The Past and the Future of VSTs

2021 ◽  
Author(s):  
Yingying Wang ◽  
Mélanie Gauthier ◽  
Caroline Laroye ◽  
Véronique Decot ◽  
Danièle Bensoussan
Keyword(s):  
Immune Reconstitution ◽  
Viral Infections ◽  
Wide Distribution ◽  
Third Party ◽  
Close System ◽  
Hematopoietic Stem ◽  
Promising Alternative ◽  
Automated Generation ◽  
Immunomagnetic Isolation ◽  
Promising Perspective

Viral infections are major complications of Hematopoietic Stem Cell Transplantation (HSCT). As efficacy of anti-viral drugs is limited in absence of immune reconstitution and often associated with severe side effects, infusion of Virus-Specific T cells (VSTs) becomes a promising alternative treatment for viral infections and diseases after HSCT. A lot of improvement in VST generation has been made since 1992, date of first attempts. Regarding stimulation antigen, pools of peptides from viral immunodominant proteins become the best choice compared to whole proteins or other types of antigens. In respect with generation methods, a huge improvement has been done both with cell culture thanks to faster protocols of expansion and with immunomagnetic isolation thanks to fully automated generation of VSTs with a close system. This latest kind of VST generation is fast (within 24 hours), compliant with GMP guidelines and allows a wide distribution among cell therapy laboratories. Furthermore, cell source is no longer limited to the HSCT donor. Third-party donors either related or unrelated are also sought. A promising perspective could be the generation of CART based on VSTs aiming both at targeting the malignant cells and controlling the viral infections simultaneously.

Higher Prevalence But Similar Infectious Profile Overtime After Haploidentical Transplantation Compared With HLA-Identical Transplantation For Hematological Diseases

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4528-4528
Author(s):  
Roberto Crocchiolo ◽  
Luca Castagna ◽  
Andrea Vai ◽  
Barbara Sarina ◽  
Stefania Bramanti ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Immune Reconstitution ◽  
Viral Infections ◽  
Conflicts Of Interest ◽  
Fungal Infections ◽  
Infectious Complications ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Haplo Group

Introduction a major limitation of hematopoietic stem cell transplantation (HSCT) from haploidentical donor is the impaired immune reconstitution due to extensive immunosuppression necessary to overcome HLA disparity. Recently, a platform for T-cell repleted HSCT from haploidentical donor (haplo-HSCT) using post-transplant cyclophosphamide (CTX) has been reported, with low TRM and high reproducibility. However, little has been reported so far about immune reconstitution and, in particular, incidence of infections after this type of transplantation. Aims of the study to describe infectious complications after T-cell replete haplo-HSCT after NMA conditioning performed at our center and to compare them with HLA-identical transplantations performed at the same center. Patients and Methods data on patients with hematological malignancies who underwent haplo-HSCT were collected and compared with RIC/NMA-HSCT from HLA-identical donors. Transplants included were those performed up to 31st December 2012. Infections were classified as FUO, bacterial, micotic or viral and prevalence over five post-transplant intervals was estimated: days 0-30, 31-100, 101-180, 181-365, >365. Prevalence for each time period was defined as the number of infectious events/patients at risk. Results we identified a total of 72 and 40 patients transplanted from HLA-identical or haploidentical donor respectively. Median follow-up was longer in HLA-identical vs. haploidentical (34 vs. 15 months, p<0.0001). Among 38 out of 40 haplo-HSCT patients, a total of 96 infectious events occurred, with a median of 3 events/patient (range: 0-6). Etiologies were as follows: 39 bacterial, 6 fungal and 51 viral. Bacterial infections occurred mostly between day 0 and +30, whereas viral infections/reactivations between +30 and +100 (see Figure 1a). In the HLA-identical cohort, 166 events occurred among 64 out of 72 patients, with a median of 2 events/patient (range: 0-8); etiologies were: 84 bacterial, 9 fungal and 73 viral. FUO events were 19 and 34 among haplo- and HLA-identical transplants respectively. Prevalence of infections was lower in HLA-identical compared with haplo-HSCT group, but subdistribution of etiologies was similar overtime (see Figure 1b), with bacterial and FUO mostly before day+30 and viral events mostly between +30 and +100. Importantly, no fungal infections occurred beyond day +180 in haplo group, probably due to the low incidence of chronic GVH. Conversely, higher prevalence of bacterial events observed in HLA-identical group may be due to chronic GVH. Deaths due infection were 25% in haplo group (10/40, occuring between +13 and +152) and 11% (8/75) among HLA-identical transplants. Conclusion RIC haplo-SCT with post-transplant CTX shows a slightly higher rate of infectious complications compared with HLA-identical ones. Subdistribution of etiologies is similar, with the highest prevalence of viral infections between +30 and +100 and no fungal events after +180. Thus, in haplo-SCT, immunological recovery appears to be satisfactory after +180. Future comparisons with other alternative stem cell sources (i.e. cord blood) are warranted. Disclosures: No relevant conflicts of interest to declare.

