Anti-tumor cytotoxic T lymphocytes targeting solid tumors: Ready for clinical trials

Cytotherapy ◽  
2012 ◽  
Vol 14 (1) ◽  
pp. 4-6
Author(s):  
Claudia Rossig
Keyword(s):  
Clinical Trials ◽  
T Lymphocytes ◽  
Solid Tumors ◽  
Cytotoxic T Lymphocytes

scholarly journals Metabolic radiolabeling and in vivo PET imaging of cytotoxic T lymphocytes to guide combination adoptive cell transfer cancer therapy

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Dehua Lu ◽  
Yanpu Wang ◽  
Ting Zhang ◽  
Feng Wang ◽  
Kui Li ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Solid Tumors ◽  
Cytotoxic T Lymphocytes ◽  
Pet Imaging ◽  
Stage Migration ◽  
Cell Transfer ◽  
Tumor Infiltration ◽  
Antitumor Effects

Abstract Background Adoptive T cell transfer-based immunotherapy yields unsatisfactory results in the treatment of solid tumors, partially owing to limited tumor infiltration and the immunosuppressive microenvironment in solid tumors. Therefore, strategies for the noninvasive tracking of adoptive T cells are critical for monitoring tumor infiltration and for guiding the development of novel combination therapies. Methods We developed a radiolabeling method for cytotoxic T lymphocytes (CTLs) that comprises metabolically labeling the cell surface glycans with azidosugars and then covalently conjugating them with 64Cu-1,4,7-triazacyclononanetriacetic acid-dibenzo-cyclooctyne (64Cu-NOTA-DBCO) using bioorthogonal chemistry. 64Cu-labeled control-CTLs and ovalbumin-specific CTLs (OVA-CTLs) were tracked using positron emission tomography (PET) in B16-OVA tumor-bearing mice. We also investigated the effects of focal adhesion kinase (FAK) inhibition on the antitumor efficacy of OVA-CTLs using a poly(lactic-co-glycolic) acid (PLGA)-encapsulated nanodrug (PLGA-FAKi). Results CTLs can be stably radiolabeled with 64Cu with a minimal effect on cell viability. PET imaging of 64Cu-OVA-CTLs enables noninvasive mapping of their in vivo behavior. Moreover, 64Cu-OVA-CTLs PET imaging revealed that PLGA-FAKi induced a significant increase in OVA-CTL infiltration into tumors, suggesting the potential for a combined therapy comprising OVA-CTLs and PLGA-FAKi. Further combination therapy studies confirmed that the PLGA-FAKi nanodrug markedly improved the antitumor effects of adoptive OVA-CTLs transfer by multiple mechanisms. Conclusion These findings demonstrated that metabolic radiolabeling followed by PET imaging can be used to sensitively profile the early-stage migration and tumor-targeting efficiency of adoptive T cells in vivo. This strategy presents opportunities for predicting the efficacy of cell-based adoptive therapies and for guiding combination regimens. Graphic Abstract

Novel heteroclitic XBP1 peptides evoking antigen-specific cytotoxic T lymphocytes targeting various solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3067-3067
Author(s):  
Jooeun Bae ◽  
Ruben Carrasco ◽  
John Daley ◽  
Glen Dranoff ◽  
Kenneth Carl Anderson ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Solid Tumors ◽  
Cell Lines ◽  
Cytotoxic T Lymphocytes ◽  
Solid Tumor ◽  
Ex Vivo ◽  
Effector Memory ◽  
Repeated Stimulation ◽  
Hypoxic Conditions ◽  
The Unfolded Protein Response

