Jurnal Internasional Menargetkan limfoma sel B EbV-positif dan T / NK
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Adoption of the transfer of EBV-specific cytotoxic T cells (EBV-CTLs) has proven to be very successful in the prevention and treatment of EBV-driven posttransplant lymphoproliferative disease ( PTLD) follows HSCT. 2 In immunocompromised patients, B cells that grow beyond usually express all 9 of the latent EBV protein, which is the target of T cell response antigens in healthy viruses. 3 This same latent protein is expressed in an in-vitro-modified EBV B-lymphoblastoid cell line (LCL) which is conventionally used to expand virus-specific T cells from the blood. 3 As a result, preparations for EBV-CTL stimulated by LCL have extensive EBV antigen specificity 4 and can restore virus-specific T-cell immunity, which leads to elimination of EBV-positive B cells proliferate. 2  In terms of rejecting the article, McLaughlin et al. Focused on the more challenging EBV-positive lymphoma that appears in immunocompetent individuals. These tumors are much more difficult to target with elevated T cell therapy because expression of viral proteins is limited to latent immunogenic proteins, including EBNA1, LMP1, and LMP2. 3 Specific T cells for these proteins are generally present at low frequencies in the blood and are only a small part of EBV-CTLs stimulated by LCL. 4 To address this problem, McLaughlin et al. Used an elegant approach involving LMP1 and LMP2 overexpression in dendritic cells and LCLs produced preparations of enriched T-cells in LMP-specific T cells (LMP-Ts). Importantly, the authors have previously shown that autologous LMP-Ts can be administered safely and can induce long-lasting responses in patients with recurrent / refractory EBV lymphoma. 5
McLaughlin et al. Now assess LMP-T infusion in allogeneic HSCT settings. Donor-derived LMP-Ts was given to 26 patients who had undergone allogeneic HSCT for EBV-positive B-cell or T / NK cell lymphoma or lymphoproliferative disorders. The prognosis of these patients is usually poor, especially for those with T / NK cell disease. 6 LMP-Ts was infused as either adjuvant therapy in patients with a high risk of relapse (n = 19) or as a treatment for active disease (n = 7). Importantly, allogeneic LMP-Ts is well tolerated, and only 1 dose-limiting toxicity occurs which is potentially due to T-cell infusion. The single incidence of de novo graft-versus-host disease is associated with subterapeutic immune suppression and is rapidly resolved.
overall, a 2-year overall survival (OS) is 68%. In line with data from the International Blood & Marrow Transplant Research Center, OS is better for patients with B cells (OS, 80%; n = 10) than T / NK-cells (OS, 60%; n = 16). However, a 2-year OS increase seen in both subsets of the disease compared with the historical cohort, where OS 2 years is 60% to 75% for lymphoma derived from B cells and 30% to 50% for T / NK cells 6 7 Furthermore, the OS was even higher in the subset of patients who received LMP-Ts as adjuvant therapy after allogeneic HSCT (OS, 78%; n = 19; see figure). These patients, who are at high risk for relapse, included 2 individuals with aggressive EBV-positive NK / T-T-cell lymphoma who remained disease-free for up to 3 years after LMP-T infusion. Overall, this study clearly demonstrates the safety and efficacy of LMP-T infusion to reduce the rate of recurrence of EBV latency II B- and postalogenic NK / T-lymphoma cells when administered as adjuvant therapy, offering hope for patients with this aggressive disease.
The challenge now is to further increase the success of LMP-T therapy in patients with relapsing or active disease at infusion, where the response rate is much lower (OS 2 years, 43%; see figure). 1 Optimizing T cell therapy in this setting requires a deeper understanding of which individuals in this diverse group of patients respond to LMP-Ts and why others do not. Investigating viral and immunological variables that influence patient outcomes can reveal mechanistic insights for future treatment optimization. In this case, McLaughlin et al. Provided some important clues from their in vitro analysis of LMP-Ts infusion. Because of the individual nature of such treatments, LMP-T preparations cannot be avoided in their composition variables. Thus, although all products have in-vitro reactivity to EBV, they are very different in their cellular constituents and in the diversity of LMP1 and LMP2 epitopes recognized. However, 2 interesting observations warrant further investigation: (1) patients who respond generally receive T-cell products that contain higher LMP2 reactivity and maintain a greater frequency of LMP2-specific T cells in the blood, indicating the magnitude of the LMP2 specific response maybe important. ; and (2) 2 patients who relapsed post-LMP-T administration were saved by non-selective lymphocyte donor infusion. Although it is not possible to evaluate latent protein expression of EBV in tumors from these 2 patients, this observation supports the development of T-cell therapy with a broader antigen-specific repertoire. 1 Interestingly, previous analyzes of third-party polyclonal EBV-CTL used to treat PTLD have shown that antigen predominant specificities present in infused T cells do not always correlate with clinical response. 4 Thus, the characteristics of T cells that develop in vivo, in combination with a comprehensive evaluation of the expression of EBV antigens in tumors, can explain the exact specificity needed for an effective therapeutic response.
Micro-tumor environmental investigations can provide additional pathways to further improve LMP-T therapy for EBV-positive B and T / NK cell lymphoma. EBV LMP1 has been shown to promote the expression of postal immune examination inhibitors, programmed cell death ligand 1 (PD-L1), 8 involving PD-1 receptors in T cells to inhibit signaling. In particular, PD-L1 expression has recently been reported in tumor biopsy from patients with EBV-positive B-cell 8 and NK / T-cell 9 lymphoma. Thus, in patients with active disease, infused T cells may need to overcome local immunosuppression at the tumor site. Further characterization of the tumor microenvironment in future studies will show whether LMP-T therapy will benefit from the concomitant administration of clinically available monoclonal antibodies and target immune post-examination inhibitors. 10 Increasing in vivo efficacy from LMP-Ts infusion can further improve outcomes for patients with EBV-positive B-and T / NK cell lymphoma after allogeneic HCST
- © 2018 by the American Society of Hematology