Third Party Donor Derived EBV Specific T Cells for the Treatment of Refractory EBV-Related Malignancies in Immunodeficient Recipients

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 577-577
Author(s):  
Susan E. Prockop ◽  
Ekaterina Doubrovina ◽  
Juliet N Barker ◽  
Karim Baroudy ◽  
Farid Boulad ◽  
...  
Keyword(s):  
T Cells ◽  
Organ Transplant ◽  
Organ Donor ◽  
Primary Immunodeficiency Disease ◽  
Solid Organ Transplant ◽  
Third Party ◽  
Solid Organ ◽  
Hla Alleles ◽  
Immunodeficiency Disease

Abstract Abstract 577 Adoptive immunotherapy is an effective strategy for the treatment of EBV+ lymphoproliferative diseases (EBV-LPD) arising after an allogeneic hematopoietic stem cell (HSCT) or solid organ transplant (SOT). This approach is, however, often limited by an inability to generate donor derived in vitro expanded EBV-specific cytotoxic T-lymphocyte (EBV-CTL) lines in a timely manner and/or the fact that EBV CTL lines derived from HLA non-identical donors may be restricted by non-shared HLA alleles. To date, we have treated 25 consecutive patients with an EBV LPD (N=20) or EBV Leiomyosarcoma (LMS) (N=5) with in vitro expanded EBV-CTLs derived from a donor other than the patient or their transplant (HSCT or SOT) donor. EBV CTLS were selected from a bank of 345 lines generated under GMP conditions from normal HSCT donors. Each donor was specifically consented for use of their T cells in patients other than their designated transplant recipient. Patients were recipients of unmodified (n=4), T cell depleted (n=5) or unrelated cord blood (n=5) HSCT, a solid organ transplant (n=6), a combined SOT and HSCT (n=1), or were non-transplanted patients with a primary immunodeficiency disease (n=4). EBV disease in transplanted patients was of host origin in 5 of 10 evaluable HSCT recipients, in 3 of 4 evaluable solid organ recipients, and in the one patient who underwent a combined HSCT/solid organ transplant. Third party EBV-CTLs were selected on the basis of HLA matching at a minimum of 2/8 recipient alleles. Where possible EBV-CTLs were selected that were restricted through HLA alleles present on the EBV+ tumor. HLA restriction was evaluated in vitro in 20 EBV-CTL donor lines. The restriction was at a single HLA allele (n=12), at two alleles (n=6) and at >than two alleles (n=2). Patients received infusions of 3rd party EBV-CTLs after failing a median of 2 prior therapies including rituximab in all but one case of EBV LPD. Four patients failed prior infusions with EBV-CTLs which were autologous (n=1), derived from their original HSCT (n=2) or from their solid organ donor (n=1). In two patients who progressed after treatment with EBV CTLs generated from their HSCT or organ donor, it was demonstrated that the donor derived EBV CTLs were restricted by a non-shared HLA allele. Patients received a median of 5 infusions most at 1×106 EBV-CTL/kg/infusion. Four patients received EBV-CTLs from >1 3rd party donor. Nine patients achieved a completed response. Nine patients died of progressive disease, 6 shortly after the first infusion (17–29 days). Two patients with LMS achieved long term stable disease (46 and 8 months); 5 achieved partial remissions which have been sustained in 4 (11- 68 months), and 1 patient progressed after 10 months in a partial remission. Response to EBV CTL therapy did not correlate with the degree of HLA matching between donor and recipient or donor and tumor. Radiographic and clinical responses correlated with detectable increases in the frequency of CTL precursors in the blood. However durable EBV CTL engraftment was not seen. One patient developed mild skin GvHD after infusion with 3rd party EBV-CTLs, but tolerated subsequent infusion of EBV-CTLs from an alternate 3rd party donor. Although no SOT recipient developed anti-HLA antibodies, one developed and episode of steroid responsive renal transplant rejection more than 6 months after infusion of EBV CTLs without evidence of donor (by STR analysis) in biopsied tissue. This study demonstrates a high response rate among patients with otherwise refractory EBV malignancy treated with EBV specific 3rd party CTLs restricted by HLA alleles shared by the tumor. Treatment failures correlated with the use of EBV CTLs restricted by HLA alleles not shared by the tumor. In addition two patients with a primary immunodeficiency disease who were unable to mount an endogenous EBV T cell response had transient but not durable responses to 3rd party cells. EBV CTLs can be effective when selected based on restriction to shared alleles despite significant HLA disparity. The bank of EBV specific T cells can provide an immediate source of HLA partially matched appropriately restricted T cells for adoptive immunotherapy to treat EBV associated malignancy. This enables treatment early in the course of disease and the use of EBV-CTL lines previously prepared and characterized in terms of HLA restriction. This is anticipated to maximize the response rate. Disclosures: No relevant conflicts of interest to declare.

