Successful treatment of EBV-associated posttransplantation lymphoma after cord blood transplantation using third-party EBV-specific cytotoxic T lymphocytes

Barker, Juliet N.; Doubrovina, Ekaterina; Sauter, Craig S.; Jaroscak, Jennifer Joi; Perales, Miguel Angel; Doubrovin, Mikhail; Prockop, Susan E.; Koehne, Guenther; O’Reilly, Richard J.

doi:10.1182/blood-2010-04-281873

Cited by 200 publications

(165 citation statements)

References 15 publications

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“…In contrast, DLI was far more efficacious in both rituximab and rituximab/chemotherapy failures. The efficacy of adoptive T-cell therapies for PTLD post allo-SCT is well established 1,11,12,15,30 and we would support this approach as the optimal salvage for SCT-PTLD refractory to rituximab treatment. Available data suggest that unselected DLIs, donor-derived EBV-specific CTLs and banked third-party EBV-CTLs have equivalent therapeutic efficacy.…”

Section: Survivalmentioning

confidence: 81%

EBV-associated post-transplant lymphoproliferative disorder following in vivo T-cell-depleted allogeneic transplantation: clinical features, viral load correlates and prognostic factors in the rituximab era

Fox

Burns

Parker

et al. 2013

Bone Marrow Transplant

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EBV-associated post-transplant lymphoproliferative disease (PTLD) following Alemtuzumab-based allo-SCT is a relatively uncommon and challenging clinical problem but has not received detailed study in a large cohort. Quantitative-PCR (qPCR) monitoring for EBV reactivation post allo-SCT is now commonplace but its diagnostic and predictive value remains unclear. Sixtynine patients with PTLD following Alemtuzumab-based allo-SCT were studied. Marked clinicopathological heterogeneity was evident; lymphadenopathy was frequently absent, whereas advanced extranodal disease was common. The median viral load at clinical presentation was 49 300 copies/mL (50-65 200 000 copies/mL) and, notably, 23% and 45% of cases, respectively, had p10 000 and p40 000 copies/mL. The overall response rate to rituximab as first-line therapy was 70%. For rituximab failures, chemotherapy was ineffectual but DLIs were successful. A four-parameter prognostic index predicted response to therapy (OR 0.30 (0.12-0.74); P ¼ 0.009] and PTLD mortality (hazard ratio (HR) 1.81 (1.12-2.93) P ¼ 0.02) on multivariate analysis. This is the largest detailed series of EBV-associated PTLD after allo-SCT. At clinical presentation, EBV-qPCR values are frequently below customary thresholds for pre-emptive therapy, challenging current paradigms for monitoring and intervention. A four-point score identifies a proportion of patients at risk of rituximab-refractory disease for whom alternative therapy is needed.

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Section: Survivalmentioning

confidence: 81%

EBV-associated post-transplant lymphoproliferative disorder following in vivo T-cell-depleted allogeneic transplantation: clinical features, viral load correlates and prognostic factors in the rituximab era

Fox

Burns

Parker

et al. 2013

Bone Marrow Transplant

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“…As for possible interventions for established disease, infusion of EBV-specific cytotoxic T-lymphocytes could also be effective after UCBT. 25,26 Unfortunately, the widespread application of this therapy is limited as it is only available in a reduced group of highly specialized centers.…”

Section: Discussionmentioning

confidence: 99%

EBV-associated post-transplant lymphoproliferative disorder after umbilical cord blood transplantation in adults with hematological diseases

Sanz

Arango

Senent

et al. 2013

Bone Marrow Transplant

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We analyzed the incidence, clinicopathological features, risk factors and prognosis of patients with EBV-associated post-transplant lymphoproliferative disorder (EBV-PTLD) in 288 adults undergoing umbilical cord blood transplantation (UCBT) at a single institution. Twelve patients developed proven EBV-PTLD at a median time of 73 days (range, 36-812). Three-year cumulative incidence (CI) of EBV-PTLD was 4.3% (95% CI: 1.9-6.7). All patients presented with extranodal involvement. Most frequently affected sites were the liver, spleen, central nervous system (CNS), Waldeyer's ring and BM in 7, 6, 4, 3 and 3 patients, respectively. One patient had polymorphic and 11 had monomorphic EBV-PTLD (7 diffuse large B-cell lymphomas not otherwise specified, 4 plasmablastic lymphomas). We confirmed donor origin and EBV infection in all histological samples. EBV-PTLD was the cause of death in 11 patients at a median time of 23 days (range, 1-84). The 3-year CI of EBV-PTLD was 12.9% (95% CI: 3.2-22.5) and 2.6% (95% CI: 0.5-4.7) for patients receiving reduced-intensity conditioning (RIC) and myeloablative conditioning, respectively (Po0.0001). In conclusion, adults with EBV-PTLD after UCBT showed frequent visceral and CNS involvement. The prognosis was poor despite routine viral monitoring and early intervention. An increased risk of EBV-PTLD was noted among recipients of RIC regimens.