scholarly journals ATIR101 administered after T-cell-depleted haploidentical HSCT reduces NRM and improves overall survival in acute leukemia

Leukemia ◽  
2020 ◽  
Vol 34 (7) ◽  
pp. 1907-1923 ◽  
Author(s):  
Denis Claude Roy ◽  
Irwin Walker ◽  
Johan Maertens ◽  
Philippe Lewalle ◽  
Eduardo Olavarria ◽  
...  
Keyword(s):  
T Cell ◽  
Acute Leukemia ◽  
Viral Infections ◽  
Donor Cell ◽  
Third Party ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Observational Cohort ◽  
Severe Infections ◽  
One Year

Abstract Overcoming graft-versus-host disease (GvHD) without increasing relapse and severe infections is a major challenge after allogeneic hematopoietic stem-cell transplantation (HSCT). ATIR101 is a haploidentical, naïve cell-enriched T-cell product, depleted of recipient-alloreactive T cells to minimize the risk of GvHD and provide graft-versus-infection and -leukemia activity. Safety and efficacy of ATIR101 administered after T-cell-depleted haploidentical HSCT (TCD-haplo + ATIR101) without posttransplant immunosuppressors were evaluated in a Phase 2, multicenter study of 23 patients with acute leukemia and compared with an observational cohort undergoing TCD-haplo alone (n = 35), matched unrelated donor (MUD; n = 64), mismatched unrelated donor (MMUD; n = 37), and umbilical cord blood (UCB; n = 22) HSCT. The primary endpoint, 6-month non-relapse mortality (NRM), was 13% with TCD-haplo + ATIR101. One year post HSCT, TCD-haplo + ATIR101 resulted in lower NRM versus TCD-haplo alone (P = 0.008). GvHD-free, relapse-free survival (GRFS) was higher with TCD-haplo + ATIR101 versus MMUD and UCB (both P < 0.03; 1-year rates: 56.5%, 27.0%, and 22.7%, respectively) and was not statistically different from MUD (1 year: 40.6%). ATIR101 grafts with high third-party reactivity were associated with fewer clinically relevant viral infections. Results suggest that haploidentical, selective donor-cell depletion may eliminate requirements for posttransplant immunosuppressors without increasing GvHD risk, with similar GRFS to MUD. Following these results, a randomized Phase 3 trial versus posttransplant cyclophosphamide had been initiated.

scholarly journals Immune reconstitution after cord blood transplants supported by coinfusion of mobilized hematopoietic stem cells from a third party donor

2009 ◽  
Vol 44 (4) ◽  
pp. 213-225 ◽  
Author(s):  
T Martín-Donaire ◽  
M Rico ◽  
G Bautista ◽  
R Gonzalo-Daganzo ◽  
C Regidor ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Cord Blood ◽  
Immune Reconstitution ◽  
Third Party ◽  
Hematopoietic Stem

scholarly journals T cells for viral infections after allogeneic hematopoietic stem cell transplant

Blood ◽  
2016 ◽  
Vol 127 (26) ◽  
pp. 3331-3340 ◽  
Author(s):  
Catherine M. Bollard ◽  
Helen E. Heslop
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Adoptive Transfer ◽  
Viral Infections ◽  
Third Party ◽  
Direct Selection ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Specific Immunity

Abstract Despite recent advances in the field of allogeneic hematopoietic stem cell transplantation (HSCT), viral infections are still a major complication during the period of immune suppression that follows the procedure. Adoptive transfer of donor-derived virus-specific cytotoxic T cells (VSTs) is a strategy to rapidly restore virus-specific immunity to prevent or treat viral diseases after HSCT. Early proof of principle studies demonstrated that the administration of donor-derived T cells specific for cytomegalovirus or Epstein-Barr virus (EBV) could effectively restore virus-specific immunity and control viral infections. Subsequent studies using different expansion or direct selection techniques have shown that donor-derived VSTs confer protection in vivo after adoptive transfer in 70% to 90% of recipients. Because a major cause of failure is lack of immunity to the infecting virus in a naïve donor, more recent studies have infused closely matched third-party VSTs and reported response rates of 60% to 70%. Current efforts have focused on broadening the applicability of this approach by: (1) extending the number of viral antigens being targeted, (2) simplifying manufacture, (3) exploring strategies for recipients of virus-naïve donor grafts, and (4) developing and optimizing “off the shelf” approaches.

