Research progress and challenges of personalized neoantigen tumor vaccines

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Research progress and challenges of personalized neoantigen tumor vaccines

Research progress and challenges of personalized neoantigen tumor vaccines.  Vaccines have traditionally been used to prevent infectious diseases; however, the ability of this drug to induce and amplify antigen-specific immune responses has long been considered a potentially valuable tool for the treatment of cancer.

Early therapeutic vaccination strategies focused on abnormally expressed or overexpressed self-antigens in tumors, called tumor-associated antigens (TAA).

However, this strategy is due to TAA-specific T cells that are affected by central and/or peripheral tolerance. Basically it was unsuccessful. In addition, such TAAs are also expressed to a certain extent in non-malignant tissues, which increases the risk of vaccine-induced autoimmune toxicity.

Mutations in tumor cells can produce new self-antigen epitopes, called neoepitopes or neoantigens. Vaccines based on neoantigens rather than traditional TAAs have several advantages.

First, neoantigens are only expressed by tumor cells, so they can trigger a true tumor-specific T cell response, thereby preventing “off-target” damage to non-tumor tissues.

Second, neoantigens are new epitopes derived from somatic mutations, which may bypass the central tolerance of T cells to their own epitopes, thereby inducing immune responses to tumors.

In addition, the neoantigen-specific T cell response enhanced by these vaccines persists and provides the potential for immune memory after treatment, which provides the possibility of long-term prevention of disease recurrence.

Identification of immunogenic neoantigens

In order to identify tumor-specific somatic mutations, tumor biopsy samples and non-tumor tissue samples (usually peripheral blood mononuclear cells) are collected from patients for full exon sequencing of tumor and germline DNA. In addition, RNA sequencing provides effective information on the expression of the mutant gene and further confirmation of the mutation.

Depending on the type of tumor, a large number of tumor-specific mutations can usually be identified; however, not all mutations cause new epitopes to be recognized by the immune system due to HLA limitations. It is known that there are more than 16,000 HLA-A, HLA-B, and HLA-C alleles. Therefore, when predicting potential immunogenic epitopes, HLA typing needs to be considered.

Using computational methods to predict MHC-I binding epitopes, peptides with a strong affinity for HLA (IC50<150 nmol/l) are considered to be more likely to induce CD8+ T cell responses. At present, various calculation methods for predicting the epitopes presented by MHC-I have been developed, including the use of mass spectrometry to further improve the prediction algorithm. However, so far, epitope prediction methods have mainly focused on MHC-I binding epitopes, and the more flexible binding epitopes of MHC-II make epitope prediction more complicated.

In addition to computational methods, another method of inducing a neoantigen-specific immune response is to use tumor lysates. Autologous APCs, usually DCs, can be isolated from the patient, exposed to tumor lysate, and then injected back into the patient with the purpose of stimulating the immune response to TAAs or neoantigens. This method avoids the sequencing and computational analysis required to identify patient-specific neoantigens. However, TAAs are unlikely to be immunogenic. In addition, due to the high abundance of non-immunogenic self-antigens, the ability of relevant new epitopes to stimulate immune responses may be reduced.

Quality of immunogenic neoantigens

The success of the neoantigen platform depends to a large extent on the tumor mutation burden (TMB). It is reasonable to assume that tumors with high TMB may have a corresponding high number of tumor neoantigens, which can be used for vaccine targeting and have better ICI Reaction.

However, the occurrence of high TMB is not always consistent with the response of ICI. In addition to the tumor’s inherent drug resistance mechanism, other reasons for this difference may be directly related to the “quality” of the neoantigen, that is, the ability of the neoantigen to produce the final TH1 cell and/or CTL response to the tumor.

The “quality” of neoantigens includes: (1) Exogenous degree, which is a measure of the heterogeneity of neoantigens compared with wild-type proteins. The stronger the endogenous, the weaker the immunogenicity, and the easier it is to clear through immune tolerance; ( 2) Clonal distribution, clonal mutations cause most tumor cells to express neoantigens, and low-distribution mutations are more likely to lose expression under the selective pressure of ICI; (3) The mutation status of tumors, compared with passenger mutations, driver mutations are even less Escape easily occurs; (4) Affinity and expression of MHC presenting molecules; (5) Affinity of TCR and MHC complex.

Considerations for neoantigen vaccine protocol

Many factors should be considered when designing a therapeutic vaccination program.

After sample collection, the time required to generate a personalized vaccine is a key factor, especially in a metastatic disease environment; the production time depends on the choice of the vaccine platform, however, while designing and manufacturing a personalized vaccine, it can be Patients implement combination therapies to cultivate a favorable immune environment. Adjuvant therapy can also be given at the time of vaccination or after vaccination to enhance the immune response.

