Clonal analysis of in vivo activated CD8+ cytotoxic T lymphocytes from a melanoma patient responsive to active specific immunotherapy

1993 ◽  
Vol 37 (1) ◽  
pp. 15-25 ◽  
Author(s):  
June Kan-Mitchell ◽  
Xiu Qing Huang ◽  
Lawrence Steinman ◽  
Jorge R. Oksenberg ◽  
William Harel ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Melanoma Patient ◽  
Specific Immunotherapy ◽  
Clonal Analysis ◽  
Active Specific Immunotherapy

PERSPECTIVES IN ACTIVE SPECIFIC IMMUNOTHERAPY WITH AUTOLOGOUS IMMATURE DENDRITIC CELLS COMBINED WITH PHOTODYNAMIC THERAPY AND CYCLOPHOSPHAMIDE IN PATIENTS WITH DISSEMINATED MELANOMA RESISTANT TO STANDARD THERAPY

2017 ◽  
Vol 63 (2) ◽  
pp. 336-345
Author(s):  
Irina Baldueva ◽  
N. Avdokina ◽  
Aleksey Belyaev ◽  
Aleksandr Shcherbakov ◽  
Tatyana Semiglazova ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Photodynamic Therapy ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Standard Therapy ◽  
Specific Immunotherapy ◽  
Active Specific Immunotherapy ◽  
Dc Vaccine ◽  
Immature Dendritic Cells ◽  
Melanoma Patients

There are described the results of clinical and immunological efficacy assessment of active specific immunotherapy with autologous immature dendritic cells (DC) combined with photodynamic therapy (PDT) and cyclophosphamide (C) in disseminated melanoma patients, resistant to standard therapy. 27 patients treated in the N.N. Petrov Research Institute of Oncology were included in the study from 2007 till 2016. Immunotherapy was conducted in a 21-day cycles. Therapy included following steps: 1) preparation of individual vaccine preparation from bone-marrow derived DC with immune phenotype CD34-/CD14VCD1a+/CD83VCD80-/+/CD86-/+/HLA-DR+; 2) Intramuscular 300 mg C injection in day 1 of treatment cycle for elimination T-lymphocytes with immunosuppressing activity; 3) PDT with chlorin salts at day 4 six hours before start of vaccinotherapy; 4) Daily intralesional injections of DC vatccine in irradiated lesions in the dose 1х106 DC cells/ kg. Clinical and immunological efficacy was assessed in 27 patients. Fourteen (52%) patients received 1-2 cycles of therapy, 13(48%) received 3 or more cycles. No complete response was seen. Partial response (RECIST 1.1) was found in 2 (7,4%) patients, stable disease in 8 (29,6%) patients. Seventeen (63%) patients progressed. Median time to progression (TTP) was 2.5 month, median overall survival (OS) 8.4 month. One-year survival was 5% and 37% for TTP and OS, respectively. No adverse events (AE) of grade 4-5 (CTC AE v4) were seen. Grade 3 fever was registered in 4% of patients. Grade 1-2 AE were found in 54% of patients. Immunologic assessment revealed significant decline of immunoregulatory index (CD/ CD8) caused by prevalence of cytotoxic T-lymphocytes in peripheral blood of responding patients (patients with clinical benefit). Tendency for elevation of absolute number of activates T-helpers and cytotoxic T-lymphocytes together with low T-regulatory cells concentration was also found. Combination therapy using immunomodulatory effects of C, PDT and DC vaccine in 21-day treatment cycles produce promising activity and favorable toxicity profile in heavily pretreated disseminated melanoma patients.

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

scholarly journals Identification of Two New HLA-A*1101-Restricted Tax Epitopes Recognized by Cytotoxic T Lymphocytes in an Adult T-Cell Leukemia Patient after Hematopoietic Stem Cell Transplantation

2005 ◽  
Vol 79 (15) ◽  
pp. 10088-10092 ◽  
Author(s):  
Nanae Harashima ◽  
Ryuji Tanosaki ◽  
Yukiko Shimizu ◽  
Kiyoshi Kurihara ◽  
Takao Masuda ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
T Lymphocytes ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cytotoxic T Lymphocytes ◽  
Cell Leukemia ◽  
Hematopoietic Stem ◽  
Adult T Cell Leukemia

ABSTRACT We previously reported that Tax-specific CD8+ cytotoxic T lymphocytes (CTLs), directed to single epitopes restricted by HLA-A2 or A24, expanded in vitro and in vivo in peripheral blood mononuclear cells (PBMC) from some adult T-cell leukemia (ATL) patients after but not before allogeneic hematopoietic stem cell transplantation (HSCT). Here, we demonstrated similar Tax-specific CTL expansion in PBMC from another post-HSCT ATL patient without HLA-A2 or A24, whose CTLs equally recognized two newly identified epitopes, Tax88-96 and Tax272-280, restricted by HLA-A11, suggesting that these immunodominant Tax epitopes are present in the ATL patient in vivo.

scholarly journals Targeting necroptosis in muscle fibers ameliorates inflammatory myopathies

