How to develop personalized neoantigen vaccines?

Common prophylactic vaccines introduce antigens into a person's body to make immune system generate antibodies for those antigens, and become immune to the associated illness. While tumor vaccines are administered to patients with malignant tumors to activate the patient’s autoimmune response and kill the tumor cells. Traditional tumor vaccines mainly target tumor-associated antigens (TAAs), which are existing in both tumor cells and normal cells. Several clinical trials targeting TAAs with anti-tumor vaccines have failed to achieve the desired therapeutic effect. Neoantigens, differed from the traditional TAAs, are tumor-specific antigens. Compared to TAAs, neoantigens possess stronger immunogenicity and higher affinity toward MHC, and are not affected by central immunological tolerance. Therefore designing specific neoantigens-based vaccines would be a better solution for tumor immunotherapy. The first human clinical trial using neoantigen vaccines was reported in 2015 by Carreno and colleagues. In their study, they vaccinated three patients with advanced melanoma with personalized dendritic cell-based vaccines designed to activate T cells specific for mutations in the patients' cancer and indeed expanded the T cells immunity and breadth of the antitumor immune response [9]. 

Major types of neoantigen vaccine

Tumor vaccines targeting neoantigens mainly include nucleic acid, dendritic cell (DC)-based, tumor cell, and synthetic long peptide (SLP) vaccines [1]. (Fig. 3)

Fig. 3 Major types of neoantigen vaccines. In vivo, neoantigens are eventually presented to CD4+ T cells and CD8+ T cells to induce specific immune responses and achieve anti-tumor effects [1].

Each method has distinct advantages and disadvantages. In brief, dendritic cell (DC)-based vaccines have low toxicity, but are not very potent and require additional steps to have antigens loaded and presented. The RNA neoantigen vaccine has unique advantages. It only requires a small amount of tumor cells to extract RNA and prepare vaccines. RNA vaccines can avoid integration into host cell genome which may lead to potential risks, they have less side effects and lower autoimmunity. But the possiblity of rapid degradation and clearance may lead to lower potency. Peptides are an attractive choice as vaccines due to their potential to directly function as pivotal T-cell epitopes [11]. The advantages include their low toxicity profiles, specificity for target, relatively low cost, and can be prepared by chemical synthesis. In the meanwhile, multiple peptide epitopes can be incorporate in a single vaccine to increase the chance of activating multiple T-cells and avoid tumor escape caused by loss or changes of epitopes during tumor progression [11,12,13]. The peptide vaccine tends to be the most commonly used in clinical trials. 

How to develop personalized neoantigen vaccines?

Although there are some differences among the companies developing neoantigen vaccines, normally there is a general process. 

Fig. 4 How neoantigen vaccines work. Source: CB Insights [14]

The first step is to select the neoantigens that will be most effective and decide whether they are public (also called “shared”) or personized. Public neoantigens, are mutation-based antigens common amongst certain tumor types or repeatedly occur in many patients. For people with tumors bearing a specific public neoantigen, an off-the-shelf vaccine can be developed and administered to multiple patients [15]. However, neoantigens always differ from patient to patient, and tumor to tumor. For those patients without a public neoantigen, a vaccine needs to be purely personalized to ensure antitumor response. Thus, personalized treatment is more complex and costly. With the significantly improvement of prediction algorithms and the using of sophisticated machine learning methods, many companies are now able to improve the success rate of selecting neoantigen candidates. 

Once the neoantigens are selected, the next step is to develop and manufacture the vaccine based on different strategies.

-Chemically synthesize the neoantigen peptide, then inject the purified neoantigen into the patient to elicit T-cell response.

-Synthesize the RNA or DNA as templates.

-Use a virus to infect cancer cells, lysing and spilling the neoantigens into the environment.

-In the lab, generate antigen presenting cells (APCs) from a patient’s own blood and reinject it back into the patient, where the APCs will stimulate T-cell activity [15]. 

At last when the vaccine is ready, it is administered to the patients. Comparative studies have shown that the combination of tumor vaccine and other therapies can be more effective than monotherapy. So mapping out how these neoantigen vaccines could combine with other therapies or drugs is also an important part for successful clinical response. 

Strategies to improve personalized neoantigen vaccines for cancer 

In the paper published by Catherine J. Wu and colleagues, they proposed four strategies that can be expected to improve the neoantigen vaccines in the near term, as illustrated in the below figure [16].

Fig. 6 Strategies to improve personalized neoantigen vaccines for cancer [16].

First one, improving the antigen prediction. Improve HLA-binding algorithms to increase the possibilities of targeting neoantigens that are expressed by cancer cells and mass spectrometry-based approaches can identify peptides that are processed and presented by the tumor cell [16].

Second, developing combination therapy. Personalized neoantigen vaccines can be combined with other therapies such as checkpoint blockade to prevent immune escape. Complementary therapies to reverse immune suppression in the tumor microenvironment, such as depleting regulatory cells, inhibiting regulatory molecules or blocking metabolic suppression, will be important to unleash the full potential of a neoantigen-based cancer vaccine [16]. Combinations of neoantigen vaccine and adaptive T cell therapy have also been successfully used to achieve anti-tumor response. Traditional treatments such as radiotherapy and chemotherapy can also enhance the role of neoantigen vaccines.

Third, developing and using preclinical models. The use of preclinical models is important to optimize dosing, administration routes, immune adjuvants and vaccine delivery approaches [16].

Fourth, improving manufacturing practices. Production of personalized vaccines could be more costly and time-consuming. Streamlined analysis and selection of epitopes and streamlined rapid manufacture of peptide or DNA will substantially lower the cost and production time of personalized vaccines [16].

Related articles