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Clinical progress and challenges of personalized neoantigen DC vaccines
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Clinical progress and challenges of personalized neoantigen DC vaccines.
In the past few decades, tumor immunotherapy has developed into a treatment method with better tumor targeting, safety and low toxicity.
Among them , the clinical application of dendritic cell ( DC ) vaccines based on personalized neoantigens has made great progress.
Neoantigen vaccine is a very attractive cancer vaccine. In addition to being used as a vaccine alone, DNA, RNA, peptides and tumor lysates can also be loaded onto DC cells.
DC vaccines have many advantages. Firstly, DC cells are antigen-presenting cells ( APC ), which are responsible for ingesting, processing antigens and presenting them to T cells to activate immune responses.
New antigens can only exert their resistance after being absorbed by APCs and presented to T cells. Tumor effect.
Secondly, it uses DC cells as a carrier and is not limited by other factors, such as the efficiency of DNA integration, the influence of nucleases, and adjuvants.
Since the first DC vaccine sipuleucel-T was approved for clinical use in 2010, hundreds of studies and clinical trials have been conducted. These clinical studies have proved that the DC vaccine is stable, reliable and very safe. The new antigen-based DC vaccine is a safe, effective and feasible treatment strategy, which will bring new hope to cancer patients.
There are three main sources of tumor antigens: tumor-associated antigens ( TAAs ), oncogenic virus-derived antigens, and tumor-specific antigens ( TSA, neoantigens ).
Mutations in tumor cells can produce new self-antigen epitopes, called neo-epitopes 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.
Neoantigens are very attractive targets for tumor immunotherapy. Due to the development of next-generation sequencing technology and the application of machine learning algorithms, it is possible to describe genetic changes in tumor tissues, abnormal post-transcriptional mRNA processing, and abnormal mRNA translation events.
It has become possible to calculate and predict neoantigens. Therefore, neoantigen-based therapies, such as cancer vaccines, have been extensively tested in clinical trials and have proven to have good safety and effectiveness, opening up a new era of tumor immunotherapy.
Identification of 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 ( IC 50 <150nmol/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 related new epitopes to stimulate immune responses may be reduced.
In humans, the DC precursor cells in the bone marrow are divided into two main DC subgroups, plasma cell-like DC ( pDC ) and conventional DCs ( cDCs ). According to their phenotype, they include two major categories-cDC1 and cDC2.
For pDC, surface markers mainly include CD123, CD303, CD304, and CD45RA, which specifically secrete type I interferon ( IFN-I ), and at the same time present antigen to T cells and activate T cells.
For cDC1, the surface markers mainly include Cleca9A, XCR1 and CD141. cDC1 has the ability to cross-present and induce cytotoxic T cell immune response, and it can also significantly stimulate the immune response of homologous or autologous CD4+ T cells.
For cDC2, the surface markers mainly include CD1c, CD1a and CD103, which can present soluble antigens, but rarely present antigens from necrotic cells.
The principle of preparing a DC vaccine is very simple. The patient’s dendritic cell precursor cells are isolated and cultured in vitro, loaded with tumor antigens, and then transferred back to the patient. Then, DC stimulates specific anti-tumor T cells to exert anti-tumor effects.
After nearly 10 years of efforts in the field of DC vaccines, in 2000, DC-based immunotherapy was first used for patients with primary intracranial tumors. In 2010, the US FDA approved Sipuleucel-T as the first DC vaccine for the treatment of prostate cancer.
Sipuleucel-T is composed of peripheral blood mononuclear cells ( PBMC ), including APC, which is activated in vitro by PA2024, which is a recombinant protein that mainly includes prostate-specific antigen and prostatic acid phosphatase.
The results of the clinical trial of Sipuleucel-T showed that the 36-month survival rate of the Sipuleucel-T group was 31.7%, and that of the placebo group was 23%. The median survival time in the Sipuleucel-T group was 25.8 months, which was an increase of 4.1 months compared with 21.7 months in the placebo group.
This indicates that the drug can significantly prolong the survival period of patients, and the DC vaccine can bring survival benefits to patients. Another clinical trial on glioblastoma also showed the superior efficacy of DC vaccine. ICT-107 is an autologous DC vaccine that contains 6 different peptides for glioblastoma.
In the previous phase I study, 21 patients with glioblastoma treated with ICT-107 showed good tolerance. Among the 16 newly diagnosed patients, 6 patients did not have tumor recurrence, which indicates that The DC vaccine has good tolerability and anti-tumor activity.
The basis of the DC vaccine is to select immunogenic antigens so as to effectively activate the immune system as the DC matures. Since the antigen in each patient’s tumor is highly specific, DC cells loaded with personalized neoantigens are an attractive strategy.
Clinical progress of personalized neoantigen DC vaccine
Only rely on new anti original tumor vaccine can not completely eliminate the cancer. The reason is not the neoantigen itself, but because most trials use neoantigens to solve the problem of weak tumor cell antigenicity, but not the problem of deficiencies in immune cell function in cancer patients. Patients with malignant tumors usually have low immune function, and it is difficult to initiate an anti-tumor immune response in the body. One of the main reasons is that the function of antigen-presenting cells in the patient’s body is inhibited, and antigen-activated T cells cannot be effectively presented. Therefore, in order to obtain good clinical effects, immunotherapy must not only solve the problems related to antigens, but also solve the problem of immunosuppression in tumor patients. In other words, when many tumor-specific antigens are injected into the body, it is necessary to ensure that they are effectively absorbed and presented by the body’s antigen-presenting cells, and a sufficient number of effector T cells are activated.
