials for the treatment of melanoma and adjuvant treatment for colorectal cancer.
In addition to mRNA vaccines, personalized neoantigen cancer vaccines also come in a variety of forms, such as DNA vaccines and peptide vaccines. According to the results of a phase I/II clinical trial published in Nature Medicine on April 7, 2024, Geneos Therapeutics has designed a personalized neoantigen liver cancer DNA vaccine against up to 40 neoantigens in hepatocellular carcinoma cells, and a single-arm, open-label, multicenter phase I./II clinical trial has been jointly carried out through Johns Hopkins School of Medicine and other units, and good clinical trial results have also been achieved. Hepatocellular carcinoma is the most common form of primary liver cancer and has one of the highest cancer mortality rates worldwide, with a five-year survival rate of less than 10%.
The clinical trial showed that no dose-limiting toxicity or treatment-related adverse reactions of grade 3 or above were observed in 36 patients with advanced hepatocellular carcinoma previously treated with polytyrosine kinase inhibitors, using a personalized neoantigen DNA vaccine, plasmid DNA-encoded interleukin-12, and pembrolizumab (PD-1 inhibitor). In addition, 11 of the 36 patients had an objective response to the combination therapy, i.e., an objective response rate of more than 30%, and 3 patients had a complete response. Prior to this, the response rate with pembrolizumab (PD-1 inhibitor) alone was only 12% to 18%, suggesting that the combination of personalized neoantigen DNA vaccine and pembrolizumab can significantly enhance the efficacy of advanced hepatocellular carcinoma. Further studies have shown that personalized neoantigen DNA vaccines can also stimulate the proliferation of CD4+ and CD8+ T cells in patients, and can target and infiltrate liver cancer cells, thereby promoting tumor cell lysis and apoptosis.
Personalized neoantigen cancer vaccines have become the star of malignancy treatment worldwide. As of April 14, 2024, data from the U.S. Clinical Trial Information Website (Clinicaltrials.gov) shows that there are more than 90 clinical trials of personalized neoantigen cancer vaccines in different stages around the world, most of which are for refractory and recurring malignant tumors such as pancreatic cancer, non-small cell lung cancer, and brain cancer. Although no country has officially approved personalized neoantigen cancer vaccines as new drugs, these preliminary clinical trial results have brought encouraging news, and it is expected that personalized neoantigen cancer vaccine therapy will become an important tool for cancer treatment worldwide in the next few years.
Southern Weekly Contributing Writer Tang Bo
Editor-in-charge: Zhu Liyuan