Cytotoxic T Lymphocytes (CTL) Specific for Adenovirus and CMV Can Be Generated from Umbilical Cord Blood for Adoptive Immunotherapy

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3505-3505
Author(s):  
Catherine M. Bollard ◽  
Patrick Hanley ◽  
Conrad Russell Cruz ◽  
Ann M. Leen ◽  
Jeffrey J. Molldrem ◽  
...  
Keyword(s):  
T Cells ◽  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Adoptive Immunotherapy ◽  
Immune Reconstitution ◽  
Mononuclear Cells ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Promising Alternative

Abstract Umbilical cord blood (UCB) transplantation is a promising alternative source of hematopoietic stem cells for patients lacking HLA-matched donors. Nearly 60% of UCB transplants to date have been performed on minority individuals for whom an unrelated donor was not available; moreover, the naïve phenotype of UCB cells may be responsible for the lower incidence and reduced severity of GvHD in these patients. The relatively low cell numbers and naïvety of T lymphocyte populations in UCB grafts has, however, lead to delayed immune reconstitution and higher mortality due to infection. Reactivations of latent viruses such as cytomegalovirus (CMV) are particularly problematic, as is overt infection from adenovirus (Adv). Previous studies have shown that prophylactic adoptive immunotherapy with peripheral blood-derived CTL directed against CMV and Adv can effectively prevent the clinical manifestations of these viruses after hematopoietic stem cell transplant raising the possibility that a similar approach could be developed after UCB transplant. We hypothesized that virus-specific CTL could be generated from UCB for clinical use to restore anti-viral immunity and reduce viral infection post UCB transplant. Bi-virus specific CTL were generated from frozen UCB mononuclear cells using a clinical-grade recombinant adenovirus type5 vector pseudotyped with a type35 fiber carrying a transgene for CMVpp65 as a source of Adv and CMV antigens. UCB-derived dendritic cells were transduced with this Ad5f35pp65 vector as the initial source of antigen presenting cells to stimulate virus-specific CTL in the presence of IL-7, IL-12 and IL-15. This was followed by 2 rounds of weekly stimulation with autologous UCB-derived EBV-lymphoblastoid cell lines (LCL) transduced with the same vector in the presence of IL-15 and IL-2. UCB from donors of varied HLA types were selected. 40×106 UCB mononuclear cells (available in the 20% fraction of frozen UCB units) were thawed and used in the manufacturing process. After 3 rounds of stimulation, 9 CTL cultures contained a mean of 83% (range 64–94%) CD8+ve T-cells and 27% (range 12–40%) CD4+ve T-cells. Flow cytometric analysis of memory markers after 3 weeks expansion revealed a predominance of CD45RA− CD62L− T-cells (69±18%; range 25–93%) with a smaller population of CD45RA− CD62L+ T-cells (10±5%; range 1–23%). Evaluable UCB CTL lines showed specific cytolytic activity in 51Cr release assays against targets loaded with CMV and Adv antigens. The observed cytotoxicity was specific because unloaded targets and MHC-mismatched targets were not killed. IFNγ ELISPOT assays on CTL lines demonstrated a mean of 209 (range 45–694) and 74 (range 0–188) spot forming cells/1×105 T-cells following incubation with CMV-pp65 and Adv-hexon/penton peptides respectively. No significant response to CMV-IE1 peptides was demonstrated. The expanded UCB CTL had a broad Vβ repertoire and were specific for multiple viral epitopes. In addition, the virus-specific T cells were shown to be expanded only from T-cells with a naïve phenotype (CD45RA+/CCR7+). These results demonstrate that, despite the generally naïve nature of UCB lymphocytes, bi-virus-specific responses can be expanded in vitro and could potentially be used clinically in UCBT patients who develop infectious complications prior to immune reconstitution.

Immune reconstitution is preserved in hematopoietic stem cell transplantation coadministered with regulatory T cells for GVHD prevention

Blood ◽  
2011 ◽  
Vol 117 (10) ◽  
pp. 2975-2983 ◽  
Author(s):  
Aline Gaidot ◽  
Dan Avi Landau ◽  
Gaëlle Hélène Martin ◽  
Olivia Bonduelle ◽  
Yenkel Grinberg-Bleyer ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Regulatory T Cells ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Immune Reconstitution ◽  
Third Party ◽  
Hematopoietic Stem

Abstract Recipient-specific regulatory T cells (rsTreg) can prevent graft-versus-host disease (GVHD) by inhibiting donor T-cell expansion after hematopoietic stem cell transplantation (HSCT) in mice. Importantly, in adult humans, because of thymus involution, immune reconstitution during the first months after HSCT relies on the peripheral expansion of donor T cells initially present in the graft. Therefore, we developed a mouse model of HSCT that excludes thymic output to study the effect of rsTreg on immune reconstitution derived from postthymic mature T cells present within the graft. We showed that GVHD prevention with rsTreg was associated with improvement of the limited immune reconstitution compared with GVHD mice in terms of cell numbers, activation phenotype, and cytokine production. We further demonstrated a preserved in vivo immune function using vaccinia infection and third-party skin-graft rejection models, suggesting that rsTreg immunosuppression was relatively specific of GVHD. Finally, we showed that rsTreg extensively proliferated during the first 2 weeks and then declined. In turn, donor Treg proliferated from day 15 on. Taken together, these results suggest that rsTreg GVHD prevention is associated with improved early immune reconstitution in a model that more closely approximates the biology of allogeneic HSCT in human adults.

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