scholarly journals CLINICAL RESPONSES TO ODRONEXTAMAB (REGN1979): CORRELATION WITH LOSS OF CD20 EXPRESSION AS A POTENTIAL MECHANISM OF RESISTANCE AND BASELINE BIOMARKERS OF TUMOR T CELLS

2021 ◽  
Vol 39 (S2) ◽  
Author(s):  
J Brouwer‐Visser ◽  
N Fiaschi ◽  
R. P Deering ◽  
A Dhanik ◽  
K. J Cygan ◽  
...  
Keyword(s):  
T Cells ◽  
Potential Mechanism ◽  
Mechanism Of Resistance ◽  
Cd20 Expression ◽  
Clinical Responses

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.

In Vivo Validation Of Trogocytosis In Neuroblastoma – A Potential Mechanism Of Resistance To Anti-GD2 Immunotherapy

2021 ◽  
Author(s):  
Abigail K. Zamora ◽  
Michael J. Zobel ◽  
Jianping Sun ◽  
Michael Sheard ◽  
Robert Seeger ◽  
...  
Keyword(s):  
Potential Mechanism ◽  
Mechanism Of Resistance ◽  
In Vivo Validation

scholarly journals Intracellular expression of Tat alters mitochondrial functions in T cells: a potential mechanism to understand mitochondrial damage during HIV-1 replication

Retrovirology ◽  
2015 ◽  
Vol 12 (1) ◽  
Author(s):  
Sara Rodríguez-Mora ◽  
Elena Mateos ◽  
María Moran ◽  
Miguel Ángel Martín ◽  
Juan Antonio López ◽  
...  
Keyword(s):  
T Cells ◽  
Mitochondrial Damage ◽  
Potential Mechanism ◽  
Mitochondrial Functions ◽  
Intracellular Expression ◽  
Hiv 1

scholarly journals First-in-human phase 1 clinical study of the IL-15 superagonist complex ALT-803 to treat relapse after transplantation

Blood ◽  
2018 ◽  
Vol 131 (23) ◽  
pp. 2515-2527 ◽  
Author(s):  
Rizwan Romee ◽  
Sarah Cooley ◽  
Melissa M. Berrien-Elliott ◽  
Peter Westervelt ◽  
Michael R. Verneris ◽  
...  
Keyword(s):  
T Cells ◽  
Clinical Study ◽  
Cell Expansion ◽  
Phase 1 ◽  
Single Agent ◽  
Cd8 T Cell ◽  
Key Points ◽  
Clinical Responses ◽  
Human Use

Key Points Single-agent IL-15/IL-15Rα-Fc (ALT-803) therapy was well tolerated and resulted in clinical responses in patients who relapsed post-HCT. First-in-human use of ALT-803 promoted NK and CD8+ T-cell expansion and activation in vivo without stimulating regulatory T cells.

The Use of Autologous LMP2-Specific Cytotoxic T Lymphocytes (CTL) for the Treatment of Relapsed EBV-Positive Hodgkin Disease and Non-Hodgkin Lymphoma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 773-773
Author(s):  
Catherine M. Bollard ◽  
Elizabeth Buza ◽  
Helen Huls ◽  
Teresita Lopez ◽  
Stephen Gottschalk ◽  
...  
Keyword(s):  
T Cells ◽  
Partial Response ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Progressive Disease ◽  
Residual Tumor ◽  
Cell Transplant ◽  
Dose Escalation Study ◽  
Non Hodgkin Lymphoma ◽  
Clinical Responses

