Immunotherapeutic strategies: the melanoma example

Immunotherapy ◽  
2009 ◽  
Vol 1 (4) ◽  
pp. 679-690
Author(s):  
Annelies Jorritsma ◽  
Ton NM Schumacher ◽  
John BAG Haanen
Keyword(s):  
T Cell ◽  
Adoptive Immunotherapy ◽  
Low Frequency ◽  
Cell Repertoire ◽  
Very High Frequency ◽  
In Vitro Expansion ◽  
Clinical Responses ◽  
Application Potential ◽  
T Cell Transfer

T-cell-based immunotherapy can be induced by nonspecific activation, by antigen-specific immunization, or by adoptive immunotherapy. In this review, progress in these areas is discussed as based on data from clinical trials for the treatment of metastatic melanoma. Nonspecific immunotherapy has been shown to result in low, but in some cases significant, levels of objective tumor responses, and is often associated with autoimmune reactions. Antigen-specific targeting of tumors via vaccination has only resulted in low to very low levels of objective responses, and these strategies seem to have most value when the T-cell repertoire is not affected by tolerance. Finally, adoptive immunotherapy can be applied by in vitro expansion of autologous lymphocytes that have escaped tolerance or by genetic transfer of allogeneic T-cell receptors (TCRs). Autologous adoptive T-cell transfer has resulted in a very high frequency of clinical responses when combined with chemotherapy and IL-2 administration in single-center studies. Although TCR gene transfer has, until now, only resulted in a low frequency of clinical responses, it does have a broader application potential, and optimization of this strategy is likely to improve its efficacy.

In vitro expansion of polyclonal T-cell subsets for adoptive immunotherapy by recombinant modified vaccinia Ankara

2006 ◽  
Vol 34 (4) ◽  
pp. 497-507 ◽  
Author(s):  
Corinna La Rosa ◽  
Zhongde Wang ◽  
Simon F. Lacey ◽  
Maria M. Lalimarmo ◽  
Aparna Krishnan ◽  
...  
Keyword(s):  
T Cell ◽  
Adoptive Immunotherapy ◽  
T Cell Subsets ◽  
In Vitro Expansion

In vitro expansion of antigen-specific CD8+ T cells distorts the T-cell repertoire

2014 ◽  
Vol 405 ◽  
pp. 199-203 ◽  
Author(s):  
Dan Koning ◽  
Ana I. Costa ◽  
Raiza Hasrat ◽  
Bart P.X. Grady ◽  
Sanne Spijkers ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
In Vitro Expansion

scholarly journals BCR/ABL leukemia oncogene fusion peptides selectively bind to certain HLA-DR alleles and can be recognized by T cells found at low frequency in the repertoire of normal donors

Blood ◽  
1996 ◽  
Vol 88 (6) ◽  
pp. 2118-2124 ◽  
Author(s):  
G Pawelec ◽  
H Max ◽  
T Halder ◽  
O Bruserud ◽  
A Merl ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mononuclear Cells ◽  
Low Frequency ◽  
Myelogenous Leukemia ◽  
Fusion Peptides ◽  
Cell Repertoire ◽  
Peripheral Blood Mononuclear ◽  
Hla Dr

Chronic myelogenous leukemia (CML) is characterized by the t(9;22) translocation that results in chimeric genes encoding bcr/abl fusion proteins. Junction-spanning sequences represent unique tumor-specific moieties that might be exploited therapeutically. We investigate here the binding of synthetic bcr/abl peptides to various HLA-DR alleles and their recognition by T cells from normal donors and CML patients. A 23- mer b3/a2 peptide bound very strongly to isolated HLA-DRB1*1101 (Dw5) and relatively strongly to DRB1*0301 (Dw3) and DRB1*0402 (Dw10) molecules, as estimated using a competition assay. It failed to bind to several other DR alleles, including three different DR4 alleles. In contrast, a 23-mer b2/a2 peptide bound only to the DRB1*0301 (Dw3) allele. Peripheral blood mononuclear cells from normal donors were sensitized in vitro against the b3/a2 peptide. After four repetitive stimulations, T cells responding to the peptide were found at low frequency in 5 of the 11 donors tested. Three of the five were HLA- DR11+, and all three of the DR11+ donors tested were found to respond. T cells recognizing bcr/abl peptides were not identified in any of the CML patients studied, regardless of HLA type. Finally, even peptide- reactive T-cell lines from normal donors were not stimulated by native CML cells in the absence of exogenous peptide. These results show the presence of low-frequency major histocompatability complex class II- restricted bcr/abl-responses in the normal T-cell repertoire of donors with certain HLA types, but suggest that unmodified tumor cells cannot be recognized by such peptide-sensitized T cells.

