RNA cancer vaccines

The immune system protects the organism from pathogenic microorganisms and other harmful substances, and the activation of the cells of the immune system is based on the ability of the immune system to distinguish antigens of its own tissues from foreign antigens. Characteristics of malignant diseases are genetic mutations in cells that lead to uncontrolled cell proliferation, the appearance of neoantigens associated with malignant tumors, tumor associated antigens (TAA), immunosuppression and avoidance of immune surveillance.

Immunotherapy of malignant diseases aims to trigger the immune system to recognize and destroy malignant cells. Newer immunotherapies based on immune checkpoints inhibitors have shown efficacy against several types of advanced cancers, but the overall rate of beneficial effects of this therapy is below 30%. Therefore, there is a need to improve current immunotherapies for malignancies. There are several strategies to improve immunotherapy in oncology, some of which are currently being researched and developed are vaccines against malignant tumors and nanoparticle-based immunotherapy.

1. Nanoparticles in immunotherapy of malignant tumors

The versatility and adaptability of nanoparticles make them promising platforms for immunotherapy of various cancers. For example, nanoparticles can deliver certain material to cells, tumor antigens or mRNA, which will then trigger a strong activation of immune cells. Nanoparticles also enable the delivery of various therapeutic agents, thus forming the basis for combined cancer immunotherapy. Nanoparticle platforms are designed to deliver tumor antigens, whole tumor cells, and chemotherapeutic or phototherapeutic agents in a manner that efficiently and safely activates the host immune system against tumor cells.

Nanovaccines offer a unique platform for the delivery of personalized tumor antigens and aids to elicit a strong immune response against malignant tumors. Nanovaccines, which deliver a total lysate of tumor cells or are created from a lysate of tumor cells, may increase the repertoire of tumor antigens as immune targets for the antitumor immune response.

Immunotherapies for oncological diseases, including cancer vaccines, immune checkpoint inhibitors or chimeric T cell receptors (CARs) have been attractive treatment modalities in recent years.

Among these approaches, cancer vaccines designed to deliver tumor antigens and adjuvants to activate antigen-presenting cells and induce an antitumor immune response have shown significant efficacy in inhibiting tumor growth, preventing tumor recurrence and metastasis. However, therapeutic outcomes in preclinical trials were unsatisfactory, in part due to the ineffective five-step vaccination cascade consisting of:

a) antigen identification,
b) antigen encapsulation,
c) delivery of antigen,
e) antigen release and
e) presentation of antigen to T cells

In recent years, it has been shown that different nanobiomaterials have great potential to enhance the vaccination cascade against malignant tumors and thus improve the antitumor effects.

2. mRNA vaccines in the immunotherapy of malignant diseases

mRNA vaccines are a relatively new class of vaccines, which combine the potential of mRNA to encode almost any protein, safety, and flexible manufacturing process. The simplest use of mRNA vaccines in oncology is to immunize patients with an iRNA vaccine that encodes tumor antigens (TAAs). Another application of mRNA cancer vaccines is the production of personalized vaccines. This is possible because mRNA vaccines are produced by a generic method, which can be used for the rapid production of mRNA vaccines that are specific to the patient’s neoantigens that are identified by tumor analysis. In addition to being used directly to vaccinate patients, mRNAs can also be used in cell therapies to transfect patient cells in vitro and administer such modified cells to the patient. One such application is the transfection of dendritic cells (DC) of a patient with mRNA encoding TAA, leading to the presentation of peptides derived from TAA to DC and the activation of antigen-specific T cells in vivo.

MODERNA (USA) creates personalized cancer vaccines based on mRNA, ie vaccines for one patient. Through the process of gene sequencing, mutations found on malignant cells of the patient are identified, which are called neoepitopes and which the immune system distinguishes from healthy cells. Using algorithms developed by the bioinformatics team, 20 neoepitopes present in a patient’s cancer are predicted to elicit the strongest immune response, based on the patient’s unique immune system characteristics and certain malignant cell mutations. A vaccine is then created, a single mRNA molecule that encodes each of these mutations.

When the mRNA vaccine made in this way is injected, it allows the antigen presenting the patient’s cells to express selected neoepitopes of the tumor cells. After that, the immune system recognizes the neoepitopes, triggers an immune response directed at the malignant cells and destroys them.

mRNA vaccines have the potential to improve clinical outcome when given in conjunction with checkpoint inhibitors. To this end, in 2016, MODERNA and MERCK teamed up and developed one of the mRNA cancer vaccines (mRNA-4157), which is used in combination with Merck’s anti-PD-1 therapy, KEITRUDA. A phase 1 study is currently being conducted to evaluate the safety, tolerability, and immunogenicity of mRNA-4157 alone in subjects with solid tumor resection and in combination with KEITRUDA in subjects with inoperable solid tumors (KEINOTE-603). This mRNA cancer vaccine failed to work with Merck’s checkpoint inhibitor in colorectal cancer in phase 1 of the study, but reduced tumors in half of patients with head and neck cancers.

