Optimized polyepitope neoantigen DNA vaccines elicit neoantigen-specific immune responses in preclinical models and in clinical translation
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PROVIDER: PRJNA699932 | ENA |
REPOSITORIES: ENA
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Project description:Optimized polyepitope neoantigen DNA vaccines elicit neoantigen-specific immune responses in preclinical models and in clinical translation
| PRJNA699931 | ENA
Project description:Personal Neoantigen Cancer Vaccines
| PRJNA401959 | ENA
Project description:BackgroundPreclinical studies and early clinical trials have shown that targeting cancer neoantigens is a promising approach towards the development of personalized cancer immunotherapies. DNA vaccines can be rapidly and efficiently manufactured and can integrate multiple neoantigens simultaneously. We therefore sought to optimize the design of polyepitope DNA vaccines and test optimized polyepitope neoantigen DNA vaccines in preclinical models and in clinical translation.MethodsWe developed and optimized a DNA vaccine platform to target multiple neoantigens. The polyepitope DNA vaccine platform was first optimized using model antigens in vitro and in vivo. We then identified neoantigens in preclinical breast cancer models through genome sequencing and in silico neoantigen prediction pipelines. Optimized polyepitope neoantigen DNA vaccines specific for the murine breast tumor E0771 and 4T1 were designed and their immunogenicity was tested in vivo. We also tested an optimized polyepitope neoantigen DNA vaccine in a patient with metastatic pancreatic neuroendocrine tumor.ResultsOur data support an optimized polyepitope neoantigen DNA vaccine design encoding long (≥20-mer) epitopes with a mutant form of ubiquitin (Ubmut) fused to the N-terminus for antigen processing and presentation. Optimized polyepitope neoantigen DNA vaccines were immunogenic and generated robust neoantigen-specific immune responses in mice. The magnitude of immune responses generated by optimized polyepitope neoantigen DNA vaccines was similar to that of synthetic long peptide vaccines specific for the same neoantigens. When combined with immune checkpoint blockade therapy, optimized polyepitope neoantigen DNA vaccines were capable of inducing antitumor immunity in preclinical models. Immune monitoring data suggest that optimized polyepitope neoantigen DNA vaccines are capable of inducing neoantigen-specific T cell responses in a patient with metastatic pancreatic neuroendocrine tumor.ConclusionsWe have developed and optimized a novel polyepitope neoantigen DNA vaccine platform that can target multiple neoantigens and induce antitumor immune responses in preclinical models and neoantigen-specific responses in clinical translation.
| S-EPMC8059244 | biostudies-literature
Project description:Although irradiated induced-pluripotent stem cells (iPSCs) as a prophylactic cancer vaccine elicit an antitumor immune response, the therapeutic efficacy of iPSC-based cancer vaccines is not promising due to their insufficient antigenicity and the immunosuppressive tumor microenvironment. Here, we found that neoantigen-engineered iPSC cancer vaccines can trigger neoantigen-specific T cell responses to eradicate cancer cells and increase the therapeutic efficacy of RT in poorly immunogenic colorectal cancer (CRC) and triple-negative breast cancer (TNBC). We generated neoantigen-augmented iPSCs (NA-iPSCs) by engineering AAV2 vector carrying murine neoantigens and evaluated their therapeutic efficacy in combination with radiotherapy. After administration of NA-iPSC cancer vaccine and radiotherapy, we found that ~60% of tumor-bearing mice achieved a complete response in microsatellite-stable CRC model. Furthermore, splenocytes from mice treated with NA-iPSC plus RT produced high levels of IFN secretion in response to neoantigens and had a greater cytotoxicity to cancer cells, suggesting that the NA-iPSC vaccine combined with radiotherapy elicited a superior neoantigen-specific T-cell response to eradicate cancer cells. The superior therapeutic efficacy of NA-iPSCs engineered by mouse TNBC neoantigens was also observed in the syngeneic immunocompetent TNBC mouse model. We found that the risk of spontaneous lung and liver metastasis was dramatically decreased by NA-iPSCs plus RT in the TNBC animal model. Altogether, these results indicated that autologous iPSC cancer vaccines engineered by neoantigens can elicit a high neoantigen-specific T-cell response, promote tumor regression and reduce the risk of distant metastasis in combination with local radiotherapy.
