Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer
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ABSTRACT:
PROVIDER: EGAS00001003306 | EGA |
REPOSITORIES: EGA
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Project description:The goal of the sequencing study was to determine the neoantigen profile of melanoma patients. We performed whole exome sequening of the tumor and respective patien matched PBMC samples (2x50nt) and RNA-sqeuencing of the tumor samples. The was analyzed for somatic point mutaions, using the RNA-Seq data to determine mutation expression. This study contains the patient matched RNA-Sequencing data.
| EGAS00001003307 | EGA
Project description:Neoantigen-reactive cytotoxic T lymphocytes play a vital role in precise cancer cell elimination. In this study, we demonstrate the effectiveness of personalized neoantigen-based T cell therapy in inducing tumor regression in two patients suffering from heavily-burdened metastatic ovarian cancer. Our approach involved the development of a robust pipeline for ex vivo expansion of neoantigen-reactive T lymphocytes. Neoantigen peptides were designed and synthesized based on the somatic mutations of the tumors and their predicted HLA binding affinities. These peptides were then presented to T lymphocytes through co-culture with neoantigen-loaded dendritic cells for ex vivo expansion. Subsequent to cell therapy, both patients exhibited significant reductions in tumor marker levels and experienced substantial tumor regression. One patient achieved repeated cancer regression through infusions of T cell products generated from newly identified neoantigens. Transcriptomic analyses revealed a remarkable increase in neoantigen-reactive cytotoxic lymphocytes in the peripheral blood of the patients following cell therapy. These cytotoxic T lymphocytes expressed polyclonal T cell receptors (TCR) against neoantigens, along with abundant cytotoxic proteins and pro-inflammatory cytokines. The efficacy of neoantigen targeting was significantly associated with the immunogenicity and TCR polyclonality. Notably, the neoantigen-specific TCR clonotypes persisted in the peripheral blood after cell therapy. Our findings indicate that personalized neoantigen-based T cell therapy triggers cytotoxic lymphocytes expressing polyclonal TCR against ovarian cancer, suggesting its promising potential in cancer immunotherapy.
2023-12-01 | GSE248401 | GEO
Project description:Personalized cancer vaccines aim to activate and expand cytotoxic anti-tumor CD8+ T cells to recognize and kill tumor cells. However, the role of CD4+ T cell activation in the clinical benefit of these vaccines is not well defined. We previously established a personalized neoantigen vaccine (PancVAX) for the pancreatic cancer cell line Panc02, which activates tumor-specific CD8+ T cells but required combinatorial checkpoint modulators to achieve therapeutic efficacy. To determine the effects of neoantigen-specific CD4+ T cell activation, we generated a new vaccine (PancVAX2) targeting both MHCI- and MHCII-specific neoantigens. Tumor-bearing mice vaccinated with PancVAX2 had significantly improved control of tumor growth and long-term survival benefit without concurrent administration of checkpoint inhibitors. PancVAX2 significantly enhanced priming and recruitment of neoantigen-specific CD8+ T into the tumor with lower PD1 expression after reactivation compared to the CD8+ vaccine alone. Vaccine-induced neoantigen- specific Th1 CD4+ T cells in the tumor were associated with decreased T regulatory cells (Tregs). Consistent with this, PancVAX2 was associated with more pro-immune myeloid-derived suppressor cells and M1-like macrophages in the tumor demonstrating a less immunosuppressive tumor microenvironment. This study demonstrates the biological importance of prioritizing and including CD4 T cell-specific neoantigens for personalized cancer vaccine modalities.
2023-12-11 | GSE244992 | GEO
Project description:Cancer is characterized by an accumulation of somatic mutations, of which a significant subset can generate cancer-specific neoepitopes that are recognized by autologous T cells. Neoepitopes are emerging as important targets for cancer immunotherapy, including personalized cancer vaccination strategies. We used whole-exome and RNA sequencing analysis to identify potential neoantigens for a patient with non-small cell lung cancer. Sequencing revealed a low tumor mutational burden: 2,219 sequence variants were identified from the primary tumor, of which 23 were expressed in the transcriptome, involving 18 gene products. We assessed autologous T-cell reactivity to the candidate neoantigens using a long peptide approach and could demonstrate spontaneous T-cell responses to 5/18 (28%) mutated gene variants. Further, analysis of the TCR repertoire of neoantigen-specific CD4+ and CD8+ T cells revealed TCR clonotypes that were expanded in both blood and tumor tissue. In parallel, the 18 gene variants were incorporated into a Modified Vaccinia Ankara-based vaccine, which was evaluated in the transgenic HLA-A*02-restricted HHD mouse model. Following vaccination, de novo T-cell responses were generated to 4/18 (22%) mutated gene variants, of which 2 were also observed in the autologous setting; we determined the MHC restriction of the T-cell responses and used in silico prediction tools to determine the likely neoepitopes. Our study demonstrates the feasibility of efficiently identifying tumor-specific neoantigens that can be targeted by vaccination in tumors with a low mutational burden, and promises successful clinical application, with trials currently underway.
2022-04-27 | GSE179879 | GEO
Project description:Adoptive cell transfer (ACT) using neoantigen-specific T cells is an effective immunotherapeutic strategy. However, the difficulty in identifying and screening neoantigen-specific T cells limits its widespread application. Here, we prepared neoantigen-reactive T cells (NRTs) after immunization with a tumor lysate-loaded dendritic cell (DC) vaccine (OCDC) for ACT. Our results demonstrated that the OCDC vaccine could induce a neoantigen-specific immune response, and it was feasible to prepare NRTs by loading immunogenic neoantigens onto DCs and coculturing them with spleen lymphocytes from mice immunized with the OCDC vaccine. We then transferred these NRTs back to the LL/2 tumor-bearing mice after OCDC vaccine immunization and found that OCDC vaccine and NRTs adoptive transfer combination treatment could induce a stronger antitumor response. Furthermore, we found that infused NRTs could migrate into the tumor microenvironment to exert antitumor effects. Our research provides a new and convenient method of preparing NRTs for ACT. The clinical translation of this approach has the potential to increase ACT efficacy.