Cell-Mediated Immune Responses After Influenza Vaccination of Solid Organ Transplant Recipients: Secondary Outcomes Analyses of a Randomized Controlled Trial

2019 ◽  
Vol 221 (1) ◽  
pp. 53-62 ◽  
Author(s):  
Arnaud G L’huillier ◽  
Victor H Ferreira ◽  
Cedric Hirzel ◽  
Yoichiro Natori ◽  
Jaclyn Slomovic ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Influenza A ◽  
Organ Transplant ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Solid Organ Transplant ◽  
Solid Organ ◽  
Cell Responses ◽  
Influenza A H1n1

Abstract Background Despite annual immunization, solid organ transplant (SOT) patients remain at increased risk for severe influenza infection because of suboptimal vaccine immunogenicity. We aimed to compare the CD4+ and CD8+ T-cell responses of the high-dose (HD) and the standard-dose (SD) trivalent inactivated vaccine. Methods We collected peripheral blood mononuclear cells pre- and postimmunization from 60 patients enrolled in a randomized trial of HD versus SD vaccine (30 HD; 30 SD) during the 2016–2017 influenza season. Results The HD vaccine elicited significantly greater monofunctional and polyfunctional CD4+ and CD8+ T-cell responses against influenza A/H1N1, A/H3N2, and B. For example, median vaccine-elicited influenza-specific polyfunctional CD4+ T cells were higher in recipients of the HD than SD vaccine after stimulation with influenza A/H1N1 (1193 vs 0 per 106 CD4+ T cells; P = .003), A/H3N2 (1154 vs 51; P = .008), and B (1102 vs 0; P = .001). Likewise, vaccine-elicited influenza-specific polyfunctional CD8+ T cells were higher in recipients of the HD than SD vaccine after stimulation with influenza B (367 vs 0; P = .002). Conclusions Our study provides novel evidence that HD vaccine elicits greater cellular responses compared with the SD vaccine in SOT recipients, which provides support to preferentially consider use of HD vaccination in the SOT setting.

Repertoire, memory subsets, and function of EBV-specific CD8+T cells in peripheral blood from stable solid organ transplant patients

2003 ◽  
Vol 64 (10) ◽  
pp. S41
Author(s):  
Camila Macedo ◽  
Iulia Popescu ◽  
Alison Logar ◽  
Kareem Abu-Elmagd ◽  
Ron Shapiro ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Organ Transplant ◽  
Solid Organ Transplant ◽  
Solid Organ ◽  
Transplant Patients ◽  
And Function

Adoptively Transferred CMV-Specific T-Cells Responsive to Immunodominant CMVpp65 Epitopes Extend Durable in-Vivo Suppression of Clonogenic CMVpp65 [+] Human Colon Carcinoma Cells in Comparison to T-Cells Responsive to Subdominant Epitopes