2024-04-03 | GSE262852 | GEO
Project description:The goal of therapeutic cancer vaccines and immune checkpoint therapy (ICT) is to eliminate cancer by expanding and/or sustaining T cells with anti-tumor capabilities. Here, we compared effective therapeutic tumor-specific mutant neoantigen (NeoAg) synthetic long peptide (SLP) cancer vaccines with anti-CTLA-4 and/or anti-PD-1 ICT in preclinical models. Effective NeoAg SLP vaccines and ICT required both CD8 and CD4 T cells. Both NeoAg SLP vaccines and ICT induce expansion of intratumoral NeoAg-specific CD8 T cells, though the degree of expansion and acquisition of effector activity was much more substantial following NeoAg SLP vaccination. Further, we found that NeoAg SLP vaccines are particularly adept at inducing proliferating and stem-like NeoAg-specific CD8 T cells. While NeoAg SLP vaccines and anti-PD-1 affected the CD4 T cell compartment, it was to less of an extent than observed with anti-CTLA-4, which notably induced ICOS+Bhlhe40+ Th1-like CD4 T cells. Although effective NeoAg SLP vaccines or ICT expanded intratumoral M1-like iNOS+ macrophages, NeoAg SLP vaccines maintained, rather than suppressed as observed with ICT, M2-like CX3CR1+CD206+ macrophages expressing the TREM2 receptor. While combining NeoAg SLP vaccination with ICT induced superior efficacy compared to either therapy in isolation, we also assessed a novel combination of NeoAg SLP vaccination and anti-TREM2, demonstrating enhanced efficacy of this combination associated with a decrease in intratumoral CX3CR1+CD206+ macrophages and promotion of IFN-g+ NeoAgspecific CD8 T cells. These findings highlight the utility of combining NeoAg SLP vaccines with ICT, as well as novel combinatorial therapy targeting the myeloid compartment via TREM2 blockade to enhance NeoAg SLP vaccine efficacy.
2024-10-10 | GSE276904 | GEO
Project description:The goal of therapeutic cancer vaccines and immune checkpoint therapy (ICT) is to eliminate cancer by expanding and/or sustaining T cells with anti-tumor capabilities. Here, we compared effective therapeutic tumor-specific mutant neoantigen (NeoAg) synthetic long peptide (SLP) cancer vaccines with anti-CTLA-4 and/or anti-PD-1 ICT in preclinical models. Effective NeoAg SLP vaccines and ICT required both CD8 and CD4 T cells. Both NeoAg SLP vaccines and ICT induce expansion of intratumoral NeoAg-specific CD8 T cells, though the degree of expansion and acquisition of effector activity was much more substantial following NeoAg SLP vaccination. Further, we found that NeoAg SLP vaccines are particularly adept at inducing proliferating and stem-like NeoAg-specific CD8 T cells. While NeoAg SLP vaccines and anti-PD-1 affected the CD4 T cell compartment, it was to less of an extent than observed with anti-CTLA-4, which notably induced ICOS+Bhlhe40+ Th1-like CD4 T cells. Although effective NeoAg SLP vaccines or ICT expanded intratumoral M1-like iNOS+ macrophages, NeoAg SLP vaccines maintained, rather than suppressed as observed with ICT, M2-like CX3CR1+CD206+ macrophages expressing the TREM2 receptor. While combining NeoAg SLP vaccination with ICT induced superior efficacy compared to either therapy in isolation, we also assessed a novel combination of NeoAg SLP vaccination and anti-TREM2, demonstrating enhanced efficacy of this combination associated with a decrease in intratumoral CX3CR1+CD206+ macrophages and promotion of IFN-g+ NeoAgspecific CD8 T cells. These findings highlight the utility of combining NeoAg SLP vaccines with ICT, as well as novel combinatorial therapy targeting the myeloid compartment via TREM2 blockade to enhance NeoAg SLP vaccine efficacy.
2024-10-10 | GSE276902 | GEO
Project description:Individualized mRNA Neoantigen Vaccines provoke substantial T cell immunity in Pancreatic Cancer
| PRJNA917312 | ENA
Project description:Microbial systems have been synthetically engineered to deploy therapeutic payloads in vivo. With emerging evidence that bacteria naturally home to tumors and modulate anti-tumor immunity one promising application is the development of bacterial vectors as precision cancer vaccines. In this study, we engineered probiotic E. coli Nissle 1917 (EcN) as an anti-tumor vaccination platform optimized for enhanced production and cytosolic delivery of neoepitope-containing peptide arrays, with increased susceptibility to blood clearance and phagocytosis. These features enhance both safety and immunogenicity, achieving a system which drives potent and specific T cell–mediated anti‑cancer immunity that effectively controls or eliminates tumor growth and extends survival in advanced murine primary and metastatic solid tumors. We demonstrate that the elicited anti-tumor immune response involves extensive priming and activation of neoantigen-specific CD4+ and CD8+ T cells, broader activation of both T and NK cells, and a reduction of tumor-infiltrating immunosuppressive myeloid and regulatory T and B cell populations. Taken together, this work leverages the advantages of living medicines to deliver arrays of tumor‑specific neoantigen–derived epitopes within the optimal context to induce specific, effective, and durable systemic anti-tumor immunity.
2024-07-21 | GSE244808 | 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