Comparative study of micro‐transplantation from <scp>HLA</scp> fully mismatched unrelated and partly matched related donors in acute myeloid leukemia

Hu, Kaiwen; Du, Xin; Guo, Mingzhou; Yu, Changhong; Qiao, Jie; Sun, Qi‐Yun; Zuo, Houjuan; Cai, Bo; Huang, Ya‐Jing; Ai, Hui‐Sheng; Zheng, Dong; Wang, Yichuan

doi:10.1002/ajh.25780

Cited by 8 publications

(9 citation statements)

References 27 publications

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“…Importantly, the induced host tumor-specific CTLs persisted long-term in vivo to protect against tumor recurrence. Collectively, data from our studies and others [71][72][73][74] indicate that allogeneic cells have the potential to induce host anti-tumor immunity and may induce long-term protection against both solid tumors and AML.…”

Section: Discussionsupporting

confidence: 60%

“…Recent clinical studies have demonstrated that HLAmismatched granulocyte colony-stimulating factor-mobilized donor peripheral blood stem cell (G-PBSC) infusion after regular chemotherapy improves the outcome in elderly patients with acute myeloid leukemia (AML) [71][72][73][74]. Although the recipients did not receive any GVHD prophylaxis, GVHD was rarely observed.…”

Section: Discussionmentioning

confidence: 99%

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Alloantigen-activated (AAA) CD4+ T cells reinvigorate host endogenous T cell immunity to eliminate pre-established tumors in mice

Mochizuki

Kobayashi

Takahashi

et al. 2021

J Exp Clin Cancer Res

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Background Cancer vaccines that induce endogenous antitumor immunity represent an ideal strategy to overcome intractable cancers. However, doing this against a pre-established cancer using autologous immune cells has proven to be challenging. “Allogeneic effects” refers to the induction of an endogenous immune response upon adoptive transfer of allogeneic lymphocytes without utilizing hematopoietic stem cell transplantation. While allogeneic lymphocytes have a potent ability to activate host immunity as a cell adjuvant, novel strategies that can activate endogenous antitumor activity in cancer patients remain an unmet need. In this study, we established a new method to destroy pre-developed tumors and confer potent antitumor immunity in mice using alloantigen-activated CD4+ (named AAA-CD4+) T cells. Methods AAA-CD4+ T cells were generated from CD4+ T cells isolated from BALB/c mice in cultures with dendritic cells (DCs) induced from C57BL/6 (B6) mice. In this culture, allogeneic CD4+ T cells that recognize and react to B6 mouse-derived alloantigens are preferentially activated. These AAA-CD4+ T cells were directly injected into the pre-established melanoma in B6 mice to assess their ability to elicit antitumor immunity in vivo. Results Upon intratumoral injection, these AAA-CD4+ T cells underwent a dramatic expansion in the tumor and secreted high levels of IFN-γ and IL-2. This was accompanied by markedly increased infiltration of host-derived CD8+ T cells, CD4+ T cells, natural killer (NK) cells, DCs, and type-1 like macrophages. Selective depletion of host CD8+ T cells, rather than NK cells, abrogated this therapeutic effect. Thus, intratumoral administration of AAA-CD4+ T cells results in a robust endogenous CD8+ T cell response that destroys pre-established melanoma. This locally induced antitumor immunity elicited systemic protection to eliminate tumors at distal sites, persisted over 6 months in vivo, and protected the animals from tumor re-challenge. Notably, the injected AAA-CD4+ T cells disappeared within 7 days and caused no adverse reactions. Conclusions Our findings indicate that AAA-CD4+ T cells reinvigorate endogenous cytotoxic T cells to eradicate pre-established melanoma and induce long-term protective antitumor immunity. This approach can be immediately applied to patients with advanced melanoma and may have broad implications in the treatment of other types of solid tumors.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Alloantigen-activated (AAA) CD4+ T cells reinvigorate host endogenous T cell immunity to eliminate pre-established tumors in mice

Mochizuki

Kobayashi

Takahashi

et al. 2021

J Exp Clin Cancer Res

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“…MST is an important treatment for patients who cannot tolerate standard allo-HSCT or lack suitable donors (2)(3)(4)(5)(6). Donor selection for MST is broad, ranging from HLA fully mismatched unrelated donors to HLA partly matched related donors and the efficacy of unrelated donor-derived MST is believed to be similar to or higher than that of related donorderived MST (2,3). HLA haplotype homozygous donors have been reported to cause fatal transfusion-associated GVHD when patients receive a transfusion of nonirradiated blood components as early as 1990.…”

Section: Discussionmentioning

confidence: 99%

“…Infusion of HLA-mismatched donor granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood stem cells (G-PBSCs) combined with chemotherapy (microtransplantation [MST]) is capable of producing donor microchimerism (donor cells<1%), improving survival, and precluding GVHD (2). It's a safe and effective treatment for older patients with AML (2)(3)(4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

Case report: Rare persistent complete donor chimerism and GVHD following micro-transplantation from HLA haplotype homozygous donors

Liu

Cui

et al. 2022

Front. Immunol.

