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Personalized dendritic cell vaccine facilitates the preparation of neoantigen-reactive T cells for adoptive transfer (scRNA-Seq)

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE271085 | GEO | 2024/07/05

REPOSITORIES: GEO

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Personalized dendritic cell vaccine facilitates the preparation of neoantigen-reactive T cells for adoptive transfer (scTCR-Seq)

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

Neoantigen-Augmented iPSC-based Cancer Vaccine Combined with Local Radiotherapy Promotes Systemic Antitumor Immunity in Poorly Immunogenic Cancers

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

Neoantigen-specific stem cell memory-like CD4+ T cells mediate immunotherapy of solid tumors

Project description:The expansion of neoantigen (NeoAg)-specific T cells often accompanies clinical responses to immunotherapies, highlighting the importance of these cells for antitumor immunity. While NeoAg-specific CD8+ T cells have been broadly studied, the role of NeoAg-specific CD4+ T cells is less well understood. To study the antitumor mechanisms of NeoAg-specific CD4+ T cells, we sorted single CD4+ T cells specific for an epitope derived from a mutated clathrin heavy chain gene (CLTCH129>Q) expressed by the murine squamous cell carcinoma VII (SCC VII) tumor. T cell receptor (TCR) sequencing analysis revealed the presence of four distinct TCR clonotypes and expression of these TCRs in primary cells was sufficient to confer preferential recognition of CLTCH129>Q as compared to the corresponding wildtype CLTC epitope. Despite differences in TCR avidity, both moderate and high avidity CD4+ T cells were capable of proliferating to similar levels in response to tumor antigen in vivo and enhancing primary tumor immunity in a CD8+ T cell- and CD40L-dependent manner. Finally, we demonstrate that adoptive cellular therapy (ACT) with T stem cell memory (TSCM)-like CLTCH129>Q-specific CD4+ T cells differentiated ex vivo in culture with IL-7 and IL-15 promotes therapeutic tumor immunity associated with enhanced T cell persistence, maintenance of adoptively transferred TSCM-like cells in the tumor-draining lymph node (tdLN), and activation of CD8+ T cells in the tdLN. Overall, these findings illuminate the mechanistic role of NeoAg-specific CD4+ T cells in tumor immunity, provide insights into the impact of TCR avidity on the helper functions of CD4+ T cells, and highlight the therapeutic potential of ACT with TCR-engineered CD4+ T cells.

2023-05-24 | GSE229221 | GEO

Mutational and neoantigen load predict clinical benefit of adoptive T cell therapy in melanoma

Project description:Purpose: Utility of immunological treatment in cancer has increased; however, many patients do not respond to treatment. Identification of robust predictive biomarkers is required to correctly stratify patients. Although clinical trials based on adoptive T cell therapy (ACT) have yielded high response rates and many durable responses in melanoma, 50-60% of the patients have no clinical benefit. Herein, we searched for predictive biomarkers to ACT in melanoma. Methods: Whole exome- and transcriptome sequencing, neoantigen prediction and immune cell signature analysis were applied to pre-treatment melanoma samples from 27 patients recruited to a clinical phase I/II trial of ACT in stage IV melanoma. All patients had previously been treated with other immunotherapies. Results: We found that clinical benefit was associated with significantly higher neoantigen load (P=0.025). High mutation and neoantigen load were significantly associated with improved progression-free and overall survival (P=8x10^-4 and P=0.001, respectively). Further, gene-expression analysis of pre-treatment biopsies showed that clinical benefit was associated with strong immune activation signatures including a high MHC-I antigen processing and presentation score. Conclusions: These results improve our understanding of clinical benefit of ACT in melanoma, which can lead to clinically useful predictive biomarkers to be used for selecting patients that benefit from these highly intensive treatment regimens.

2017-12-04 | GSE100797 | GEO

Personalized dendritic cell vaccine facilitates the preparation of neoantigen-reactive T cells for adoptive transfer (scRNA-Seq)

Project description:Personalized dendritic cell vaccine facilitates the preparation of neoantigen-reactive T cells for adoptive transfer (scRNA-Seq)

| PRJNA1129585 | ENA

Personalized dendritic cell vaccine facilitates the preparation of neoantigen-reactive T cells for adoptive transfer (scTCR-Seq)

Project description:Personalized dendritic cell vaccine facilitates the preparation of neoantigen-reactive T cells for adoptive transfer (scTCR-Seq)

| PRJNA1129586 | ENA

A Study of Personalized Neoantigen Cancer Vaccines

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

Adenoviral based-vaccine promotes neoantigen specific CD8+ T cell stemness and tumor rejection

Project description:Upon chronic antigen exposure, CD8+ T cells become exhausted acquiring a dysfunctional state correlated with the inability to control infection or tumor. In contrast to exhausted T cells, stem-like CD8+ T progenitors maintain the ability to promote and sustain effective immunity. Adenovirus (Ad) vectored vaccines encoding tumor neoantigens have been shown to eradicate large tumors when combined with anti-Programmed cell death protein 1 (αPD-1) in murine models, however the mechanisms and translational potential have not yet been elucidated. Here, we show that gorilla Ad vaccine targeting tumor neoepitopes enhance responses to αPD-1 therapy, by improving immunogenicity and anti-tumor efficacy. Single cell RNA-seq demonstrated that the combination of Ad vaccine and αPD-1 increased the number of murine polyfunctional neoantigen specific CD8+ T cells over αPD-1 monotherapy, with an accumulation of Tcf1+ stem-like progenitors in draining lymph nodes and effector CD8+T cells in tumors. Combined TCR sequencing analysis highlighted a broader spectrum of neoantigen specific CD8+ T cells upon vaccination compared to αPD-1 monotherapy. The translational relevance of these data is supported by results obtained in the first 12 patients with metastatic deficient mismatch repair (dMMR) tumors vaccinated with an Ad vaccine encoding shared neoantigens. Expansion and diversification of TCRs was observed in post-treatment biopsies of patients with clinical response, as well as an increase in tumor infiltrating T cells with an effector memory signature. These findings indicate a promising mechanism to overcome resistance to PD-1 blockade, by promoting immunogenicity and broadening the spectrum and magnitude of neoantigen-specific T cells infiltrating tumors.

2022-10-11 | GSE206811 | GEO

Improved expansion, functionality and tumor targeting of adoptively transferred T cells with kinetically engineered IL-2

Project description:The adoptive transfer of cancer-specific T cells in combination with high dose interleukin-2 (IL-2) is able to induce effective anti-tumor responses. However, tumors frequently relapse after an initial response and the known toxicities of IL-2 further limit the use of this therapy. NKTR-214 is a CD122-biased polyethylene glycol (PEG)-genetically engineered IL-2 designed to provide sustained signaling through the heterodimeric IL-2 receptor pathway (IL-2Rβγ) to preferentially activate and expand CD8 T and natural killer (NK) cells over T regulatory cells (Tregs) in the tumor. We report that combination of adoptive T cell transfer (ACT) and NKTR-214 markedly increases the proliferation, homing and polyfunctionality of antitumor T cells into the tumor. The treatment is well tolerated and leads to robust anti-tumor response in the aggressive B16F10 model. These results suggest that NKTR-214 could improve the efficacy of ACT protocols tested in humans.

2019-08-07 | GSE118748 | GEO

A novel cooperative therapeutic regimen using gene fusion neoantigen-specific TCR-engineered T cells mediated sustained preclinical efficacy in solid tumors independent on inherent mutation profiling

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