Cord Blood Lymphocytes After TCR Gene Transduction Are Functional, Retain An Early Differentiation Phenotype and Are Suitable for Adoptive Immunotherapy

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3117-3117
Author(s):  
Frederick E Chen ◽  
Guido Frumento ◽  
Yong Zheng ◽  
Mohammad Raeiszadeh ◽  
Paul AH Moss ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Cord Blood ◽  
Adoptive Immunotherapy ◽  
Effector Memory ◽  
Cd8 Cells ◽  
In Vitro Expansion

Abstract Abstract 3117 The efficacy of adoptive T cell therapy largely depends on the in vivo persistence of infused cells (Robbins PF et al. J Immunol 2004;173 :7125), that is related to the differentiation stage. The less differentiated central memory (CM) T cells display superior proliferation, persistence and anti-tumor response following infusion when compared to the more differentiated effector memory (EM) T cells. However both T cell receptor (TCR) gene transfer and in vitro expansion of antigen-specific T lymphocytes necessitate lymphocyte activation; with lymphocytes from adult donors this results in accumulation of highly differentiated EM CD45RA+ (EMRA) cells with reduced half life and proliferative capability. Cord blood (CB) lymphocytes are predominantly naïve (N), and we have studied the potential utility of these cells for TCR transduction-based immunotherapy. T cells from CB samples were activated by anti-CD3 antibody plus IL-2, and transduced with a TCR specific for a peptide from the EBV LMP2 molecule using a retroviral vector. Lymphocytes from adult donors were also transduced as controls. We found that after transduction CB and adult lymphocytes showed comparable levels of TCR expression. Moreover, both CB and adult T cells rapidly shifted toward a more mature phenotype, CB cells becoming mainly CM (60%), and adult T cells becoming mainly EM (52%). In keeping with their phenotype, the expression CD57, a marker of replicative senescence was low in CB T lymphocytes (18%) and high in adult T lymphocytes (68%). To asses if the transduced cells were able to respond to specific antigen stimulation, transduced lymphocytes were incubated with peptide-pulsed autologous dendritic cells. CB T cells expanded as effectively as lymphocytes from adult donors with a 50-fold increase in cell count after 3 week culture, with no indication that the expansion was leveling off. At that time point more than 50% of the cells expressed the transduced TCR both in CB and in adult samples. Further, CB cultures were dominated by EM accounting for a mean of 55% of the cells at the end of the culture period with very few EMRA. In contrast, adult blood cell cultures were characterised by a marked increase in EMRA which came to comprise a mean of 66% of the final population. Further phenotypic analysis at the end of the in vitro expansion demonstrated that CD27, a marker of less differentiated T cells, was expressed on 85% of transduced CB T cells but only on 39% of adult T cells, confirming that CB lymphocytes had retained a less differentiated phenotype. To investigate the effector function of the transduced cells we demonstrated that after further stimulations. polyfunctional CB CD8 cells secreting IFNg, IL2 and TNFa increased from 0.8% after the first stimulation to 4.5% after re-stimulation. In contrast, polyfunctional transduced CD8 T cells from adults decreased from 2.0% to 0.9% during the same period. Both transduced CB and adult CD8 cells demonstrated effective HLA-restricted, antigen-specific target cell lysis in a standard chromium release assay. Our results suggest that TCR-transduced CB T cells have greater in vivo expansion potential, making these cells potentially more suitable for adoptive immunotherapy, particularly in those cases where autologous lymphopheresis or donor lymphocyte infusion is not an option. Disclosures: No relevant conflicts of interest to declare.

scholarly journals IMMU-31. QUANTITATIVE EVALUATION OF ROUTES OF ADMINISTRATION OF IMMUNOTHERAPEUTIC T CELLS TO ORTHOTOPIC GLIOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii111-ii111
Author(s):  
Lan Hoang-Minh ◽  
Angelie Rivera-Rodriguez ◽  
Fernanda Pohl-Guimarães ◽  
Seth Currlin ◽  
Christina Von Roemeling ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Ex Vivo ◽  
Adoptive T Cell Therapy ◽  
Whole Body ◽  
T Cell Therapy ◽  
Clinical Responses