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“…Surprisingly, third-party EBV-specific T cells can eliminate EBV-associated posttransplantation lymphoma despite likely immune recognition and rejection of foreign HLA by the patient immune system (31). Interestingly, there is no evidence that such mismatched CTLs reactive to EBV (32)(33)(34)(35) or cytomegalovirus (36) cause graftversus-host disease. These results, and the results presented here, bear promise that antigen-specific allogeneic T cells reactive to self-TAA can be generated from a single HLA-A2 neg donor for transfer to multiple HLA-A2 pos patients.…”

Section: Discussionmentioning

confidence: 99%

Alloreactive cytotoxic T cells provide means to decipher the immunopeptidome and reveal a plethora of tumor-associated self-epitopes

Kumari

Wälchli

Fallang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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HLA molecules presenting peptides derived from tumor-associated self-antigens (self-TAA) are attractive targets for T-cell-based immunotherapy of cancer. However, detection of such epitopes is hampered by self-tolerance and limitations in the sensitivity of mass spectrometry. Here, we used T cells from HLA-A2-negative donors as tools to detect HLA-A2-bound peptides from two leukemiaassociated differentiation antigens; CD20 and the previously undescribed cancer target myeloperoxidase. A high-throughput platform for epitope discovery was designed using dendritic cells cotransfected with full-length transcripts of self-TAA and HLA-A2 to allow presentation of all naturally processed peptides from a predefined self-protein on foreign HLA. Antigen-reactive T cells were directly detected using panels of color-coded peptide-HLA multimers containing epitopes predicted by a computer algorithm. Strikingly, cytotoxic T cells were generated against 37 out of 50 peptides predicted to bind HLA-A2. Among these, 36 epitopes were previously undescribed. The allorestricted T cells were exquisitely peptide-and HLA-specific and responded strongly to HLA-A2-positive leukemic cells with endogenous expression of CD20 or myeloperoxidase. These results indicate that the repertoire of self-peptides presented on HLA class I has been underestimated and that a wealth of self-TAA can be targeted by T cells when using nontolerized T-cell repertoires.C ytotoxic T cells (CTLs) selectively kill target cells that express defined peptides in complex with MHC class I molecules on the cell surface. Most tumor-associated antigens (TAA) are wild-type self-proteins, and T cells that recognize peptides from these antigens with high affinity are deleted during thymic development. Thus, the utility of T cells for detection of self-peptides presented on self-HLA is limited by tolerance. This may be one reason why the number of epitopes identified from TAA after 2 decades of intense research amounts to less than 600 (1). The ability to rapidly identify new CTL epitopes would likely facilitate the development of effective immunotherapeutic strategies against cancer.MHC molecules can be isolated from cells and the associated peptides eluted for identification by MS. Ultimately, this approach may provide a description of the entire MHC-bound peptide repertoire: the immunopeptidome (2, 3). This is, however, a daunting task, and it is unclear whether current MS-based protocols already provide the required sensitivity. Indeed, although 100,000-750,000 peptide-MHC class I complexes are expressed for each allelic product on the cell surface (for HLA-A and HLA-B loci) (3, 4), the largest HLA ligandome identified to date contains 14,065 peptides (5). In contrast, the predicted number of different HLA class I ligands would be 352,000 using the well-renowned computer algorithm NetMHCpan, considering that on average, 4.4% of all nonamers bind HLA class I (6) and that a cell contains at least 8 × 10 6 distinct nonamers (7). Thus, there is a very large gap between the numb...

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Successful treatment of EBV-associated posttransplantation lymphoma after cord blood transplantation using third-party EBV-specific cytotoxic T lymphocytes

Cited by 200 publications

References 15 publications

EBV-associated post-transplant lymphoproliferative disorder following in vivo T-cell-depleted allogeneic transplantation: clinical features, viral load correlates and prognostic factors in the rituximab era

EBV-associated post-transplant lymphoproliferative disorder following in vivo T-cell-depleted allogeneic transplantation: clinical features, viral load correlates and prognostic factors in the rituximab era

EBV-associated post-transplant lymphoproliferative disorder after umbilical cord blood transplantation in adults with hematological diseases

Alloreactive cytotoxic T cells provide means to decipher the immunopeptidome and reveal a plethora of tumor-associated self-epitopes

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