Cancer cells have characteristics of genetic variabilities and accumulate somatic mutations rapidly. The genome sequencing of cancer cells has identified heterogeneity and tens to thousands of somatic mutations that vary among individual patients. Nonsynonymous somatic mutations may alter the amino acid coding sequences and create abnormal proteins that become highly expressed and promote cell proliferation. Tumor-specific antigens (TSAs), also known as neoantigens, are created by the process of genomic codon interchanges, editing, antigen processing and presentation. Neoantigens can be presented by the major histocompatibility complex (MHC, also known as human leukocyte antigen (HLA) in humans) on the cell surface and recognized by the T lymphocytes. They are tumor-specific and not expressed by normal cells, which makes them ideal therapeutic targets. Targeting neoantigens has the potential to maximize therapeutic specificity, while minimizing the risk of autoimmunity.
In recent years, immunotherapies have advanced a new era of cancer treatment. In 2011, FDA first approved an immune checkpoint inhibitor (ICI), ipilimumab, a monoclonal antibody targeting CTLA-4, which extended the overall survival rate of patients with metastatic melanoma. Developed as the next generation of immunotherapy, it uses personal and precision vaccines as well as T cell therapies to direct T cells directly toward a patient’s tumors. In 2018, Dr. James P. Allison was awarded the Nobel Prize in Medicine for his work on cancer therapy by inhibition of negative immune regulation. There are other (or newer) ICIs (such as anti-PD1 and anti-PD-L1 antibodies), considered to be effective therapies in subsets of patients with a variety of tumor types such as metastatic melanoma, non-small cell lung cancer (NSCLC), prostate cancer, renal cell carcinoma, and so on. However, the use of ICI carries a risk to develop immune-related adverse events, which occur via activation of the patient's immune system, leading to serious and even fatal reactions. Additional efforts are needed to improve the response rates and tumor antigen specificity of ICI, and address the incidence of immune-related adverse events. The first chimeric antigen receptor- (CAR-) T cell immunotherapy, anti-CD19 CAR-T for B cell lymphoma, was approved by the USFDA in August 2017. Subsequently, there has been an increasing number of clinical trials using CAR-T therapy to treat cancers. CAR-T cells target the tumor-associated antigens (TAAs), such as CD19 in B cell malignancies and ERBB2 in breast cancers, which are also expressed in normal cells. While CAR-T therapies have shown significant promise in acute lymphoid leukaemia, treating solid cancers with CAR-T cells remains a challenge due to the lack of suitable tumor-associated antigens and low overall objective response rates.
Neoantigens have been considered an important therapeutic approach to cancer treatment. Neoantigens could be represented by HLA and recognized by T lymphocytes of the immune system. The presence of such cancer neoantigen recognizing T cells has been associated with effective antitumor immunity in humans. Neoantigen-specific T cells are crucial to clinical responses. The isolated T cell clones or T cell receptor (TCR-) engineered T lymphocytes establish the epitope patterns of neoantigens recognized by T cells. There are increasing neoantigen-based cancer vaccines designed to target the unique immunogenic mutations in each patient's tumor. Recent success of personalized cancer vaccines can be attributed to the RNA mutanome vaccine and peptide-based vaccine induced by poly-specific therapeutic immunity. Neoantigen cancer vaccines are capable of eliciting strong T cell responses to neoepitopes in patients with melanoma. Neoantigens arise from non-synonymous mutations and other genetic alterations in cells. Neoantigens are mutated peptides present as HLA on the cell surface, and theoretically more attractive therapeutic targets because they are different from the others and seen as non-self by the immune system. Normal cells do not express Neoantigens and therefore, neoantigen-specific immune reactions are not subjected to central and peripheral tolerance. Several neoantigens have been identified for different types of cancers, including melanoma, lung cancer, hepatoma, and renal cancers. Neoantigen vaccines and immune checkpoint inhibition act as complementary treatments that might often be used together, especially for patients with large tumors or metastatic disease, and can lead to an increased tumor-specific immune response.
In order to generate personalized cancer vaccine, somatic mutations within cancer cells can be identified using whole exome sequencing. Based on the mutations identified, a personalized cancer vaccine can be designed to target the specific epitopes of mutated neoantigens, and may consist of synthetic peptides or genes encoding the shared tumor antigens, accompanied by the presence of adjuvants such as poly-ICLC, GM-CSF and BCG.
