Treatment of Epstein-Barr-virus-positive post-transplantation lymphoproliferative disease with partly HLA-matched allogeneic cytotoxic T cells

Haque, Tanzina; Wilkie, Gwen; Taylor, Clare; Amlot, Peter; Murad, Parvez; Iley, Angela; Dombagoda, Dilani; Britton, Kate; Swerdlow, Anthony; Crawford, Dorothy H.

doi:10.1016/s0140-6736(02)09672-1

Cited by 334 publications

(211 citation statements)

References 21 publications

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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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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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“…Khanna et al used autologous LCL-stimulated CTLs in a lung transplant recipient with PTLD who had regression of liver and lung lungs after treatment [Khanna 1999]. Haque et al generated a bank of EBV-specific CTLs from healthy EBV-seropositive donors which were cryopreserved and subsequently infused into patients, based on the closest possible HLA match [Haque 2002]. In this study, 7 patients with established PTLD after SOT were treated.…”

Section: Immune-based Treatments For Type III Latency Malignancies Inmentioning

confidence: 99%

Current understanding of the role of Epstein–Barr virus in lymphomagenesis and therapeutic approaches to EBV-associated lymphomas

Cohen

Bollard

Khanna

et al. 2008

Leukemia & Lymphoma

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“…Similarly, the adoptive transfer of Epstein-Barr virus-specific donor-derived T cells has been successfully used to treat Epstein-Barr virus-induced malignancies after allogeneic stem cell transplantation (1,2) and solid organ transplants (3)(4)(5). More recently, it was demonstrated that adoptive T cell transfer into patients conditioned by lymphoablative chemotherapy resulted in strong antitumor effects in melanoma patients (6,7).…”

Section: T He Infusion Of Allogeneic T Cells Into Patients With Leukementioning

confidence: 99%

A critical role of T cell antigen receptor-transduced MHC class I-restricted helper T cells in tumor protection

Morris

Tsallios

Bendle

et al. 2005

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

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Adoptive transfer of antigen-specific CD4 ؉ and CD8 ؉ T cells is one of the most efficient forms of cancer immunotherapy. However, the isolation of antigen-specific CD4 ؉ T cells is limited because only few tumor-associated helper epitopes are identified. Here, we used T cell antigen receptor gene transfer to target CD4 ؉ T cells against an MHC class I-presented epitope of a model tumor antigen. IFN-␥-producing CD4 ؉ T cells were unable to expand in vivo and to provide help for tumor rejection. In contrast, CD4 ؉ T cells producing high levels of IL-2 expanded in vivo, provided help for cytotoxic T lymphocyte-mediated tumor rejection, and developed T cell memory. The data demonstrate in vivo synergy between T cell antigen receptor-transduced CD4 ؉ and CD8 ؉ T cells specific for the same epitope resulting in long-term tumor protection.T cell antigen receptor gene transfer ͉ tumor immunotherapy T he infusion of allogeneic T cells into patients with leukemia can provide long-term leukemia-free survival. Similarly, the adoptive transfer of Epstein-Barr virus-specific donor-derived T cells has been successfully used to treat Epstein-Barr virus-induced malignancies after allogeneic stem cell transplantation (1, 2) and solid organ transplants (3-5). More recently, it was demonstrated that adoptive T cell transfer into patients conditioned by lymphoablative chemotherapy resulted in strong antitumor effects in melanoma patients (6, 7).Indirect evidence suggests that the success of the adoptive immunotherapy treatments described above may be related to the use of antigen-specific CD4 ϩ and CD8 ϩ T lymphocytes. For example, in melanoma the clinical response to infusion of CD8 ϩ T cell clones was much less impressive than the effect of adoptive transfer of mixed CD4 ϩ and CD8 ϩ T cells, although a direct comparison in patients after lymphoablative conditioning has not yet been performed (6,8). Administration of IL-2 can improve the antimelanoma efficacy of transferred CD8 ϩ T cells (9), suggesting an important role of this cytokine that is typically produced by CD4 ϩ T helper cells. Superiority of mixed CD4 ϩ and CD8 ϩ T cells was also suggested by adoptive cell transfer experiments in immunocompromised patients at risk of CMV disease. The cell dose of cloned CD8 ϩ T cells used to control CMV was Ϸ1,000-fold higher than the dose of CMV-specific CD8 ϩ T cells given together with CMV-specific CD4 ϩ T cells (10, 11).The generation of tumor antigen-specific CD4 ϩ helper T cells is limited by the paucity of known MHC class II-binding tumor epitopes and the lack of expression of MHC class II molecules on most tumor cells. In contrast, a large number of CD8 ϩ T cellrecognized tumor epitopes presented by MHC class I molecules has been identified, and in many cases cytotoxic T lymphocyte (CTL) clones against such epitopes were isolated. In this study, we explored in a murine model system whether the T cell antigen receptor (TCR) genes of tumor-specific CTL can be transferred to CD4 ϩ T cells to generate MHC class I-restricted, tumor-...

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Treatment of Epstein-Barr-virus-positive post-transplantation lymphoproliferative disease with partly HLA-matched allogeneic cytotoxic T cells

Cited by 334 publications

References 21 publications

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

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

Current understanding of the role of Epstein–Barr virus in lymphomagenesis and therapeutic approaches to EBV-associated lymphomas

A critical role of T cell antigen receptor-transduced MHC class I-restricted helper T cells in tumor protection

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