3067 Background: Activation of the unfolded protein response (UPR) allows for tumor cells to survive prolonged endoplasmic reticulum stress and hypoxic conditions. XBP1 is an upstream element and a critical transcriptional activator of the UPR, and its up-regulation in a variety of human solid tumor cancers makes it as a promising immunotherapeutic target. The purpose of these studies was to evaluate immunogenic HLA-A2 XBP1-specific peptides for their ability to elicit cytotoxic T lymphocytes (CTL) against a variety of solid tumor cell lines. Methods: Upon the validation of XBP1 peptides for their strong HLA-A2 bindings and stabilities, peptide-specific CTL were generated ex vivo by repeated stimulation of CD3+ T lymphocytes obtained from HLA-A2+normal donors with XBP1 peptides-pulsed antigen-presenting cells, either dendritic cells or T2 cells. Results: A cocktail of heteroclitic XBP1 US184-192 (YISPWILAV) and heteroclitic XBP1 SP367-375 (YLFPQLISV) peptides with significantly improved HLA-A2 affinity and stability from their native counterparts were used to evoke XBP1 antigen-specific CTL. The CTL were predominantly CD3+CD8+ T cells (>80%) containing a high percentage of Effector Memory (EM; CCR7-CD45RO+) cells, which were distinctively evoked by repeated stimulation with the XBP1 peptides. In addition, the XBP1-CTL displayed a high level of cellular activation (CD69+/CD3+CD8+). The XBP1-CTL demonstrated effective anti-tumor responses including cell proliferation and IFN-g production, as well as degranulation (cytotoxic activity) against HLA-A2+breast cancer (MB231, MCF7), colon cancer (LS180, SW480) and pancreatic cancer (8902, Panc1, PL45) cell lines, which over-express both unspliced and spliced XBP1 antigens. Importantly, the specific anti-tumor activities were detected primarily in the EM CTL subset. Conclusions: These results suggest the immunotherapeutic potential of a cocktail of heteroclitic XBP1 US184-192 and XBP1 SP367-375 peptides to elicit effective anti-tumor responses against various solid tumors, and provide the framework for clinical development of vaccine trials to improve patient outcome.

scholarly journals ELISPOT Assay for Monitoring Cytotoxic T Lymphocytes (CTL) Activity in Cancer Vaccine Clinical Trials

Cells ◽  
2012 ◽  
Vol 1 (2) ◽  
pp. 111-126 ◽  
Author(s):  
Anatoli M. Malyguine ◽  
Susan Strobl ◽  
Kimberly Dunham ◽  
Michael R. Shurin ◽  
Thomas J. Sayers
Keyword(s):  
Clinical Trials ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Cancer Vaccine ◽  
Elispot Assay ◽  
Ctl Activity

scholarly journals Evidence for a graft-versus-tumor effect in a patient treated with marrow ablative chemotherapy and allogeneic bone marrow transplantation for breast cancer

Blood ◽  
1996 ◽  
Vol 88 (4) ◽  
pp. 1501-1508 ◽  
Author(s):  
B Eibl ◽  
H Schwaighofer ◽  
D Nachbaur ◽  
C Marth ◽  
A Gachter ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
T Lymphocytes ◽  
Solid Tumors ◽  
Cytotoxic T Lymphocytes ◽  
Antitumor Effect ◽  
Allogeneic Bone Marrow Transplantation ◽  
Breast Cancer Cell Lines ◽  
Target Cells ◽  
Allogeneic Bone

Graft-versus-leukemia (GvL) has been shown to be an important immune- mediated antitumor effect in hematologic malignancies. It is still unknown whether such an immunemediated antitumor effect has clinical implications in patients with solid tumors. A 32-year-old woman with inflammatory breast cancer received a bone marrow transplant (BMT) from her HLA-identical sibling. During graft-versus-host disease (GvHD) cytotoxic T lymphocytes were grown and tested in a chromium-release assay against B and T lymphocytes of the patient and donor and against a panel of breast cancer cell lines. Resolution of liver metastases was observed simultaneously with clinical GvHD in the first weeks after transplant. In addition, minor histocompatibility antigen (MiHA)- specific and major histocompatibility complex (MHC) class I antigen- restricted cytotoxic T lymphocytes recognizing breast carcinoma target cells were isolated from the blood of the patient. Pretreatment of such target cells with tumor necrosis factor (TNF)-alpha but not with interferon (IFN)-alpha or IFN-gamma increased susceptibility of these cells to lysis by cytotoxic T lymphocytes. Clinical course and in vitro results suggest that a graft-versus-tumor (GvT) effect might exist after allogeneic BMT for breast cancer. However, clinical experience on a larger scale would be required to determine the clinical efficacy of GvT effects in patients with solid tumors.

scholarly journals Broad Recognition of Circulating HIV-1 by HIV-1-Specific Cytotoxic T-Lymphocytes with Strong Ability to Suppress HIV-1 Replication

2018 ◽  
Vol 93 (1) ◽  
Author(s):  
Hayato Murakoshi ◽  
Nozomi Kuse ◽  
Tomohiro Akahoshi ◽  
Yu Zhang ◽  
Takayuki Chikata ◽  
...  
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
T Cell Responses ◽  
Aids Vaccine ◽  
Cell Responses ◽  
Hiv 1

