New natural enemy of tumor? New antigen vaccine clinical trials are underway

▲TG-Bio has joined hands with more than 600 industry colleagues and will open in April ▲Vaccines in the traditional sense are mainly used to prevent infectious diseases.
However, these drugs can induce and enhance the ability of antigen-specific immune responses, and have long been considered A potentially valuable tool for the treatment of cancer.

Vaccines targeting tumor cell neoantigens are currently undergoing large-scale clinical trials.
This vaccine is designed to trigger the response of patients' newborn T cells to neoantigens.

Neoantigens refer to new epitopes of self-antigens produced by tumor cells undergoing genetic mutations.
This antigen is only expressed in tumor cells and can therefore cause a true tumor-specific T cell response, thereby preventing off-target damage to non-malignant tissues.
.

With the emergence of next-generation sequencing technology, new antigen selection algorithms have gradually matured, and a large number of bioinformatics platforms can be used to screen treatment-related neoantigen targets to quickly develop personalized treatment plans.

In addition, the development of MHC I binding epitope prediction algorithms has paved the way for the identification of potentially immunogenic neoantigens.

In general, these scientific advances have made it possible to produce personalized therapeutic cancer vaccines (TCVs) that can be tailored to each patient’s tumor.

On January 20, 2021, Professor Patrick A.
Ott and his colleague Eryn Blass from the Dana Farber Cancer Institute in Boston, USA published an article entitled "Advances in the development of personalized neoantigen-based therapeutic" in Nature Reviews-Clinical Oncology.
"Cancer vaccines" review.

This article outlines the complex process required to generate personalized neoantigen vaccines, reviews the types of T cells induced by vaccines found in tumors, and summarizes strategies to enhance T cell responses.

In addition, Professor Ott also discussed the current clinical research status of testing personalized neoantigen vaccines in cancer patients, and his vision for future clinical research on this novel and personalized immunotherapy.

Fig.
1.
Personalized neoantigen-based vaccination has the potential to induce long-lasting tumor-specific memory T cell populations.
Figure 1.
Personalized neoantigen-based vaccination has the potential to induce long-lasting tumor-specific memory T cell populations.
It is possible that personalized vaccination based on neoantigens may induce a durable tumor-specific memory T cell population.

After vaccination, both neoantigen-specific CD4+ T cells and CD8+ T cells can be induced by newborn or by enhancing the existing neoantigen-specific T cell response.

These T cells proliferate rapidly and kill tumor cells expressing neoantigens.

After the tumor is eradicated, the responding T cell population shrinks.

Studies have found that vaccine-induced neoantigen-specific T cells have the potential to produce long-lived central memory T (TCM) cells and effector memory T (TEM) cells.

Whether neoantigen-based vaccination can produce tissue resident memory T (TRM) cells or peripheral memory T (TPM) cells is still unknown.

Table 1 summarizes several key clinical trials of personalized neoantigen vaccines, mainly for melanoma and glioblastoma.
The vaccine format involves mRNA, peptides and dendritic cells.

Among them, the latest research report by Zhuting Hu, Donna E.
Leet, etc.
showed that eight patients with stage IIIB/C or IVM1a/b melanoma after undergoing the clinical trial numbered NCT01970358 for 4 years, the neoantigen-specific T cell response in the body continued for a long time Exist, neoantigen-specific T cells with memory phenotype were detected in vitro.

And with the passage of time, new antigen-specific T cell clones have gradually diversified, and a variety of T cell receptor clonotypes have appeared, showing unique functional affinity.

In other words, after 4 years of treatment, the immune response triggered by this vaccine is still strong and can effectively control cancer cells.

The relevant research results will be published in the journal Nature Medicine on January 21, 2021.

 Table 1.
Several key clinical trials of individualized neoantigen vaccines.
In the past 50 years, therapeutic cancer vaccines (TCVs) as an investigational immunotherapy have received a lot of research in clinical trials.
The field of oncology has developed into a promising drug.

At present, the advanced TCV platform is rapidly expanding, and investment and innovation are also in progress.