The neoantigens from the cancer vaccine or dead cancer cells are captured by antigen present in cells (APCs). Next, the activated APCs migrate to the lymph nodes and the MHC molecules present the neoantigens to T lymphocytes. The specific TCR recognizes the neoantigens, resulting in the priming and activation of T cell immunity. Neoantigen-specific T cells expand, traffic and infiltrate the tumor microenvironment. The expanded T cells specifically bind to the neoantigens of cancer cells via the interaction of the TCR/neoantigen/MHC complex. The CD4+ T cells augment the immune response against cancers, and CD8+ cytotoxic T lymphocytes (CTL) directly kill the cancer cells through the degranulation of granzyme, granulysin or perforin. The lysed tumor cells release more neoantigens, which produce the adaptive immune memory response and lead to the expansion of molecularly heterogeneous T cells against cancers.
The designing strategies and immunology of personalized neoantigen cancer vaccine (I–III)Source
|Cell based vaccines||
Clinical trials on use of neoantigens for cancer treatment have revealed promising results. For example, Carreno et al. (Washington University School of Medicine, Division of Oncology) identified somatic mutations in tumor from three patients with melanoma by whole exome sequencing. The authors used an HLA binding prediction algorithm to initially filter the candidate HLA-A∗02: 01 epitopes containing residues arising from mutations and then evaluated the MHC-epitope binding, using competitive assays. The patients received autologous dendritic cells pulsed with top 7 neoantigen peptides, which showed higher binding affinity to the HLA-A∗02 : 01. They found that dendritic cell neoantigen vaccine increased the diversity of melanoma neoantigen-specific T cells. These neoantigens could be endogenously processed and presented to T cells, and the T lymphocytes produced by vaccination could recognize the target cells transfected with the corresponding tandem minigene constructs.
Ott et al. (affiliated to Chang Gung Memorial Hospital and Chang Gung University, National Yang-Ming University, The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University) enrolled six patients with melanoma. The authors identified the tumor-specific mutations by using exome sequencing and produced personalized peptide vaccines, which could bind to the individual MHC proteins. Each patient was vaccinated using the synthetic long peptides representing up to twenty predicted personal tumor neoantigens. The vaccination induced polyfunctional CD4+ and CD8+ T cells targeting 60% and 16% of the 97 unique neoantigens used across patients. These T cells could discriminate mutated and wild-type antigens, and some of them could directly recognize autologous tumor. Four of the six patients had no recurrence at 25 months after vaccination. The other two patients with recurrent disease were subsequently treated with anti-PD-1 therapy, leading to complete tumor regression.
Sahin et al. (affiliated to University Medical Center of the Johannes Gutenberg University) presented that personalized RNA mutanome vaccines elicited poly-specific therapeutic immunity against melanoma. This study involved applying a process comprising the comprehensive identification of individual mutations, computational prediction of neoantigens with high binding affinity to MHC proteins, and designing and manufacturing of an RNA-based vaccine unique to each patient. All patients developed T cell response against multiple vaccine neoantigens. The cumulative rate of metastatic events was significantly reduced after the injection of the vaccine, resulting in a sustained progression-free survival. Two out of five patients with metastatic disease had a vaccine-related objective response, and a patient developed complete response to vaccination in combination with PD-1 blockade therapy. These promising results demonstrate that personalized neoantigen cancer vaccine has opened up a new path to cure the disease.
Nouscom, a next-generation immunotherapy company developing personalized cancer neoantigen vaccines, announced in June 2019, that its Investigational New Drug (IND) application for the first clinical trial of its lead candidate NOUS-209 has been cleared by the USFDA. NOUS-209 is a therapeutic vaccine for gastric, colorectal and gastro-oesophageal junction Microsatellite Instable (MSI) cancers (tumors characterized by a defective DNA mismatch repair system), in combination with the anti-PD-1 checkpoint inhibitor Pembrolizumab. The trial is expected to begin during the third quarter of 2019.
GEN-009, Genocea’s lead neoantigen vaccine candidate, has generated promising results from its ongoing Phase 1/2a trial. GEN-009 monotherapy elicited T cell responses to 91% of the vaccine neoantigens administered. Also, GEN-009 has been proven to be unique in its ability to elicit ex vivo CD8+ T cell responses, which were observed for 47% of vaccine neoantigens. The CD8+ T cell response frequency was 53%, including the results seen after in vitro stimulation.