Abstract SIGNIFICANCE Adoptive T cell therapy (ACT) has emerged as the most effective treatment against advanced malignant melanoma, eliciting remarkable objective clinical responses in up to 75% of patients with refractory metastatic disease, including within the central nervous system. Immunologic surrogate endpoints correlating with treatment outcome have been identified in these patients, with clinical responses being dependent on the migration of transferred T cells to sites of tumor growth. OBJECTIVE We investigated the biodistribution of intravenously or intraventricularly administered T cells in a murine model of glioblastoma at whole body, organ, and cellular levels. METHODS gp100-specific T cells were isolated from the spleens of pmel DsRed transgenic C57BL/6 mice and injected intravenously or intraventricularly, after in vitro expansion and activation, in murine KR158B-Luc-gp100 glioma-bearing mice. To determine transferred T cell spatial distribution, the brain, lymph nodes, heart, lungs, spleen, liver, and kidneys of mice were processed for 3D imaging using light-sheet and multiphoton imaging. ACT T cell quantification in various organs was performed ex vivo using flow cytometry, 2D optical imaging (IVIS), and magnetic particle imaging (MPI) after ferucarbotran nanoparticle transfection of T cells. T cell biodistribution was also assessed in vivo using MPI. RESULTS Following T cell intravenous injection, the spleen, liver, and lungs accounted for more than 90% of transferred T cells; the proportion of DsRed T cells in the brains was found to be very low, hovering below 1%. In contrast, most ACT T cells persisted in the tumor-bearing brains following intraventricular injections. ACT T cells mostly concentrated at the periphery of tumor masses and in proximity to blood vessels. CONCLUSIONS The success of ACT immunotherapy for brain tumors requires optimization of delivery route, dosing regimen, and enhancement of tumor-specific lymphocyte trafficking and effector functions to achieve maximal penetration and persistence at sites of invasive tumor growth.

scholarly journals 762 A combination of functional biomarkers improves identification of the tumor-specific reactive T cell repertoire

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A810-A810
Author(s):  
Arianna Draghi ◽  
Katja Harbst ◽  
Inge Svane ◽  
Marco Donia
Keyword(s):  
T Cells ◽  
T Cell ◽  
De Novo ◽  
Autologous Tumor ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Simple Method ◽  
Functional Biomarkers

BackgroundDetecting the entire repertoire of tumor-specific reactive T cells is essential for investigating the broad range of T cell functions in the tumor-microenvironment. At present, assays identifying tumor-specific functional activation measure either upregulation of specific surface molecules, de novo production of the most common antitumor cytokines or mobilization of cytotoxic granules.MethodsIn this study, we combined transcriptomic analyses of tumor-specific reactive tumorinfiltrating lymphocytes (TILs), TIL-autologous tumor cell co-cultures and commonly used established detection protocols to develop an intracellular flow cytometry staining method encompassing simultaneous detection of intracellular CD137, de novo production of TNF and IFNy and extracellular mobilization of CD107a.ResultsThis approach enabled the identification of a larger fraction of tumor-specific reactive T cells in vitro compared to standard methods, revealing the existence of multiple distinct functional clusters of tumor-specific reactive TILs. Publicly available datasets of fresh tumor single-cell RNA-sequencing from four cancer types were investigated to confirm that these functional biomarkers identified distinct functional clusters forming the entire repertoire of tumor-specific reactive T cells in situ.ConclusionsIn conclusion, we describe a simple method using a combination of functional biomarkers that improves identification of the tumor-specific reactive T cell repertoire in vitro and in situ.

scholarly journals Dual dependence on BCL2 and MCL1 in T-cell prolymphocytic leukemia

2020 ◽  
Vol 4 (3) ◽  
pp. 525-529 ◽  
Author(s):  
Victoria M. Smith ◽  
Oliver Lomas ◽  
Donna Constantine ◽  
Lianne Palmer ◽  
Anna H. Schuh ◽  
...  
Keyword(s):  
T Cell ◽  
Prolymphocytic Leukemia ◽  
Key Points ◽  
Clinical Responses

Key Points Treatment of relapsed refractory T-PLL with venetoclax monotherapy results in only transient and minor clinical responses. In vitro analyses pre- and postvenetoclax indicate dual dependence on BCL2 and MCL1; combined BCL2 and MCL1 inhibition are synergistic.

In Vitro Expansion of Antigen-Specific Cytotoxic T Lymphocytes by HLA-A*0201 Transfected K562 for Monitoring of T-cell Responses

2005 ◽  
Vol 28 (6) ◽  
pp. 635
Author(s):  
Jianda Yuan ◽  
Humilidad F Gallardo ◽  
Teresa Rasalan ◽  
Rajaram Ranganathan ◽  
Jian Wang ◽  
...  
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
T Cell Responses ◽  
Cell Responses ◽  
In Vitro Expansion
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