Abstract EBV-associated Hodgkin’s Disease (HD) and some non-Hodgkins lymphoma (NHL) show type II latency expressing the subdominant EBV antigens EBNA1, LMP1 and LMP2, which may serve as targets for immunotherapy approaches. In previous studies, we used polyclonal EBV-specific CTL in patients with relapsed EBV +ve HD and saw 2 complete and 1 partial response in 11 patients. Analyses of EBV-CTL lines showed that small populations of T cells reactive against the tumor-associated antigen LMP2 were present in the majority of the infused lines, with some expansion in the peripheral blood following infusion. We therefore hypothesized that CTL specifically targeting LMP2 might have greater efficacy in these patients. LMP2-CTL were generated from 14 patients using Dendritic Cells for initial stimulations then Lymphoblastoid Cell Lines (LCL) both of which had been genetically modified to overexpress LMP2 by transduction with an Ad5f35LMP2 vector. Polyclonal LMP2-CTL lines recognized 1–7 (median 2) LMP2 epitopes, as determined using pentamers and overlapping LMP2 peptide pools in ELISPOT assays. A mean of 22.8% (5–42.1%) of CD8+ T cells bound HLA-restricted LMP2 pentamers, compared to a mean of 0.11% (0.01–0.24%) of LMP2-pentamer positive CD8+ T cells found in CTL generated with genetically unmodified LCL from the same patients. So far, 11 patients have been treated on this dose escalation study - 6 patients have been treated on dose level (DL)1 (2 doses of CTL at 2x107/m2/dose given 2 wks apart in the outpatient clinic), 4 patients on DL2 (2x107/m2 and 1x108/m2) and 1 patient on DL3 (1x108/m2 and 2x108/m2). No immediate toxicity was observed. After CTL infusion, an increase in the frequency of EBV +/- LMP2-specific T cells could be detected in the blood in 8/10 evaluated patients (range 2–17.6 fold). Five of 6 patients who received LMP2-CTL as adjuvant therapy post stem cell transplant or chemotherapy remain in remission up to 22mths post LMP2-CTL. 1 patient presented with progressive disease 8 wks post CTL therapy. Five patients had detectable disease at the time of CTL therapy of whom 1 had progressive disease 8 wks post CTL and 4 had clinical responses (1 very good partial response and 3 clinical or radiologic complete responses). One of these 3 patients was evaluated 7 wks after receiving CTLs, which were predominantly CD4+ve (91.6%). Biopsies showed minimal residual NHL cells with increased CD4+ve T cells compared to pre-CTL biopsy specimens. Imaging studies performed 1 wk later were negative for NHL. This patient received 2 extra doses of CTL (given 8 wks apart) and re-evaluations showed CR on PET and CT scans. Two other patients had stable disease 8 wks post LMP2-CTL. Both patients received 2 further doses of LMP2-CTL. One patient is without evidence of disease 12 months post CTL. The other patient had a complete radiological response. This patient had a supraclavicular lymph node resection, which showed selective accumulation of LMP2-tetramer +ve T cells (0.3% compared to 0.01% in the peripheral blood) with few residual tumor cells. Immunotherapy with autologous LMP2-CTL is therefore well tolerated in patients with relapsed EBV+ve HD/NHL and infused LMP2-CTL cells can accumulate at tumor sites and induce clinical responses.

Development of an Effective Safety Switch for Selective Elimination of Human T Cells In Vivo after Adoptive Transfer.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5488-5488
Author(s):  
Tom van Meerten ◽  
Henk Rozemuller ◽  
Wendy J.M. Mackus ◽  
Paul W.H.I. Parren ◽  
Jan G.J. van de Winkel ◽  
...  
Keyword(s):  
T Cells ◽  
Adoptive Transfer ◽  
Regulatory Elements ◽  
Retroviral Vectors ◽  
Chimeric Antibody ◽  
Human T Cells ◽  
Cd20 Expression ◽  
Cd20 Antibody ◽  
Cd20 Antibodies

Abstract Adoptive transfer of T cells is frequently associated with unwanted side effects. In order to tackle these effects one could introduce a safety switch into the cells that permits their selective in vivo elimination. The human CD20 gene in combination with CD20 antibodies was recently proposed as a novel safety switch. In such a system, T cells may be genetically modified with a CD20-encoding vector prior to adoptive transfer. If necessary, CD20-transgenic cells can be eliminated in vivo through administration of CD20 antibodies, such as the chimeric antibody rituximab (RTX) that is currently used to treat CD20+ lymphoma. RTX activates the complement system and recruits immune effector cells, resulting in rapid death of CD20+ cells. Recently, a novel human CD20 antibody, Humab 7D8, was shown to have superior activity over RTX. In this study a set of CD20-encoding retroviral vectors was generated, which either lacked or contained one or both of two regulatory elements: the woodchuck posttranscriptional regulatory element (WPRE) to increase CD20 expression, and the chicken hypersensitivity site 4 insulator element (INS) to achieve a position independent expression of CD20 and to increase the safety profile of the vector by preventing activation of cellular (onco)genes by the retroviral enhancer. We found that the level of CD20 expression obtained with vectors containing INS was 2-fold lower than with vectors lacking INS. Additional inclusion of WPRE restored the level to that of the vector without INS. In addition, INS greatly enhanced the homogeneity of CD20 expression in T cells. Moreover, after 3 months in culture, all cells generated with CD20-INS had retained CD20 expression, while 60% of cells transduced with the control CD20 vector had lost CD20 expression. Complement dependent cell kill (CDC) of both RTX and HuMab 7D8 was dependent on the level of CD20 expression (p<0.01). However, while very low CD20-expressing cells were completely resistant against RTX they could be effectively killed by HuMab 7D8. For maximal kill of CD20-high cells, a 100-fold lower dose of HuMab 7D8 was required, compared to RTX. In vivo efficacy was studied through bioluminescent imaging of luciferase+ CD20-transgenic T cells. After transfer of CD20+ cells in immune deficient RAG2−/−gamma c−/− mice, both CD20 antibodies were capable of eliminating >99% of CD20+ cells, prolonging survival of mice from 20 till 42 days. In conclusion, we developed a safe vector that leads to homogeneous and stable expression of CD20 on human T cells. These cells can be killed effectively in vivo with HuMab 7D8, a recently developed CD20 antibody. This system will be applicable to other approaches that require inclusion of a safety switch in ex vivo modified cells.