Neon Therapeutics’ NEO-PTC-01, a neoantigen vaccine for the treatment of breast cancer, is awaiting complete process development before the filing of a Clinical Trial Application (CTA) in Europe during the second half of 2019. Neon Therapeutics expects to submit an Investigational New Drug (IND) application to the USFDA for a Phase 1b clinical trial during the second half of 2019.
US20190022202A1 filed by Vaccibody AS deals with a therapeutic anticancer neoepitope vaccine comprising a nucleotide sequence encoding a targeting unit, a dimerization unit, and an antigenic unit, with each subunit comprising a part of a cancer neoepitope sequence and an antigenic unit comprising a final cancer neoepitope sequence.
US20190070275A1 filed by Oceanside Biotechnology deals with a protein comprising an antigenic cancer peptide covalently and non-covalently attached to a mature major histocompatibility complex (MHC) class II peptide. The protein is non-toxic to the patient, and increases the average survival time of a population, providing > 75% reduced tumour growth rate.
US20180055922A1 filed by Dana-farber Cancer Institute, Inc. and The General Hospital Corporation deals with a method for identifying tumor-specific neoantigens that alone or in combination with other tumor-associated peptides serve as active pharmaceutical ingredients of vaccine compositions which stimulate anti-tumor responses.
WO2019094396A1 filed by Nektar therapeutics and Nouscom AG, deals with administering a neoantigen-based vaccine composition comprising a first vector encoding multiple immunogenic polypeptide fragments and a long acting, IL-2R-selective agonist composition.
US20190065675A1 filed by Gritstone Oncology, Inc. deals with a method for identifying neoantigens from a tumor cell of a subject by obtaining exome, transcriptome or whole genome tumor nucleotide sequencing data which is used to obtain data on peptide sequences of a set of neoantigens. The peptide sequence of each neoantigen comprises an alteration that makes it distinct from the corresponding wild-type, parental peptide sequence.
WO2018213803A1 filed by Neon Therapeutics deals with a method for identifying tumor-specific polypeptide sequence for preparing an immunogenic neoantigens and methods for the treatment of disease.
There has been extensive collaboration among companies with a view to strengthen their capabilities and be among the first to reach the market. A few such collaborations have been listed below.
NEC Corporation announced in May 2019, that it had become the first Japanese company to join the Tumor neoantigEn SeLection Alliance (TESLA) founded and managed by the Parker Institute for Cancer Immunotherapy and the Cancer Research Institute (CRI). This global bioinformatics collaborative includes scientists from more than 35 of the leading neoantigen research groups in academia, non-profit and industry, to find the best algorithms to predict which cancer neoantigens encoded in DNA and RNA can be recognized and stimulate an immune response.
Adaptive Biotechnologies announced in April 2019, that it would enter into a worldwide collaboration and licensing agreement with Genentech, to develop, manufacture and commercialize novel neoantigen directed T-cell therapies for the treatment of a broad range of cancers. The collaboration will combine Genentech’s global cancer immunotherapy research and development leadership with Adaptive’s proprietary T-cell receptor (TCR) discovery and immune profiling platform (TruTCR™) to accelerate a transformational new treatment paradigm of tailoring cellular therapy for each patient’s individual cancer. Genentech will have responsibility for clinical, regulatory and commercializational efforts, and Adaptive will be responsible for patient-specific screening on a global basis.
Genocea Biosciences, Inc., announced in May 2019, a research collaboration with Iovance Biotherapeutics, Inc. to assess the potential of applying Genocea’s neoantigen identification platform, ATLAS™, to next-generation TIL (tumor-infiltrating lymphocyte) product development.
Kite and HiFiBiO Therapeutics announced in October 2018 that the two companies have entered into a research collaboration and licensing agreement to develop technology supporting the discovery of neoantigen-reactive T cell receptors (TCRs) for the potential treatment of various cancers, including solid tumors.
NEC Corporation and Transgene announced in October 2018, that their strategic collaboration was aimed at the treatment of solid cancers. The companies will cooperate in clinically assessing the predictive capabilities of NEC's artificial intelligence ("NEC the WISE") and the therapeutic potential of Transgene's MVA-based viral vector technology, and the myvac™ platform in an individualized immunotherapy for the treatment of solid cancers. The experimental products from this collaboration are expected to enter clinical trials in 2019.