The series of statistical graphs in Figure 2 come from a personalized TCV clinical trial analysis review published in Molecular Therapy on February 3, 2021: "Personalized Cancer Vaccines: Clinical Landscape, Challenges, and Opportunities".

Researchers investigated multiple platforms, antigens, algorithms, delivery systems, clinical environments, endpoints, and preliminary clinical results.

In addition to public publications and clinical trials, data sources also include government websites, company websites, news reports, and the American Association for Cancer Research (AACR), American Society of Clinical Oncology (ASCO), and European Society of Medical Oncology (ESMO) in the past 5 years.
And the conference speeches and abstracts of the Society for Cancer Immunotherapy (SITC).

Figure 2.
Clinical Trial Landscape for Personalized TCVs Figure 2.
The survey of clinical trials of personalized TCVs shows that there are at least 23 different phase 1 or phase 2 clinical trials, most of which are in progress.

Of these trials, 20 (87%) were phase I studies, and 17 (75%) used mRNA, DNA, or peptide antigen delivery platforms.

The trial recruited patients with multiple types of solid tumors, of which non-small cell lung cancer (NSCLC) and melanoma were the most common (Figure 2.
E).

Studies have shown that the choice of target antigens is very wide.
About 75% of clinical trials use more than 10 neoantigens as targets (Figure 2.
D).

At present, the best method of administration and route of administration have not yet been determined.
Lipid nanoparticles (LNPs) are the most commonly used delivery carriers.
The route of administration is mainly intravenous injection (30%), intramuscular injection (30%) or Subcutaneous injection (25%, Fig.
2G).

40% of clinical trial patients used the method of dosing once every 3 weeks (q3w) (Figure 2.
1).

The number of vaccinations for patients per year varies greatly from 6 to 26 (Figure 2.
J).

At least 40% of these trials will evaluate multiple dose levels in clinical trials (Figure 2.
K).

In addition, many TCVs are being tested in combination with other treatments, including chemotherapy, interleukin (IL)-2 and anti-programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1), and anti-programmed death ligand 1 (PD-L1).
Cytotoxic T lymphocyte protein 4 (CTLA-4) related drugs were given in combination (Figure 2.
F).

In general, the cancer neoantigen vaccine may be the next preferred joint partner for long-term cancer treatment.
It provides a platform that can be easily combined with other existing cancer treatment methods, with the lowest biological toxicity and good safety.

The ability to quickly and comprehensively identify tumor-specific mutations provides accurate tumor-specific targets for the field of cancer vaccines.

Preliminary experiments have shown that personalized vaccines based on neoantigens can be produced, safely used to treat a single cancer patient, and cause the patient to produce a specific T cell response.

As diversified clinical trials continue, we are steadily advancing towards the ultimate goal of being able to stimulate effective and durable tumor-specific immunity in cancer patients.

References [1] Blass E, Ott PA.
Advances in the development of personalized neoantigen-based therapeutic cancer vaccines [published online ahead of print, 2021 Jan 20].
Nat Rev Clin Oncol.
2021;1-15.
doi:10.
1038/ s41571-020-00460-2[2] Shemesh CS, Hsu JC, Hosseini I, et al.
Personalized Cancer Vaccines: Clinical Landscape, Challenges, and Opportunities.
Mol Ther.
2021;29(2):555-570.
doi: 10.
1016/j.
ymthe.
2020.
09.
038[3] Hu Z, Leet DE, Allesøe RL, et al.
Personal neoantigen vaccines induce persistent memory T cell responses and epitope spreading in patients with melanoma [published online ahead of print, 2021 Jan 21 ].
Nat Med.
2021;10.
1038/s41591-020-01206-4.
doi:10.
1038/s41591-020-01206-4[4] Jou J, Harrington KJ, Zocca MB, Ehrnrooth E, Cohen EEW.
The Changing Landscape of Therapeutic Cancer Vaccines-Novel Platforms and Neoantigen Identification.
Clin Cancer Res.
2021;27(3):689-703.
doi:10.
1158/1078-0432.
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