Long-term control of recurrent or refractory viral infections after allogeneic HSCT with third-party virus-specific T cells

Withers, Barbara; Blyth, Emily; Clancy, Leighton; Yong, Agnes S. M.; Fraser, Chris; Burgess, Jane; Simms, Renee; Brown, Rebecca T.; Kliman, David; Dubosq, Ming-Celine; Bishop, David; Sutrave, Gaurav; Kris, Chun Kei; Shaw, Peter J.; Micklethwaite, Kenneth; Gottlieb, David

doi:10.1182/bloodadvances.2017010223

Cited by 122 publications

(116 citation statements)

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“…25 The use of ex vivo stimulated and expanded virus-specific T cells from either the patients themselves (or allogeneic hematopoietic cell transplantation donor) or so-called allogeneic third-party donors (neither the graft recipient nor donor) are associated with a high rate of durable responses with little toxicity. [16][17][18][26][27][28][29][30][31] However, virus-specific T cells are not widely available, limiting the use of these promising therapies.…”

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confidence: 99%

Leukoreduction system chambers are a reliable cellular source for the manufacturing of T‐cell therapeutics

et al. 2018

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BACKGROUND Following solid organ or hematopoietic cell transplantation, refractory opportunistic viral reactivations are a significant cause of morbidity and mortality but can effectively be controlled by virus‐specific T‐cell transfer. Among effective and safe strategies is the use of “third‐party” (neither from the transplant donor nor recipient) virus‐specific T cells that can be manufactured from healthy donors and used as “off‐the‐shelf” therapies. Leukoreduction system chambers (LRSCs), recovered after routine plateletpheresis, were evaluated as a potential source of peripheral blood mononuclear cells (PBMCs) for the manufacturing of clinical‐scale virus‐specific T cell. STUDY DESIGN AND METHODS PBMCs from the same donors obtained either from LRSCs or peripheral blood were compared, focusing on T‐cell function and phenotype as well as the potential to generate cytomegalovirus (CMV)‐specific T‐cell lines from both CMV seropositive and seronegative donors. RESULTS PBMCs from both sources were comparable except for a transient downregulation of CD62L expression on freshly extracted PBMCs from LRSCs. Both nonspecific stimulation using anti‐CD3/CD28 antibodies and CMV peptides revealed that LRSCs or blood T cells were equivalent in terms of expansion, differentiation, and function. Moreover, PBMCs from LRSCs can be used to generate autologous monocyte‐derived dendritic cells to prime and expand CMV‐specific T cells from seronegative donors. CONCLUSION LRSCs are a reliable source of PBMCs for the generation of virus‐specific T cells for immunotherapy. These findings have implications for the development of third‐party therapeutic T‐cell products from well‐characterized blood product donors.

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confidence: 99%

Leukoreduction system chambers are a reliable cellular source for the manufacturing of T‐cell therapeutics

et al. 2018

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“…To date, peptides from pp65, a late phase protein, are commonly used for T-cell therapies. 67 To catch infected cells in all viral replication phases, a combination of peptides from different time points would be an ideal procedure; the described peptide AQ14, derived from an IE protein, represents a perfect additional peptide that could be combined with existing therapeutic peptides.…”

Section: Discussionmentioning

confidence: 99%

Releasing the concept of HLA‐allele specific peptide anchors in viral infections: A non‐canonical naturally presented human cytomegalovirus‐derived HLA‐A24:02* restricted peptide drives exquisite immunogenicity

Pump

Schulz

Huyton

et al. 2019

HLA

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T‐cell receptors possess the unique ability to survey and respond to their permanently modified ligands, self HLA‐I molecules bound to non‐self peptides of various origin. This highly specific immune function is impaired following hematopoietic stem cell transplantation (HSCT) for a timespan of several months needed for the maturation of T‐cells. Especially, the progression of HCMV disease in immunocompromised patients induces life‐threatening situations. Therefore, the need for a new immune system that delivers vital and potent CD8+ T‐cells carrying TCRs that recognize even one human cytomegalovirus (HCMV) peptide/HLA molecule and clear the viral infection long term becomes obvious. The transcription and translation of HCMV proteins in the lytic cycle is a precisely regulated cascade of processes, therefore, it is a highly sensitive challenge to adjust the exact time point of HCMV‐peptide recruitment over self‐peptides. We utilized soluble HLA technology in HCMV‐infected fibroblasts and sequenced naturally sHLA‐A*24:02 presented HCMV‐derived peptides. One peptide of 14 AAs length derived from the IE2 antigen induced the strongest T‐cell responses; this peptide can be detected with a low ranking score in general peptide prediction databanks. These results highlight the need for elaborate and HLA‐allele specific peptide selection.