Complete Tumor Responses in Lymphoma Patients Who Receive Autologous Cytotoxic T Lymphocytes Targeting EBV Latent Membrane Proteins

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 230-230
Author(s):  
Catherine M. Bollard ◽  
Maja Stanojevic ◽  
Ann M. Leen ◽  
Teresita Lopez ◽  
Andrea N. Sheehan ◽  
...  
Keyword(s):  
T Cells ◽  
Partial Response ◽  
Hodgkin’S Lymphoma ◽  
Flow Cytometric Analysis ◽  
Hodgkin's Lymphoma ◽  
Effector Cells ◽  
Non Hodgkin Lymphoma ◽  
Tumor Associated Antigen ◽  
Clinical Responses ◽  
Non Hodgkins Lymphoma

Abstract EBV-associated Hodgkin’s Lymphoma (HL) and some non-Hodgkins lymphoma (NHL) have type II viral latency expressing the subdominant EBV antigens EBNA1, LMP1 and LMP2. These antigens may serve as targets for immunotherapy approaches and in previous studies, we used polyclonal EBV-specific CTL in patients with relapsed EBV +ve HL obtaining 2 complete and 1 partial response in 11 patients. Analyses of EBV-CTL lines showed that small populations of T cells reactive against the tumor-associated antigen LMP2 were present in the majority of the infused lines, with some expansion in the peripheral blood following infusion. We therefore hypothesized that CTL enriched for effector cells specifically targeting LMP antigens would have greater efficacy in these patients. LMP-CTL were generated using dendritic cells for initial stimulations then EBV-transformed lymphoblastoid cell lines (LCL) both of which had been genetically modified to overexpress either LMP2 alone or inactive LMP1 (ΔLMP1) and LMP2 by transduction with an Ad5f35LMP2 (n=16) or Ad5f35ΔLMP1-I-LMP2 (n=14) vector respectively. All LMP-CTL lines were polyclonal comprising CD4+ (mean 17±18%; range 1–92%) and CD8+ (mean 74 ± 25%; range 1–99%) T-cells. Flow cytometric analysis of memory markers revealed mixed populations of CD45RA- CD62L- T-cells (45±15%; range 31–63%) and CD45RA- CD62L+ T-cells (34±5%; range 28–41%). The CTL lines had specificity for CD4+ and CD8+ restricted LMP2 epitopes alone (n=19; mean 1; range 0–7) or both LMP1 and LMP2 epitopes (n=13; mean 2; range 0–6) per CTL line, as determined using overlapping LMP1 and LMP2 peptide pools in ELISPOT assays. Twenty-four patients with EBV+ Hodgkin’s Lymphoma and non-Hodgkin Lymphoma have been treated on dose escalation studies. 16 with LMP2 CTLs and 8 with LMP1/2 CTLs. No immediate toxicity was observed. After CTL infusion, increased numbers of LMP-specific T cells were detected in the blood of 15/22 evaluable patients, (range 2 to 70 fold) persisting for up to 3 months. Additionally, two patients had lymph node biopsies 3–6 months post CTL, which showed selective accumulation of LMP2-multimer positive cells in lymph nodes. 12/13 high-risk and/or multiply relapsed patients who received LMP-CTL as adjuvant treatment after chemotherapy remain in remission for a median of 2years (range &gt;3months to &gt;5years) after CTL. 11 patients had detectable disease at the time of CTL, 2 of these had progressive disease by 8 weeks and 9 had clinical responses. The median duration of the clinical responses is 1 year with one stable disease (&gt;12months), one partial response (36 months) and 7 complete responses (range 9 months to &gt;4.5 years). One of the complete responders was biopsied 7 weeks after receiving CTL, which were predominantly CD4+ (92%). Increased CD4+ T cells were seen compared to pre-CTL biopsy specimens and imaging studies confirmed remission. In conclusion, immunotherapy with CTL targeting LMP antigens is well tolerated in patients with EBV+ lymphoma and infused LMP-CTL can accumulate at tumor sites and induce complete and sustained clinical responses.

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