ABSTRACT HIV-1-specific cytotoxic T-lymphocytes (CTLs) with strong abilities to suppress HIV-1 replication and recognize most circulating HIV-1 strains are candidates for effector T cells for cure treatment and prophylactic AIDS vaccine. Previous studies demonstrated that the existence of CTLs specific for 11 epitopes was significantly associated with good clinical outcomes in Japan, although CTLs specific for one of these epitopes select for escape mutations. However, it remains unknown whether the CTLs specific for the remaining 10 epitopes suppress HIV-1 replication in vitro and recognize circulating HIV-1. Here, we investigated the abilities of these CTLs to suppress HIV-1 replication and to recognize variants in circulating HIV-1. CTL clones specific for 10 epitopes had strong abilities to suppress HIV-1 replication in vitro. The ex vivo and in vitro analyses of T-cell responses to variant epitope peptides showed that the T cells specific for 10 epitopes recognized mutant peptides which are detected in 84.1% to 98.8% of the circulating HIV-1 strains found in HIV-1-infected Japanese individuals. In addition, the T cells specific for 5 epitopes well recognized target cells infected with 7 mutant viruses that had been detected in >5% of tested individuals. Taken together, these results suggest that CTLs specific for the 10 epitopes effectively suppress HIV-1 replication and broadly recognize the circulating HIV-1 strains in the HIV-1-infected individuals. This study suggests the use of these T cells in clinical trials. IMPORTANCE In recent T-cell AIDS vaccine trials, the vaccines did not prevent HIV-1 infection, although HIV-1-specific T cells were induced in the vaccinated individuals, suggesting that the T cells have a weak ability to suppress HIV-1 replication and fail to recognize circulating HIV-1. We previously demonstrated that the T-cell responses to 10 epitopes were significantly associated with good clinical outcome. However, there is no direct evidence that these T cells have strong abilities to suppress HIV-1 replication and recognize circulating HIV-1. Here, we demonstrated that the T cells specific for the 10 epitopes had strong abilities to suppress HIV-1 replication in vitro. Moreover, the T cells cross-recognized most of the circulating HIV-1 in HIV-1-infected individuals. This study suggests the use of T cells specific for these 10 epitopes in clinical trials of T-cell vaccines as a cure treatment.

scholarly journals CHANGES IN THE IMMUNE STATUS OF PATIENTS WITH METASTATIC SOLID TUMORS DURING STEREOTACTIC RADIATION THERAPY

2020 ◽  
Vol 66 (3) ◽  
pp. 277-282
Author(s):  
Anton Zozulya ◽  
Sergey Novikov ◽  
Irina Baldueva ◽  
D. Girdyuk ◽  
Natalya Yemelyanova ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
T Lymphocytes ◽  
Solid Tumors ◽  
Cytotoxic T Lymphocytes ◽  
Malignant Tumors ◽  
Immunological Parameters ◽  
Stereotactic Radiation ◽  
Metastatic Lesions ◽  
Hla Dr ◽  
T Helpers

Purpose. To evaluate immunological status in patients with metastatic forms of solid tumors before and at different intervals after stereotactic body radiation therapy (SBRT) of metastatic lesions. Materials and methods. A quantitative assessment and analysis of blood immunological parameters was conducted before irradiation, after 3-4 weeks and 6-8 weeks after SBRT in patients with malignant tumors with oligometastases in the liver and lungs. All peripheral blood samples were analyzed by flow cytometry. Statistical analysis was performed using Friedman and Nemenyi criteria. Results. 3-4 weeks after the end of SBRT, we observed statistically significant increase of T-lymphocytes (CD3+CD19-); T-helpers (CD3+CD4+); activated T-helpers (CD3+CD4+HLA-DR+); activated cytotoxic T-lymphocytes (CD3+CD8+HLA-DR+) and decrease of B-lymphocytes (CD3-CD19+). Subsequently, after 6-8 weeks after the end of irradiation we detected decrease of T-lymphocytes (CD3+CD19-) and continuing increase in activated T-helpers (CD3+CD4+HLA-DR+) and activated cytotoxic T-lymphocytes (CD3+CD8+HLA-DR+). Conclusion. Thus, revealed dynamics of immunological parameters indicates the induction of the T-cell link of antitumor immunity against decreasing of indicators of humoral immunity.

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