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“…decrease of viral load suggesting feasibility and effectiveness as similarly described in many recent studies (summary in Table 2). 7,9,[13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] In addition, we could detect the immune response by ELISpot demonstrating an induction of penton-and hexon-specific T cells in the patient after transfer. Diligent monitoring of GvHD and anti-HAdV immune response enabled personally tailored immunosuppressive and antiviral therapy and led to control of both GvHD and HAdV infection in this patient.…”

Section: Ta B L E 2 (Continued)mentioning

confidence: 94%

Transfer of Hexon‐ and Penton‐selected adenovirus‐specific T cells for refractory adenovirus infection after haploidentical stem cell transplantation

Schultze-Florey

Tischer-Zimmermann

Heuft

et al. 2019

Transplant Infectious Dis

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Adenovirus (HAdV) infections confer a high risk of morbidity and mortality for immunocompromised patients after stem cell transplantation (SCT). Treatment with standard antiviral drugs is of limited efficacy and associated with a high rate of adverse effects. HAdV‐specific T cells are crucial for sustained viral elimination and the efficacy of adoptive T‐cell therapy with donor‐derived HAdV‐specific T cells has been reported by several investigators. Here, we report our experience with the transfer of HAdV‐specific T cells specific for penton, which was recently identified as an immunodominant target of T cells, and hexon in a 14‐year‐old boy after T‐cell‐depleted haploidentical SCT for myelodysplastic syndrome (MDS). He developed severe HAdV‐associated enteritis complicated by acute graft‐versus‐host disease (GvHD). The patient received ten infusions of allogeneic HAdV‐specific T cells manufactured from the haploidentical stem cell donor using the CliniMacs Interferon‐γ (IFN‐γ) cytokine capture and immunomagnetic selection. Initially, T cells were generated against the immunodominant target hexon and in subsequent transfers dual antigen‐specific T cells against hexon and penton were applied. T‐cell transfers were scheduled individually tailored to current immunosuppressive treatment. Each transfer was followed by reduction of HAdV load in peripheral blood and clinical improvement. Importantly, T‐cell responses to both penton and hexon pools emerged in patient blood after repetitive transfers. Unfortunately, the patient experienced bacterial sepsis, and in this context, severe GvHD requiring intensive immunosuppression followed by secondary progression of HAdV infection. The patient succumbed to multiorgan failure 283 days after SCT. This case demonstrates the feasibility of HAdV‐specific T‐cell transfer even in the presence of immunosuppressive treatment. Targeting of multiple immunodominant viral proteins may prove valuable in patients with complicated HAdV infections.

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Long-term control of recurrent or refractory viral infections after allogeneic HSCT with third-party virus-specific T cells

Abstract: Key Points Partially HLA-matched third-party CMV-specific T cells provide long-term viral control in HSCT patients with resistant CMV infection. Viral control occurs in the setting of recovery of CD8+ terminally differentiated effector T cells.

Cited by 122 publications

References 23 publications

Leukoreduction system chambers are a reliable cellular source for the manufacturing of T‐cell therapeutics

Leukoreduction system chambers are a reliable cellular source for the manufacturing of T‐cell therapeutics

Releasing the concept of HLA‐allele specific peptide anchors in viral infections: A non‐canonical naturally presented human cytomegalovirus‐derived HLA‐A24:02* restricted peptide drives exquisite immunogenicity

Transfer of Hexon‐ and Penton‐selected adenovirus‐specific T cells for refractory adenovirus infection after haploidentical stem cell transplantation

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Long-term control of recurrent or refractory viral infections after allogeneic HSCT with third-party virus-specific T cells

Abstract: Key Points Partially HLA-matched third-party CMV-specific T cells provide long-term viral control in HSCT patients with resistant CMV infection. Viral control occurs in the setting of recovery of CD8+ terminally differentiated effector T cells.

Cited by 122 publications

References 23 publications

Leukoreduction system chambers are a reliable cellular source for the manufacturing of T‐cell therapeutics

Leukoreduction system chambers are a reliable cellular source for the manufacturing of T‐cell therapeutics

Releasing the concept of HLA‐allele specific peptide anchors in viral infections: A non‐canonical naturally presented human cytomegalovirus‐derived HLA‐A*24:02 restricted peptide drives exquisite immunogenicity

Transfer of Hexon‐ and Penton‐selected adenovirus‐specific T cells for refractory adenovirus infection after haploidentical stem cell transplantation

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Resources

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Releasing the concept of HLA‐allele specific peptide anchors in viral infections: A non‐canonical naturally presented human cytomegalovirus‐derived HLA‐A24:02* restricted peptide drives exquisite immunogenicity