At these links you can see the process of production of the mRNA vaccine in the company MODERNA, as well as the importance of this new approach in the treatment of malignant tumors.

How Moderna Makes and Delivers Personalized Cancer Vaccines
Advancing mRNA-based personalized cancer vaccines – Tal Zaks, MD, PhD, Moderna CMO

3. Hydrogel nanoparticles for delivery of mRNA vaccine with immunostimulatory adjuvant

The use of mRNA vaccine technology for immunotherapy of malignant tumors has been studied in the past decade, but the success of this therapy has been limited. In cancer, mRNA vaccines are usually designed for certain tumor associated antigens, so that the immune system can recognize these neoantigens and develop an immune response and destruction of malignant cells.

Today, this technology is successfully applied to vaccines against COVID-19. In COVID-19 mRNA vaccines developed by Pfizer/BioNTech and Moderna, mRNA vaccines carry genetic information that requires cells to produce a specific viral protein, the spike protein, that binds the virus to host cells and then triggers an immune response to the protein.

mRNA is very unstable and for its FDA-approved mRNA vaccine against Covid-19 (BNT162b2), BioNTech used small fat particles known as lipid nanoparticles as mRNA carriers. Nanoparticles degrade and release mRNA when they enter cells and the mRNA itself also degrades rapidly after protein translation. The mRNA vaccine is a promising candidate for cancer immunotherapy because it can encode tumor antigens (TAAs). Inherent RNA instability and translational efficacy are major limitations of the mRNA vaccine for immunotherapy in oncology.

Scientists from China’s National Center for Nanoscience and Technology (NCNST) have now designed a hydrogel to deliver an immunostimulating adjuvant mRNA vaccine. When injected into mice with melanoma, the vaccine remained active for at least 30 days, inhibiting tumor growth and preventing metastasis, according to results published in the Journal of the American Chemical Society Nano Letters (see References).

The results of this study showed that the hydrogel delivery system has the potential to enable mRNA vaccines to achieve long-lasting antitumor effects. A team of researchers from NCNST designed a hydrogel with graphene oxide and light weight polyethyleneimine. To further enhance the stimulation and expansion of antigen-specific CD8+ cytotoxic T cells – which are crucial for the antitumor immune response – in the presence of an immunosuppressive tumor milieu, the research team added the Galdermin TLR7/8 agonist as an adjuvant.

To test their mRNA platform, the researchers used ovalbumin, a protein found in chicken egg white, as an antigen model. They mixed ovalbumin mRNA and adjuvant with hydrogel and injected them under the skin of mice with melanoma that can express ovalbumin on the surface of malignant cells. The results showed that the hydrogel continuously released the vaccine, ie both mRNA and adjuvant – in nanoparticles for at least 30 days and migrated to the lymph nodes.

Mice that received only one complete therapy injection had significantly smaller tumors compared to mice that received adjuvant and mRNA without hydrogels. Mice given complete therapy also showed the highest number of CD8 + T cells migrating into tumors.

In addition, this treatment with mRNA in hydrogel nanoparticles induced the highest levels of serum ovalbumin-specific antibodies, suggesting that it not only inhibits tumor growth but prevents the formation of distant metastases. There were no detectable lung metastases in mice that received the complete treatment, while the combination of free mRNA and adjuvant only partially reduced metastases compared to control mice treated with saline or hydrogel alone.

A team of NCNST researchers suggests that its hydrogel system has the potential as an effective mRNA platform for use in cancer immunotherapy. “This study shows the great potential of GLP-RO gels in achieving lasting and effective immunotherapy for malignant tumors,” the researchers wrote in the study.

If you have questions, comments and suggestions for topics I will be happy to answer.

References

  1. Aikins ME, Xu C, Moon JJ. Engineered Nanoparticles for Cancer Vaccination and Immunotherapy. Acc Chem Res. 2020 Oct 20;53(10):2094-2105. doi: 10.1021/acs.accounts.0c00456. Epub 2020 Oct 5. PMID: 33017150; PMCID: PMC7871038.
  2. Chen F, Wang Y, Gao J, Saeed M, Li T, Wang W, Yu H. Nanobiomaterial-based vaccination immunotherapy of cancer. Biomaterials. 2021 Feb 5;270:120709. doi: 10.1016/j.biomaterials.2021.120709. Epub ahead of print. PMID: 33581608.
  3. Fiedler K, Lazzaro S, Lutz J, Rauch S, Heidenreich R. mRNA Cancer Vaccines. Recent Results Cancer Res. 2016;209:61-85. doi: 10.1007/978-3-319-42934-2_5. PMID: 28101688.
  4. Yin Y, Li X, Ma H, Zhang J, Yu D, Zhao R, Yu S, Nie G, Wang H. In Situ Transforming RNA Nanovaccines from Polyethylenimine Functionalized Graphene Oxide Hydrogel for Durable Cancer Immunotherapy. Nano Lett. 2021 Feb 17. doi: 10.1021/acs.nanolett.0c05039. Epub ahead of print. PMID: 33594887.
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