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4298-4298
Author(s):  
Aisha N Hasan ◽  
Annamalai Selvakumar ◽  
Tzu-Yun Kuo ◽  
Richard J O'Reilly
Keyword(s):  
T Cells ◽  
Colon Carcinoma ◽  
Human Colon ◽  
Carcinoma Cells ◽  
Third Party ◽  
Hla Alleles ◽  
Colon Carcinoma Cells ◽  
Human Colon Carcinoma

Abstract Adoptively transferred transplant donor or third party donor derived CMV-specific T-cells (CMV-CTLs) can effectively prevent and treat CMV disease in HSCT recipients. T-cells (TC) respond to specific viral epitopes when presented by HLA class-I and class-II alleles on infected cells. We have infused third party CTLs from HLA partially matched donors that were chosen based on in-vitro CTL activity against epitopes presented by HLA alleles shared by the recipient, and this approach has afforded a 60% response rate among patients treated for CMV viremia and/or disease. A recurring feature of TC generated in-vitro or directly selected in-vivo is the striking preponderance of TC specific for 1-2 immunodominant epitopes presented by specific HLA alleles. However, the functional activity of such immunodominant CMV-CTLs as compared to CTLs directed against subdominant CMV epitopes has not been evaluated. To directly compare the activity of CMV-CTLs directed against immunodominant and subdominant epitopes, we developed an in-vivo model using human colon carcinoma cells transduced with CMVpp65 as a surrogate system. Human colon carcinoma cells co-expressing HLA A0201 and A2402 (cocapp65), and a melanoma cell line lacking expression of these HLA alleles (melpp65) were each transduced to also express CMVpp65 and a GFP-firefly luciferase transgene. Subcutaneous (s.c.) inoculation of 1 x 105 tumor cellsinto NOD/Scid-IL2Rgc-KO/J mice (NSG) provided consistent engraftment. CMV-CTLs responsive to either the immunodominant NLV epitope presented by HLA A0201 (A2-NLV) or the subdominant QYD epitope presented by HLA A2402 (A24-QYD) were generated from 2 donors, each co-inheriting HLA A0201 and A2402, using NIH 3T3 artificial antigen presenting cells, each expressing a single HLA class-I allele (A0201 or A2402), B7.1, LFA-3 and ICAM1. Groups of 5-6 NSG mice, each bearing 2 established tumors: cocapp65 and melpp65 (control), were intravenously injected with 2-4 x 106 of tetramer+ A2-NLV or A24-QYD specific CMV-CTLs per mouse. Control animals either did not receive any TC, or received HLA B0801- LTM specific CMV-CTLs, and IL-2 was given 2 x/week to all groups. Tumor growth was monitored for 6-8 weeks by bioluminescent imaging. Both A2-NLV and A24-QYD CMV-CTLs significantly suppressed growth of cocapp65 tumors in all treated animals with infusion of equivalent doses of epitope specific tet [+] T-cells (p = ns). No tumor suppression was observed in control animals, and there was no evidence of GvHD in CTL treated animals. A2-NLV CTLs eradicated cocapp65 tumor in 4/10 treated animals, while A24-QYD CTLs did not completely eradicate the tumor in any treated animal. In all A2-NLV treated animals, the cocapp65 remained suppressed until end of study (6 wks), while the melpp65 continued to grow. Treatment with A24-QYD CTLs induced tumor suppression after a time lag, as evidenced by initial cocapp65 growth for 10-14 days followed by suppression for 4-5 weeks and then stabilization of tumor size. In subsequent studies with animals bearing single cocapp65 xenografts, and infused with either A2-NLV or A24-QYD CTLs, the tumors remained suppressed for upto 8 weeks after A2-NLV CTL infusion, while recurrent tumor growth was observed 5 weeks after A24-QYD CTL infusion. Studies detailing the relative accumulation of CTLs within tumor tissue, as well as engraftment of CTLs in these animals are in progress. Phenotypic analysis of the infused epitope specific TC demonstrated 91-95% TEM with 5-9% TCM, with a highly restricted oligoclonal TCRVβ repertoire. This model provides a platform for direct comparative evaluation of the in-vivo cytotoxic activity of epitope specific TC. These studies demonstrate that CMV-CTLs responsive to both immunodominant as well as subdominant epitopes, that are generated using AAPC from the same donor co-inheriting the presenting HLA alleles, can suppress the growth of clonogenic human carcinoma cells co-expressing an immunogenic viral antigen in-vivo at equivalent doses of antigen specific TC. However, less robust antigen specific cytotoxic activity was demonstrated by the subdominant A24-QYD CMV CTLs, which maybe reflective of reduced in-vivo proliferation, effector function or persistence of such TC. Experiments of define these variables contributing to disparities in the in-vivo CTL activity are in progress. Disclosures Hasan: Atara Biotherapeutics: Research Funding. O'Reilly:Atara Biotherapeutics: Research Funding.