In 2015, the first personalized neoantigen DC vaccine began to be tested in a phase 1 clinical trial. They recruited 3 stage III melanoma patients and treated them with ipilimumab. Then, somatic mutations were identified through whole exome sequencing and computer simulation of epitope prediction to screen for suitable neoantigens. In addition, 7 neoantigens were selected from each patient, loaded onto DC isolated from PBMC, cultured in vitro, and then intravenously injected into the patient for a total of three treatments. After treatment, an enhanced immune response triggered by T cells was observed, while all three patients survived and no autoimmune adverse reactions were observed, which indicates that the use of personalized neoantigen-based DC vaccines is safe and reliable.
In another trial conducted in 2020, the activity of personalized neoantigen DC vaccine in patients with advanced non-small cell lung cancer was demonstrated for the first time. In this study, a total of 12 patients with advanced lung cancer were recruited, and 13-30 peptide-based personalized neoantigens were isolated and identified from each patient’s tumor tissue. At the same time, extract PBMC from each patient, isolate DC, and then load DC cells with the corresponding neoantigen to form a personalized neoantigen DC vaccine to treat the patient. The study showed an overall objective response rate of 25% and a disease control rate of 75%. In addition, only mild and transient side effects were observed.
Currently, a number of DC vaccines loaded with personalized neoantigens are undergoing clinical trials, and most of these trials are in the first phase.
Combination therapy of personalized neoantigen DC vaccine
Combining personalized neoantigen DC vaccines with other strategies ( such as chemotherapy and immune checkpoint inhibitors ) is another effective way to improve the efficacy of tumor therapy vaccines.
Chemotherapy is considered to be an immunotherapy partner, which improves the effect of immunotherapy by enhancing antigen production and presentation and inducing T cell immune responses.
In a clinical trial, a pp65-loaded DC vaccine was used in combination with a dose-enhanced temozolomide.
The results showed that the median PFS was 25.3 months and the OS was 41.1 months, both of which were much higher than the statistical median survival ( less than 15 months ) of newly diagnosed glioma patients .
The combination of neoantigen vaccines with immune checkpoint inhibitors, such as anti-PD-1, anti-PD-L1 and anti-CTLA-4 antibodies, is believed to generate a powerful T cell immune response to kill tumors. In a phase I trial, 16 melanoma patients used a combination of MART-1 peptide-loaded DCs and the anti-CTLA-4 antibody tremelimumab, and they achieved a higher durable objective tumor response rate than treatment alone.
Challenges of personalized neoantigen DC vaccines
Although current clinical applications have shown effectiveness, personalized tumor neoantigen DC vaccines are still limited in several aspects.
(I) Selection of neoantigens: The sequencing and screening of tumor neoantigens requires individual detection and analysis of each patient’s tumor, which is a complicated and time-consuming process.
In addition, the production of neoantigens requires better production conditions to ensure the consistency of neoantigens.
Therefore, there is an urgent need to develop and widely apply advanced technologies. It is believed that in the near future, the time and production cost of this process will be greatly reduced.
(Ii) The source and maturation conditions of DC cells: The DC cells used in personalized neoantigen DC cell vaccines are also individualized.
It is necessary to extract DC cells from each patient and culture them separately. In addition, the maturation of DC cells requires the stimulation of antigens, cytokines ( such as GM-CSF ) and other factors ( such as LPS ).
There are still some problems in this process, such as the intensive labor required in the in vitro culture process and the skills required to induce DC maturation.
Therefore, in future research, efforts need to be made to optimize in vitro culture while inducing mature and high-quality DCs.
(Iii) The efficiency of DC migration: The DC injected back into the patient should migrate to the lymphatic organs to stimulate T cells to achieve an effective immune response. Some pro-inflammatory cytokines, such as prostaglandin E2 ( PGE2 ), can promote DC to a certain extent Migration. However, the selective migration of DC and its residence in non-lymphoid and lymphoid organs are strictly regulated events. In future studies, molecular regulation mechanisms need to be clarified in order to improve the stimulation conditions of DC vaccines in clinical trials. lay the foundation.
Personalized tumor neoantigens are highly specific to individuals, and tumor vaccines against neoantigens can effectively induce T cells to produce a strong immune response against tumors.
The key to the effectiveness of individualized tumor neoantigens is that they can be effectively absorbed and processed by APC and delivered to T cells to induce anti-tumor immune responses. However, the function of antigen presenting cells in patients with malignant tumors is usually inhibited.
Therefore, treating patients with neoantigen-loaded DC vaccines can specifically target tumors and ensure that DCs can maximize their efficacy. At present, more and more research and clinical trials of DC vaccines for gene neoantigens are underway, which is expected to bring new hope to patients with solid tumors.
1.Personalized Neoantigen-Pulsed DC Vaccines:Advances in Clinical Applications. Front Oncol. 2021; 11: 701777.
(source:internet, reference only)