On October 1, 2021, BioNTech announced that a personalized mRNA cancer vaccine BNT122 (RO7198457), developed in cooperation with Roche's Genentech, has completed its first patient administration in a Phase 2 clinical trial for the treatment of colorectal cancer. On November 19, 2021, BioNTech announced that the US FDA has granted fast-track qualification to its mRNA cancer vaccine BNT111, which for the treatment of advanced melanoma.
As a biotechnology company that has been working on mRNA technology for many years, BioNTech is committed to expanding the application of mRNA technology in other fields. In the third quarter 2021 financial results, the company not only introduced the latest progress in mRNA infectious disease vaccines, but also introduced the various applications of mRNA technology in the treatment of cancer, showing the broad prospects of mRNA technology.
▲ The broad prospects of mRNA technology ( source: BioNTech)
Infectious Disease Vaccines
In terms of infectious disease vaccines, the mRNA COVID-19 vaccines have been used in hundreds of countries and regions around the world. Over the past three months, significant progress has been made in expanding the use of COVID-19 vaccines to populations and scaling up vaccination. The results of clinical trials have shown that the mRNA COVID-19 vaccines can stimulate a strong immune response in children aged 5 to 11 years and is 90.7% effective in preventing symptomatic COVID-19.
▲mRNA vaccine shows good protective efficacy in children aged 5 to 11 years (source: BioNTech)
The advantage of mRNA technology is that vaccines encoding pathogen antigens can be rapidly generated and multiple pathogen-related antigens can be encoded in a single mRNA. This makes it a powerful option for developing vaccines for infectious diseases. In addition to the COVID-19 vaccines, the mRNA quadrivalent influenza vaccine jointly developed by BioNTech and Pfizer has recently entered the phase 1 clinical development stage. In addition, there are 9 infectious disease vaccines in the R&D pipeline that are in the preclinical development stage for the prevention of malaria, HIV, tuberculosis and other diseases.
mRNA cancer vaccines
Before the development of the COVID-19 vaccines, BioNTech already had a pipeline of mRNA-based cancer vaccines. Similar to the principle of infectious disease vaccines, the mechanism of cancer vaccines is to introduce tumor-related antigens, stimulate the body's immune response, and use the immune system to destroy cancer cells.
BioNTech's cancer vaccine platforms fall into two broad categories, iNeST and FixVac. Among them, iNeST technology platform generates mRNA cancer vaccines targeting neoantigens. Tumor cells produce neoantigens due to genetic mutations that are not present in healthy cells. The body's immune system recognizes these antigens and produces an immune response to them. However, the expression levels of these neoantigens in many tumors are too low to trigger a strong anti-cancer immune response.
INeST vaccines use mRNA to encode neoantigens expressed in a patient's tumor. When injected into the body, they express high levels of neoantigen proteins that trigger a powerful immune response. The iNeST vaccine can express up to 20 different neoantigens, triggering a more comprehensive immune response against tumor cells and preventing them from escaping the immune system.
▲Introduction of iNeST technology platform (source: BioNTech)
BNT122 is an individualized neoantigen specific immunotherapy (iNeST). It is a cancer vaccine generated using the iNeST technology platform. INeST immunotherapy is an individualized cancer therapy tailored to a specific patient's tumor. They contain unmodified, pharmacologically optimized mrnas that encode up to 20 patient-specific neoantigens. Neoantigens are proteins produced by cancer cells due to genetic mutations that are different from healthy cells and can be recognized by immune cells.
BNT122 has been administered to the first patient in a phase 2 clinical trial for adjuvant treatment of colorectal cancer patients after surgery to prevent cancer recurrence. It is used in combination with the PD-1 inhibitor pembrolizumab, and a phase 2 clinical trial for the first-line treatment of patients with advanced melanoma is also being recruited.
The cancer vaccine generated by the iNeST technology platform is a "tailored" individualized cancer vaccine, which expresses unique neoantigens expressed on tumors of different patients. However, some antigens expressed on tumors are highly expressed in most cancer patients. BioNTech’ s FixVac technology platform aims to use mRNA to express these shared tumor-associated antigens, which can target antigen-presenting cells and activate antigen-specific T cell responses. One of its advantages is that it can be generated and saved in advance, and can be used by patients immediately.
▲Introduction of FixVac technology platform (source: BioNTech)
BNT111, an investigational cancer immunotherapy for the treatment of advanced melanoma, is one of four product candidates for BioNTech's FixVac platform, which uses a combination of tumor-associated antigens encoded by mRNA to trigger powerful and precise immune response against cancer for cancer therapy. On November 19, BioNTech announced that the U.S. FDA has granted the fast-track qualification for the tumor immune mRNA vaccine BNT111 for the treatment of advanced melanoma.
BNT111 is an intravenous liposomal RNA vaccine that encodes four non-mutated, tumor-associated antigens-NY-ESO-1, MAGE-A3, tyrosinase, and TPTE, covering >90% of patients with skin melanoma. These antigens have limited expression in normal tissues, but they are widespread in melanoma and have high immunogenicity.
BNT112 is an mRNA vaccine for the treatment of prostate cancer. It encodes 5 kinds of tumor-associated antigens that appear in prostate cancer patients. Currently, it is used as a single agent or in combination with PD-1 inhibitors to treat patients with prostate cancer in phase 1/2 clinical trials. Preliminary clinical trial results showed that vaccine-induced immune responses were observed in seven vaccine-treated patients with metastatic castration-resistant prostate cancer, and T-cell immune response against all tumor-associated antigens carried by the vaccine was observed in two patients. Moreover, a decrease in prostate-specific antigen (PSA) levels was observed in two patients receiving BNT112 monotherapy, which is a manifestation of anti-tumor activity.
Since cancer vaccines can stimulate immune responses, enhancing the efficacy of immunotherapy is an important direction of development in combination with other immunotherapies. BioNTech's therapeutic vaccine can also be used in combination with CAR-T therapy in addition to immune checkpoint inhibitors.
Using mRNA vaccines to improve the efficacy of CAR-T therapy
CARVac is a unique CAR-T cell amplified mRNA vaccine developed by BioNTech. It is designed to encode antigens targeted by CAR T cells using mRNA. CARVac can selectively induce antigen presenting cells in lymph nodes to express antigens targeted by CAR T cells, thereby stimulating CAR T cell expansion in patients.
CARVac that expresses CLDN6 (a protein that is not expressed in healthy tissues but is expressed in ovarian cancer, lung cancer and other cancer types) is combined with CAR-T cell therapy targeting CLDN6, which has been shown in solid tumor models It can improve the expansion and effectiveness of CAR-T cells.
Dr. Uğur Şahin, CEO of BioNTech, pointed out that the success of COVID-19 vaccine provides a good opportunity to expand the application of mRNA in cancer vaccines and other therapeutic modalities. In addition to the above applications, the use of mRNA to express therapeutic antibodies or cytokines are being explored, which may further expand the range of diseases that mRNA therapy can treat, including inflammatory diseases, autoimmune diseases and allergies. With the continuous advancement of RNA technology, the entire biomedical field will benefit from it.
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 BioNTech Announces Third Quarter 2021 Financial Results and Corporate Update. Retrieved November 9, 2021
 Next Generation Immunotherapy. Retrieved November 9, 2021
 Third Quarter 2021, Corporate update and financial results. Retrieved November 9, 2021
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