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HLA-mismatched hematopoietic stem cell micro-transplantation (MST) is an effective treatment for older patients (≥60 years) with acute myeloid leukemia. Donor selection for MST is broad, ranging from HLA fully mismatched unrelated donors to HLA partially matched related donors. However, the influence of HLA haplotype homozygous donors such donors on MST has not been studied. Such donors has been reported to be associated with a higher risk of graft-versus-host disease (GVHD) in transfusion and cord blood transplantation (CBT). Additionally, sustained complete donor chimerism is rare in MST and usually accompanied by severe acute GVHD and death. Herein, we report the first case of MST using an HLA haplotype homozygous donor. The patient developed persistent complete donor chimerism (donor cells>95%) for 7 months and prolonged isolated thrombocytopenia (PT) for 3 months, after receiving MST from his HLA homozygous son. Grade I acute GVHD presented on day 12 post-MST and it was controlled by timely immunosuppressive treatment. Then he maintained complete molecular remission, complete donor chimerism and mild GVHD for 5 months. However, moderate overlapping GVHD with skin, oral, eyes, and intestinal involvement developed after he self-discontinued Tacrolimus treatment. Fortunately, the GVHD was controlled after intensive anti-rejection therapy and Tacrolimus is now being continued for prophylaxis. This case underscores that HLA haplotype homozygous donors might not be a good choice for MST and GVHD prophylactic should be administrated if such donors have to be selected.

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“…Recently, Ai Huisheng et al (6,(12)(13)(14) explored the application of "micro-transplantation" to treat several hematological malignancies, included MDS, AML, and Philadelphia chromosome-positive acute lymphoblastic leukemia. The (7).…”

Section: Discussionmentioning

confidence: 99%

Decitabine With or Without Micro-Transplantation for the Treatment of Intermediate or High-Risk Myelodysplastic Syndrome: A Chinese Single-Center Retrospective Study of 22 Patients

Geng

et al. 2021

Front. Oncol.

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The treatment outcomes of intermediate or high-risk myelodysplastic syndrome (MDS) remain unsatisfactory. This study was designed to evaluate the safety and efficacy of human leukocyte antigen (HLA)-mismatched hematopoietic stem cell micro-transplantation (MST) in patients with MDS. A total of 22 patients with MDS, ranging between the ages of 39 and 74, were enrolled in this study. Eleven patients were given decitabine (DAC), a DNA methyltransferase inhibitor, combined with HLA-mismatched MST (MST-DAC group), and the remaining patients were given decitabine only (DAC group). The median overall survival (OS) of the MST-DAC group was higher than that of the DAC group (24 vs. 14.3 months; HR 0.32; 95% CI: 0.11–0.96; p = 0.04), although it is a study with small samples. The overall response rate (ORR), marrow complete remission (mCR), plus hematological improvement (HI) rates of the MST-DAC group were higher than that of the DAC group (81.8 vs. 54.5%, p = 0.36; 63.6 vs. 27.3%, p = 0.09, respectively); however, there were no statistical differences between the two groups, which may be attributed to the limited number of cases evaluated in this study. No graft-vs.-host disease was observed in the MST-DAC group. Patients in the MST-DAC group demonstrated a slightly lower incidence of hematological and non-hematological adverse events (AEs). DAC combined with HLA-mismatched MST may provide a novel, effective, and safe treatment for use in intermediate or high-risk MDS pathologies.

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Comparative study of micro‐transplantation from HLA fully mismatched unrelated and partly matched related donors in acute myeloid leukemia

Cited by 8 publications

References 27 publications

Alloantigen-activated (AAA) CD4+ T cells reinvigorate host endogenous T cell immunity to eliminate pre-established tumors in mice

Alloantigen-activated (AAA) CD4+ T cells reinvigorate host endogenous T cell immunity to eliminate pre-established tumors in mice

Case report: Rare persistent complete donor chimerism and GVHD following micro-transplantation from HLA haplotype homozygous donors

Decitabine With or Without Micro-Transplantation for the Treatment of Intermediate or High-Risk Myelodysplastic Syndrome: A Chinese Single-Center Retrospective Study of 22 Patients

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