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Phase I/II Study of Autologous T Cells to Express T-Cell Receptors (TCRs) in Subjects With Solid Tumors

ABSTRACT: A Phase I/II study of autologous T cells engineered using the Sleeping Beauty transposon/transposase system to express TCR(s) reactive against neoantigens in subjects with relapsed/refractory solid tumors

DISEASE(S): Endometrial Cancer,Colorectal Cancer,Endometrial Neoplasms,Pancreatic Cancer,Lung Neoplasms,Ovarian Cancer,Squamous Cell Lung Cancer,Gynecologic Cancer,Ovarian Carcinoma,Adenosquamous Cell Lung Cancer,Non-small Cell Lung Cancer,Ovarian Neoplasms,Adenocarcinoma Of Lung,Cholangiocarcinoma,Ovary Neoplasm

PROVIDER: 2401213 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Long-Term Follow-up Study of Subjects Treated With Autologous T Cells Using the Sleeping Beauty System to Express TCRs

Project description:Long-Term Follow-Up Study for Subjects Enrolled in the Phase I/II Study of Autologous T Cells Engineered using the Sleeping Beauty System to Express T cell Receptors (TCRs) Reactive Against Cancer-specific Mutations in Subjects with Solid Tumors

| 2710397 | ecrin-mdr-crc

A Study of NT-175 in Adult Subjects With Unresectable, Advanced, and/or Metastatic Solid Tumors That Are Positive for HLA-A*02:01 and the TP53 R175H Mutation

Project description:Phase I Study of NT-175, an autologous T cell therapy product genetically engineered to express an HLA-A*02:01-restricted T cell receptor (TCR), targeting TP53 R175H mutant solid tumors.

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Proteogenomic analysis uncovers neoantigens and bacterial peptides as immunotherapy targets in colorectal cancer

Project description:Considerable progress has recently been made in cancer immunotherapy, including immune checkpoint blockade, cancer vaccine, and adoptive T cell methods. The lack of effective targets is a major cause of the low immunotherapy response rate in colorectal cancer (CRC). Here, we used a proteogenomic strategy comprising immunopeptidomics, whole exome sequencing, and 16S ribosomal DNA sequencing analyses of 8 patients with CRC to identify neoantigens and bacterial immunopeptides that can serve as antitumor targets. This study directly identified several personalized neoantigens and bacterial immunopeptides. Immunoassays showed that all neoantigens and 5 of 8 bacterial immunopeptides could be recognized by autologous T cells. Additionally, T cell receptor (TCR) αβ sequencing revealed the TCR repertoire of epitope-reactive CD8+ T cells. Functional studies showed that T cell receptor -T (TCR-T) could be activated by epitope pulsed lymphoblastoid cells. Overall, this study comprehensively profiled the CRC immunopeptidome, revealing several neoantigens and bacterial immunopeptides with potential to serve as immunotherapy targets in CRC.

2023-11-28 | PXD047311 |

Engineered exosomes reprogram Gli1+ cells in vivo to prevent calcification of vascular grafts and autologous pathological vessels

Project description:Engineered exosomes reprogrammed Gli1+ cells to promote SMC reconstruction and inhibit calcification in TEVBs and autologous pathological vessels.

2023-08-08 | GSE227179 | GEO

Co-culture of synovial tissue dendritic cells with autologous peripheral blood memory T-Cells across Active and Remission RA

Project description:To dissect the precise roles of ST-DC2 clusters and ST-iDC3 clusters in T-cell activation, we co-cultured each cluster separately with autologous memory CD4pos T-cells. FACS-sorted ST-DC2 clusters and ST-iDC3 clusters from synovial tissue of active RA or remission RA were co-cultured for 5 days with FACS-sorted autologous blood memory CD4pos T-cells in the presence of anti-CD3 stimulation to mimic TCR activation. We investigated the frequency and phenotype of the resultant co-culture T-cell populations by carrying out single cell sequencing and analysing the output. It was observed that the DC2 and iDC3 group could differentially support distinct T-Cell populations in both frequency, and transcriptional profile.

2024-12-09 | E-MTAB-14191 | biostudies-arrayexpress

Mis-splicing derived neoantigens and cognate T cell receptors in splicing factor mutant leukemias

Project description:Mutations in RNA splicing factors are prevalent across cancers and generate recurrently mis-spliced mRNA isoforms. Here we identified a series of bona fide neoantigens translated from highly stereotyped splicing alterations promoted by neomorphic, leukemia-associated somatic mutations in the splicing machinery. We utilized feature-barcoded peptide-MHC dextramers to isolate neoantigen-specific T cell receptors (TCR) from both healthy donors and patients with leukemia. While circulating neoantigen-specific CD8+ T cells were identified in patients with active disease, they were dysfunctional with reduced inflammatory response gene signatures. In contrast, donor CD8+ T cells with tumor-reactive TCRs were present following curative allogeneic hematopoietic cell transplant. T cells engineered with TCRs recognizing an SRSF2 mutant-induced neoantigen in CLK3 resulted in specific recognition and cytotoxicity of SRSF2 mutant leukemia. These data identify RNA mis-splicing derived neoantigens and neoantigen-specific TCRs across patients and provide proof-of-concept to genetically redirect T cells to public mis-splicing derived neoantigens in myeloid leukemias.

