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T cell receptor-engineered T cells derived from target human leukocyte antigen-DPB1-specific T cell can be a potential tool for therapy against leukemia relapse following allogeneic hematopoietic cell transplantation

Katsuyama, Naoya Kawase, Takakazu Barakat, Carolyne Mizuno, Shohei Tomita, Akihiro Ozeki, Kazutaka Nishio, Nobuhiro Sato, Yoshie Kajiya, Ryoko Shiraishi, Keiko Takahashi, Yoshiyuki Ichinohe, Tatsuo Nishikawa, Hiroyoshi Akatsuka, Yoshiki 名古屋大学

2023.11

概要

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an established treatment
for refractory hematological malignancies.1,2 Allo-HSCT is based on genetic differences between
donors and patients that form allogeneic antigens and induce various immune responses. 3-6 Infused
donor lymphocytes may lead to life-threatening graft-versus-host disease (GVHD); however, graftversus leukemia/lymphoma (GVL) can induce a strong anti-tumor effect.3,4 Although mortality and
morbidity caused by high-dose chemotherapy, infections, and organ damage have been decreased
owing to improvements in appropriate management, the survival rate after transplantation remains
at approximately 50% over the last two decades, mainly due to the unchanged rate of recurrent
malignancies, especially in patients with advanced disease.7-9 Therefore, more effective strategies
are needed to prevent relapse and establish treatment methods.10
Transplantation from Human leukocyte antigen (HLA)-A, -B, -C, -DRB1, and-DQB1-matched
unrelated donors (10 loci/10 loci) represents the first choice for patients.11 However, recent studies
showed that HLA-DPB1 antigen mismatch occurs in approximately 70% of unrelated allo-HSCT
cases, and several HLA-DPB1 mismatch combinations decrease the risk of leukemia relapse, and
may also increase the risk of GVHD.12-14 As HLA-DPB1 expression is restricted to hematopoietic
cells and to a lesser extent, inflamed non-hematopoietic tissues,15 it is unlikely that donor T cells
specific for the mismatched HLA-DP allele will induce uncontrollable severe GVHD, suggesting
that mismatched HLA-DP is a promising therapeutic target for leukemia relapse following alloHSCT. Several reports have demonstrated that CD4+ HLA-DP-restricted T cell clones isolated
from patients receiving unrelated allo-HSCT or healthy donors, exert anti-leukemic activities.15-19
Recently, chimeric antigen receptor T cells have been introduced into clinics with great success
for the treatment of relapsed and refractory CD19-positive leukemia and lymphoma as genetically
engineered T cell therapies. However, the number of promising targetable cell surface antigens is
limited, ie, in B lymphocyte malignancies.20 The other form of genetically engineered T cells is
T-cell receptor (TCR)-modified T cells; however, there have been no clinically approved products
to date. Given that TCR recognizes the major histocompatibility antigen and its bound peptides
derived from intracellular proteins, the number of targetable antigens is much higher.21,22 In this
study, by taking advantage of the features of TCR-T cells, we sought to generate CD4+ T cell
clones specific for allogeneic HLA-DP-bound antigens to treat hematological malignancies that
relapse following HLA-DP-mismatched allo-HSCT, because CD4+ cytotoxic T cells are indispensable effector T cells in cancer immunity.23 In addition, we focused on HLA-DP alleles such
as HLA-DPB1*09:01, whose frequency is relatively high in the Japanese population24 to cover
patients in this ethnic group. Finally, we demonstrated that introduction of the inducible HLA-DP
expression system could help isolate promising T cell clones with sufficient TCR affinity. ...

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References End

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T cell receptor-engineered T cells derived from target human leukocyte antigen-DPB1-specific T cell can be a potential tool for therapy against leukemia relapse following allogeneic hematopoietic cell transplantation

概要

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関連論文

Development of TCR-T cell therapy targeting mismatched HLA-DPB1 for relapsed leukemia after allogeneic transplantation

Identification of T cell receptors targeting a neoantigen derived from recurrently mutated FGFR3

Prognostic significance of plasma interleukin-6/-8 in pancreatic cancer patients receiving chemoimmunotherapy

Possible NK cell-mediated immune responses against iPSC-derived cells in allogeneic transplantation settings

B cell depletion with anti-CD20 mAb exacerbates anti-donor CD4+ T cell responses in highly sensitized transplant recipients

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学位論文種類・取得年

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T cell receptor-engineered T cells derived from target human leukocyte antigen-DPB1-specific T cell can be a potential tool for therapy against leukemia relapse following allogeneic hematopoietic cell transplantation

概要

この論文で使われている画像

関連論文

Development of TCR-T cell therapy targeting mismatched HLA-DPB1 for relapsed leukemia after allogeneic transplantation

Identification of T cell receptors targeting a neoantigen derived from recurrently mutated FGFR3

Prognostic significance of plasma interleukin-6/-8 in pancreatic cancer patients receiving chemoimmunotherapy

Possible NK cell-mediated immune responses against iPSC-derived cells in allogeneic transplantation settings

B cell depletion with anti-CD20 mAb exacerbates anti-donor CD4+ T cell responses in highly sensitized transplant recipients

参考文献