Other variables include the route of administration of the vaccine and any combination therapy, and the number of booster vaccinations. In the case of disease recurrence, tumor DNA sequencing can be repeated, and the vaccine-induced T cell response can be assessed through blood and tumor samples, thereby providing a basis for decision-making for subsequent treatment.

Clinical progress of neoantigen vaccines

At present, there are several clinical trials of personalized neoantigen vaccines in progress. These preliminary studies provide important clues for the immunogenicity and therapeutic potential of personalized neoantigen tumor vaccines.

Most of these preliminary clinical trials are performed when all tumors have been surgically removed, without any additional standard treatment, and only trial vaccines can be used. In view of the extensive clinical efficacy of ICI against PD-1 or PD-L1 in cancer, personalized neoantigen vaccines combined with PD-1 or PD-L1 inhibitors are the current development direction. Multiple ongoing clinical trials are combining personalized neoantigen vaccines with PD-1, PD-L1 and/or CTLA4 inhibitors in different tumor types.

GEN-009 is a personalized neoantigen vaccine, containing 4-20 synthetic long peptides selected using the ATLAS epitope discovery platform, using poly-ICLC preparations. In an ongoing multicenter phase I/IIa study (NCT03633110), 8 patients with solid tumors at high risk of recurrence received GEN-009, which was well tolerated by the vaccine, and only reported discomfort at the local injection site.

It was found that all patients had peripheral blood CD4+ T cells and CD8+ responses to at least one new antigen. 99% of the peptides stimulated T cell responses. It is worth noting that T cell responses usually last for more than 12 months. Further data from this trial also includes a group of patients with advanced disease who are receiving the combination of GEN-009 and PD-1 inhibitors.

RO7198457 is a personalized RNA-lipoplex neoantigen vaccine that encodes up to 20 new antigens. In a phase Ib study (NCT03289962), a combined trial with atezolizumab was conducted on 132 patients with advanced solid tumors. The results showed that 77% of patients had detected the response of circulating T cells to neoantigens with a median of 2.6 in vitro. The frequency of detection of vaccine-specific CD8+ T cells in peripheral blood was >5%, and vaccine-specific TCR was also detected in tumor specimens after vaccination.

mRNA-4157 is another lipid-encapsulated RNA neoantigen vaccine that has been tested as a monotherapy in 13 patients with high-risk resectable solid tumors, and combined with pembrolizumab in the treatment of 20 patients with unresectable advanced solid tumors, the latter Including 12 patients with disease progression before ICI treatment (NCT03313778). No dose-limiting toxicity or grade 3-4 adverse events were observed. Six clinical responses (ORR 30%) were observed in 20 patients treated with the combination therapy, including 2 (17%) of 12 patients previously treated with ICIs.

The challenge of neoantigen vaccines

Although some preliminary clinical trial data of neoantigen vaccines showed strong immunogenicity and evidence of targeted tumor cell killing, a relatively large proportion of vaccine neoepitopes did not stimulate T cell responses. The primary challenge in the field of cancer vaccine research is to improve our ability to induce T cell responses, especially the maximum activation and expansion of CD8+ T cells.

To achieve this goal, complementary therapies that promote APC function and optimal activation of T cells in lymph nodes may be needed. Possible to achieve this include ICIs, costimulatory receptor agonists (such as CD40), TLR agonists and growth factors that support DC development and/or function (such as GM-CSF) and Fms-related tyrosine kinase 3 ligands (FLT3L).

Another challenge is how to determine the vaccine delivery system so that the vaccine can be produced quickly, cost-effectively, and deployed in a timely manner. Different vaccine formats, including peptides, RNA, DNA, viral structures, or DCs, each have their advantages and disadvantages; however, there is a lack of head-to-head comparisons of these different methods in patients.

The timing of ICI administration and therapeutic vaccination is another important consideration. Combining ICIs with therapeutic vaccination regimens may be beneficial, but requires careful consideration of the most appropriate component therapy regimen.

Summary

The ability to quickly and comprehensively identify tumor-specific mutations provides a tumor-specific target that has been difficult to find for a long time in the field of tumor vaccines. Preliminary studies have shown that personalized neoantigen vaccines can bring significant clinical benefits to cancer patients, but personalized neoantigen tumor vaccines still face many challenges.

In the end, we need to develop stable, safe and maximally inducing T cell responses. Treatment strategy. Currently, many studies using different vaccine delivery platforms and combination therapies are underway, and the results are worth looking forward to.

Research progress and challenges of personalized neoantigen tumor vaccines. 

(source:internet, reference only)

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