2024-07-05 | GSE271085 | GEO
Project description:Adoptive cell transfer (ACT) using neoantigen-specific T cells is an effective immunotherapeutic strategy. However, the difficulty in identifying and screening neoantigen-specific T cells limits its widespread application. Here, we prepared neoantigen-reactive T cells (NRTs) after immunization with a tumor lysate-loaded dendritic cell (DC) vaccine (OCDC) for ACT. Our results demonstrated that the OCDC vaccine could induce a neoantigen-specific immune response, and it was feasible to prepare NRTs by loading immunogenic neoantigens onto DCs and coculturing them with spleen lymphocytes from mice immunized with the OCDC vaccine. We then transferred these NRTs back to the LL/2 tumor-bearing mice after OCDC vaccine immunization and found that OCDC vaccine and NRTs adoptive transfer combination treatment could induce a stronger antitumor response. Furthermore, we found that infused NRTs could migrate into the tumor microenvironment to exert antitumor effects. Our research provides a new and convenient method of preparing NRTs for ACT. The clinical translation of this approach has the potential to increase ACT efficacy.
2024-07-05 | GSE271086 | GEO
Project description:Neoantigen discovery in pediatric brain tumors is hampered by their low mutational burden and scant tissue availability. We developed a low-input proteogenomic approach combining tumor DNA/RNA sequencing and mass spectrometry proteomics to identify tumor-restricted (neoantigen) peptides arising from multiple genomic aberrations to generate a highly target-specific, autologous, personalized T cell immunotherapy. Our data indicate that novel splice junctions are the primary source of neoantigens in medulloblastoma, a common pediatric brain tumor. Proteogenomically identified tumor-specific peptides are immunogenic and generate MHC II-based T cell responses. Moreover, polyclonal and polyfunctional T cells specific for tumor-specific peptides effectively eliminated tumor cells in vitro. Targeting novel tumor-specific antigens obviates the issue of central immune tolerance while potentially providing a safety margin favoring combination with other immune-activating therapies. These findings demonstrate the proteogenomic discovery of immunogenic tumor-specific peptides and lay the groundwork for personalized targeted T cell therapies for children with brain tumors.
2021-11-02 | PXD029082 | Pride
Project description:Neoantigen vaccines aiming to induce and amplify tumor-specific T cell responses have received promising anti-tumor effect in early clinical trials. However, the underlying mechanism regarding response or resistance to this treatment remains unclear. Here, we observed that neoantigen vaccine-generated T cells could synergize with immune checkpoint blockade (ICB) for effective tumor control. Specifically, we performed single-cell sequencing on over 100,000 T cells and uncovered that combined therapy induced a novel antigen-specific CD8 T cell population with active chemokine signaling (Cxcr3+/Ccl5+), lower co-inhibitory receptor expression (Lag3-/Havcr2-) and higher cytotoxicity (Fasl+/Gzma+). Furthermore, the generation of antigen specific T cells in the drain lymph node is required for combination treatment mediated therapeutic effect. Signature genes of this unique population is associated with T cell clonal frequency and better survival in human. Our study comprehensively profiled the dynamics of tumor infiltrated T cells during neoantigen vaccine and ICB treatments, and high-dimensionally identified neoantigen-reactive T cell signatures for future development of better therapeutic strategies.
2022-01-10 | GSE178881 | GEO
Project description:The purpose of this study is 1) to evaluate the feasibility of manufacturing a patient-specific neoantigen cancer vaccine, which involves predicting the patient’s neoantigens and generating a vaccine that encodes the predicted neoantigens; and, 2) to identify and select patients who may be eligible for a shared neoantigen cancer vaccine where their tumor contains a specific shared mutation and who have the correct HLA allele capable of presenting the neoantigen derived from the tumor-specific mutation.
| 2293590 | ecrin-mdr-crc
Project description:<p>Neoantigens, which are derived from tumour-specific protein-coding mutations, are exempt from central tolerance, can generate robust immune responses and can function as bona fide antigens that facilitate tumour rejection. We demonstrated that a strategy that uses multi-epitope, personalized neoantigen vaccination, which has previously been tested in patients with high-risk melanoma, is feasible for tumours such as glioblastoma, which typically have a relatively low mutation load and an immunologically ‘cold’ tumour microenvironment. Here we conducted whole-exome sequencing of tumor and normal cells from individual patients with glioblastoma to identify tumor-specific mutations. We assessed the expression of mutated alleles by RNA-sequencing of tumor. We used personalized neoantigen-targeting vaccines to immunize patients newly diagnosed with glioblastoma following surgical resection and conventional radiotherapy in a phase I/Ib study. Patients who did not receive dexamethasone-a highly potent corticosteroid that is frequently prescribed to treat cerebral oedema in patients with glioblastoma-generated circulating polyfunctional neoantigen-specific CD4+ and CD8+ T cell responses that were enriched in a memory phenotype and showed an increase in the number of tumour-infiltrating T cells. Using single-cell T cell receptor analysis, we provide evidence that neoantigen-specific T cells from the peripheral blood can migrate into an intracranial glioblastoma tumour. Neoantigen-targeting vaccines thus have the potential to favourably alter the immune milieu of glioblastoma.</p>
| phs001519 | dbGaP