scholarly journals Age-Dependent Association between Low Frequency of CD27/CD28 Expression on pp65 CD8+ T Cells and Cytomegalovirus Replication after Transplantation

2009 ◽  
Vol 16 (10) ◽  
pp. 1429-1438 ◽  
Author(s):  
Sara Cantisán ◽  
Julián Torre-Cisneros ◽  
Rosario Lara ◽  
Alberto Rodríguez-Benot ◽  
Francisco Santos ◽  
...  
Keyword(s):  
T Cells ◽  
Organ Transplant ◽  
Low Frequency ◽  
Solid Organ Transplant ◽  
Solid Organ ◽  
Transplant Recipients ◽  
Cross Sectional ◽  
Organ Transplant Recipients ◽  
Hcmv Replication ◽  
Solid Organ Transplant Recipients

ABSTRACT In this cross-sectional study of 42 solid organ transplant recipients, the association of human cytomegalovirus (HCMV) replication and age with the phenotype of the HCMV-specific CD8+ T cells was analyzed by using the CMV pp65 HLA-A*0201 pentamer. A correlation between the proportion of CD28− HCMV-specific CD8+ T cells and age was observed in patients without HCMV replication (r = 0.50; P = 0.02) but not in patients with HCMV replication (r = −0.05; P = 0.83), a finding which differs from that observed for total CD8+ T cells. Within the group of patients younger than 50 years of age, patients with HCVM replication after transplantation had higher percentages of CD28− HCMV-specific CD8+ T cells (85.6 compared with 58.7% for patients without HCMV replication; P = 0.004) and CD27− HCMV-specific CD8+ T cells (90.7 compared with 68.8% for patients without HCMV replication; P = 0.03). However, in patients older than age 50 years, a high frequency of these two subpopulations was observed in patients both with and without previous HCMV replication (for CD28− HCMV-specific CD8+ T cells, 84.4 and 80.9%, respectively [P = 0.39]; for CD27− HCMV-specific CD8+ T cells 86.6 and 81.5%, respectively [P = 0.16]). In conclusion, the present study shows that in the group of recipients younger than age 50 years, HCMV replication after transplantation is associated with a high percentage of CD27− and CD28− HCMV-specific CD8+ T cells. These results suggest that the increased percentage of CD27− or CD28− HCMV-specific subsets can be considered a biomarker of HCMV replication in solid organ transplant recipients younger than age 50 years but not in older patients. Further studies are necessary to define the significance of these changes in HCMV-associated clinical complications posttransplantation.

scholarly journals HUMORAL AND CELLULAR IMMUNOGENICITY and SAFETY UP TO 4 MONTHS AFTER VACCINATION WITH BNT162B2 mRNA COVID-19 VACCINE IN HEART AND LUNG TRANSPLANTED YOUNG ADULTS