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Mari Kamiya ◽  
Fumitaka Mizoguchi ◽  
Kimito Kawahata ◽  
Dengli Wang ◽  
Masahiro Nishibori ◽  
...  
Keyword(s):  
Cell Death ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Muscle Cell ◽  
Muscle Injury ◽  
Fas Ligand ◽  
Muscle Fibers ◽  
Inflammatory Molecules

AbstractMuscle cell death in polymyositis is induced by CD8+ cytotoxic T lymphocytes. We hypothesized that the injured muscle fibers release pro-inflammatory molecules, which would further accelerate CD8+ cytotoxic T lymphocytes-induced muscle injury, and inhibition of the cell death of muscle fibers could be a novel therapeutic strategy to suppress both muscle injury and inflammation in polymyositis. Here, we show that the pattern of cell death of muscle fibers in polymyositis is FAS ligand-dependent necroptosis, while that of satellite cells and myoblasts is perforin 1/granzyme B-dependent apoptosis, using human muscle biopsy specimens of polymyositis patients and models of polymyositis in vitro and in vivo. Inhibition of necroptosis suppresses not only CD8+ cytotoxic T lymphocytes-induced cell death of myotubes but also the release of inflammatory molecules including HMGB1. Treatment with a necroptosis inhibitor or anti-HMGB1 antibodies ameliorates myositis-induced muscle weakness as well as muscle cell death and inflammation in the muscles. Thus, targeting necroptosis in muscle cells is a promising strategy for treating polymyositis providing an alternative to current therapies directed at leukocytes.

scholarly journals High Frequency of Skin-homing Melanocyte-specific Cytotoxic T Lymphocytes in Autoimmune Vitiligo

1998 ◽  
Vol 188 (6) ◽  
pp. 1203-1208 ◽  
Author(s):  
Graham S. Ogg ◽  
P. Rod Dunbar ◽  
Pedro Romero ◽  
Ji-Li Chen ◽  
Vincenzo Cerundolo
Keyword(s):  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Ex Vivo ◽  
Hla Class I ◽  
Peripheral Tolerance ◽  
Skin Homing ◽  
Autoimmune Vitiligo ◽  
Destruction Of Melanocytes

Vitiligo is an autoimmune condition characterized by loss of epidermal melanocytes. Using tetrameric complexes of human histocompatibility leukocyte antigen (HLA) class I to identify antigen-specific T cells ex vivo, we observed high frequencies of circulating MelanA-specific, A*0201-restricted cytotoxic T lymphocytes (A2–MelanA tetramer+ CTLs) in seven of nine HLA-A*0201–positive individuals with vitiligo. Isolated A2–MelanA tetramer+ CTLs were able to lyse A*0201-matched melanoma cells in vitro and their frequency ex vivo correlated with extent of disease. In contrast, no A2–MelanA tetramer+ CTL could be identified ex vivo in all four A*0201-negative vitiligo patients or five of six A*0201-positive asymptomatic controls. Finally, we observed that the A2–MelanA tetramer+ CTLs isolated from vitiligo patients expressed high levels of the skin homing receptor, cutaneous lymphocyte-associated antigen, which was absent from the CTLs seen in the single A*0201-positive normal control. These data are consistent with a role of skin-homing autoreactive melanocyte-specific CTLs in causing the destruction of melanocytes seen in autoimmune vitiligo. Lack of homing receptors on the surface of autoreactive CTLs could be a mechanism to control peripheral tolerance in vivo.

Selective elimination of leukemic CD34+ progenitor cells by cytotoxic T lymphocytes specific for WT1

Blood ◽  
2000 ◽  
Vol 95 (7) ◽  
pp. 2198-2203 ◽  
Author(s):  
Liquan Gao ◽  
Ilaria Bellantuono ◽  
Annika Elsässer ◽  
Stephen B. Marley ◽  
Myrtle Y. Gordon ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Chronic Myeloid Leukemia ◽  
T Lymphocytes ◽  
Progenitor Cells ◽  
Cytotoxic T Lymphocytes ◽  
Colony Formation ◽  
Myeloid Leukemia ◽  
Leukemia Cell

Abstract Hematologic malignancies such as acute and chronic myeloid leukemia are characterized by the malignant transformation of immature CD34+ progenitor cells. Transformation is associated with elevated expression of the Wilm's tumor gene encoded transcription factor (WT1). Here we demonstrate that WT1 can serve as a target for cytotoxic T lymphocytes (CTL) with exquisite specificity for leukemic progenitor cells. HLA-A0201– restricted CTL specific for WT1 kill leukemia cell lines and inhibit colony formation by transformed CD34+ progenitor cells isolated from patients with chronic myeloid leukemia (CML), whereas colony formation by normal CD34+ progenitor cells is unaffected. Thus, the tissue-specific transcription factor WT1 is an ideal target for CTL-mediated purging of leukemic progenitor cells in vitro and for antigen-specific therapy of leukemia and other WT1-expressing malignancies in vivo.

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