2024-05-22 | GSE268157 | 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

Project description:Neoantigens derived from non-synonymous somatic mutations, especially gene fusion mutation, are restricted to tumor cells and thus considered ideal targets for T-cell receptor-engineering T-cells (TCR-T) immunotherapy. Adoptive transfer of neoantigen-specific TCR-T cells preferentially exhibit potent cytotoxicity preferentially to tumor cells, and has shown promising efficacy in several preclinical human cancer models. However, most neoantigens are unique to individual patient, which hinders the application of TCR-T cell therapy. In this study, we first discovered a paired / TCR repertoire, Tcr-1, that specifically targeted STY-SSX fusion neoantigen shared by almost all synovial sarcomas. Engineered T-cell expressing Tcr-1 (Tcr-T1) exhibited antigen-specific HLA-A*2402-restricted antitumoral activity against synovial sarcomas cell both in vitro and in vivo. Furthermore, to furtherly extend its application beyond synovial sarcomas, we innovatively developed a cooperative therapeutic modality, in which exogenous SYT-SSX fusion neoantigen was loaded into enzyme-responsive nanoparticles (NPs) formed by mPEG-PVGLIG-PCL copolymers (FNeo-AgNPs) for tumor targeting delivery. As expected, FNeo-AgNPs were proven of great tumor penetration, and local release. In situ modification was able to direct engineered Tcr-T1 against to other malignant gastric cancer cell line with significant antigen-specific HLA-A*2402-restricted cytotoxicity resulting in remarkable tumor regression and prolonging survival in both subcutaneous and peritoneally disseminated preclinical models, despite of their inherent mutation profiles. With these favorable data, our established cooperative therapeutic modality has a great potential for further clinical investigation, and provide a now insight for future TCR-T cell therapy development.

2024-11-18 | GSE243535 | GEO

Targeting the tumor mutanome for personalized vaccination in lung cancer

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

Transcriptome profile of Responders and Nonresponders T cells infiltrated lymphocytes (TILs) co-cultured with autologous tumor cells from patients with melanoma.

Project description:Adoptive cell therapy (ACT) based on ex vivo expanded autologous tumor-infiltrating lymphocytes (TILs) can mediate durable antitumor responses even in heavily pretreated patients. However, only a subset of patients responds to ACT; efforts to identify correlates of response have focused on profiling the tumor or the TIL but rarely in an interactive environment. Interactive profiling can provide unique insights into the clinical performance of TILs since the fate, function, and metabolism of TILs are influenced by autologous tumor-derived factors. Here, we performed a suite of cell-sparing assays dubbed holistic analysis of the bioactivity of interacting T cells and autologous tumor cells (HABITAT). HABITAT profiling of TILs used for human ACT and their autologous tumor cells included function-based single-cell profiling by timelapse imaging microscopy in nanowell grids (TIMING); multi-omics using RNA-sequencing and proteomics; metabolite inference using genome-scale metabolic modeling, and pulse-chase assays based on confocal microscopy to profile the uptake and fate of fatty acids (FA). Phenotypically, the ACT TILs from both responders (Rs) and nonresponders (NRs) were comprised of predominantly effector memory T cells (TEM cells) and did not express a high frequency of programmed death ligand-1 (PD-L1) and showed no differences in TCR diversity. Our results demonstrate that while tumor cells from both Rs and NRs are efficient at uptaking FAs, R TILs are significantly more efficient at utilizing FA through fatty acid oxidation (FAO) than NR TILs under nutrient starvation conditions. While it is likely that lipid and FA uptake is an inherent adaptation of TIL populations to lipid-rich environments, performing FAO sustains the survival of TILs and allows them to sustain antitumor cytolytic activity. We propose that metabolic plasticity enabling FAO is a desirable attribute of human TILs for ACT leading to clinical responses.

2023-05-01 | GSE215037 | GEO

NKT cells co-expressing a GD2-specific chimeric antigen receptor and IL-15 mediate regression of refractory metastatic neuroblastoma

Project description:Despite remarkable progress in B cell malignancies, T cells expressing chimeric antigen receptors (CARs) remain ineffective in solid tumors in part because T cells do not traffic effectively to or survive in tumor tissues. We engineered Vα24-invariant natural killer T cells (NKTs), which intrinsically home to tumor sites, to co-express a GD2-specific CAR with interleukin (IL)15 and evaluated their therapeutic efficacy in children with relapsed/resistant neuroblastoma (NB)(NCT03294954). The first three patients received a single infusion of 3x10e6 autologous CAR-NKTs per square meter of body surface area and tolerated the treatment well. CAR-NKTs expanded in vivo, localized to the tumor, and in one patient induced a near-complete regression of bone metastatic lesions.

2020-08-10 | GSE154037 | GEO

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