2021 ◽  
Author(s):  
Nicola Cotugno ◽  
Chiara Pighi ◽  
Elena Morrocchi ◽  
Alessandra Ruggiero ◽  
Donato Amodio ◽  
...  
Keyword(s):  
T Cells ◽  
Young Adults ◽  
Cd4 T Cells ◽  
Organ Transplant ◽  
Solid Organ ◽  
Close Monitoring ◽  
Transplant Recipients ◽  
Short Term ◽  
Solid Organ Transplant Recipients

Background: Immunizations among vulnerable population, including solid organ transplant recipients (SOT), present suboptimal responses at vaccination and over time. We investigated safety and immunogenicity of the BNT162B2 mRNA COVID-19 vaccine in 34 SOT young adults as compared to 36 healthy controls (HC). Methods: immunogenicity was measured through the analysis of anti SARS-CoV2 IgG Antibodies and antigen specific CD4 T cells (CD40L+), detected by flow cytometry before vaccination, 21 days after priming (T21), 7 days after booster dose (T28) and 2-4 months after priming (T120). Baseline T and B cell immune phenotype was deeply investigated. The safety profile was investigated by close monitoring and self-reported diary. Results: Anti-S and anti-Trimeric Ab responses were significantly lower in SOT vs HC at T21 (p<0.0001) and at T28 (p<0.0001). Ten out of 34 SOT (29%) at T28 and 3 out of 33 (9%) at T120 had undetectable SARS-CoV-2 IgG. The analysis of SARS-CoV-2 specific CD4 T cells showed lower CD40L expression after in vitro stimulation in SOT compared to HC. Lower frequencies of memory B cells were found in patients not responding to vaccination. Lack of seroconversion was higher in patients treated with mycophenolate (p=0.0005). The vaccination was safe and well tolerated. Only short-term adverse events, were reported and no hospitalization or graft rejection were observed after vaccinations. Conclusions: These data show that SOT have a suboptimal immune response following mRNA vaccinations as compared to HC. Alternative strategies should be investigated to improve the immunization against SARS-CoV-2 in these patients.

scholarly journals Cellular immunity predominates over humoral immunity after the first dose of COVID-19 vaccines in solid organ transplant recipients

2021 ◽  
Author(s):  
Tina Schmidt ◽  
Verena Klemis ◽  
David Schub ◽  
Sophie Schneitler ◽  
Matthias Christian Reichert ◽  
...  
Keyword(s):  
T Cells ◽  
Humoral Immunity ◽  
Cellular Immunity ◽  
Cd8 T Cells ◽  
Organ Transplant ◽  
Solid Organ Transplant ◽  
Solid Organ ◽  
Transplant Recipients ◽  
Specific Antibodies ◽  
Solid Organ Transplant Recipients

Knowledge on the vaccine-induced cellular and humoral immunity and on immunogenicity of vector-based and mRNA vaccines in solid organ transplant recipients is limited. Therefore, SARS-CoV-2 specific T-cells and antibodies were analyzed in 40 transplant recipients and 70 age-matched controls after the first dose of vector-based or mRNA vaccines. Plasmablasts and SARS-CoV-2 specific CD4 and CD8 T-cells were quantified using flow-cytometry. Specific antibodies were analyzed by ELISA and neutralization assay. SARS-CoV-2 specific antibodies and T-cells were induced in both groups with significantly lower levels in patients. While antibodies were detected in 80% of controls and 5.3% of patients, specific CD4 and/or CD8 T-cells were more frequently found in both controls (84.3%) and patients (23.7%). The two vaccine types showed notable differences, as IgG and neutralizing activity were more pronounced after mRNA vaccination (p<0.0001 each), whereas CD4 and CD8 T-cell levels were higher after vector vaccination (p=0.009; p<0.0001). Plasmablast numbers were significantly higher in controls and correlated with SARS-CoV-2 specific IgG- and CD4 T-cell levels. In conclusion, assessment of antibodies is not sufficient to identify COVID-19-vaccine responders. Together with differences in immunogenicity among vaccines, this necessitates combined analysis of humoral and cellular immunity to reliably assess responders among immunocompetent and immunocompromised individuals.

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