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.

Human leukocyte antigen (HLA)-DPB1 antigens are mismatched in approximately 70% of allogeneic hematopoietic stem cell transplantations (allo-HSCT) from HLA 10/10 matched unrelated donors. HLA-DP-mismatched transplantation was shown to be associated with an increase in acute graft-versus-host disease (GVHD) and a decreased risk of leukemia relapse due to the graft-versus-leukemia (GVL) effect. Immunotherapy targeting mismatched HLA-DP is considered reasonable to treat leukemia following allo-HCT if performed under non-inflammatory conditions. Therefore, we isolated CD4+ T cell clones that recognize mismatched HLA-DPB1 from healthy volunteer donors and generated T cell receptor (TCR)-gene-modified T cells for future clinical applications. Detailed analysis of TCR-T cells expressing TCR from candidate clone #17 demonstrated specificity to myeloid and monocytic leukemia cell lines that even expressed low levels of targeted HLA-DP. However, they did not react to non-hematopoietic cell lines with a substantial level of targeted HLA-DP expression, suggesting that the TCR recognized antigenic peptide is only present in some hematopoietic cells. This study demonstrated that induction of T cells specific for HLA-DP, consisting of hematopoietic cell lineage-derived peptide and redirection of T cells with cloned TCR cDNA by gene transfer, is feasible when using careful specificity analysis.

The death of patients with terminal cancer: the distress experienced by their children and medical professionals who provide the children with support care.

BACKGROUND: Few studies have been conducted on the experiences of children of terminally ill patients or hospital-based medical professionals supporting such children. AIM: This study explored distress among individuals whose parents died of cancer in childhood and among hospital-based medical professionals supporting such children. DESIGN: A qualitative study. SETTING/PARTICIPANTS: The sample was 12 adults whose parents had died of cancer in childhood and 20 hospital-based medical professionals supporting children of patients' with terminal cancer. In-depth interviews were conducted, focusing on the distress experienced by the participants. The data were analysed thematically. RESULTS: Among adults whose parents died of cancer in childhood, we identified themes related to the period before death (eg, concealing the parent's illness), the time of death (eg, alienation due to isolation from the parent), soon after death (eg, fear and shock evoked by the bizarre circumstances, regrets regarding the relationship with the deceased parent before death), several years thereafter (ie, distinctive reflection during adolescence, prompted by the parent's absence) and the present time (ie, unresolved feelings regarding losing the parent). We identified seven themes among the medical professionals (eg, lack of knowledge/experience with children, the family's attempts to shield the child from the reality of death, estrangement from the family once they leave the hospital). CONCLUSIONS: An important finding of the study is that the participants' grief reaction to their parents' deaths during childhood was prolonged. Moreover, hospital medical professionals may find it difficult to directly support affected children. Comprehensive support involving organisations (eg, local communities) may be necessary for children who have lost a parent.

A national profile of the impact of parental cancer on their children in Japan.

OBJECTIVE: Dependent children under the age of 18 are particularly vulnerable to the stress of parental death from cancer or of having a parent diagnosed and treated for the disease. More and more Japanese couples are postponing parenthood, which increases their chances of developing cancer while they still have a dependent child. However, the problem has not received enough attention from healthcare professionals and policy-makers because the extent and breadth of the problem has never been examined in the Japanese population. Therefore, we aimed to estimate the nationwide incidence of cancer patients who have children under the age of 18 years, as well as the incidence of children who have a parent diagnosed with cancer in Japan. STUDY DESIGN: We calculated the proportion of patients who have children stratified by age, gender and cancer type using electronic medical records of cancer patients (20-59 years old) admitted to the National Cancer Center Hospital (NCCH) for the first time between January 2009 and December 2013. We projected these estimates onto the Japanese population using 2010 population-based cancer registry data, and repeated the projection using 2011 hospital-based cancer registry data so that estimates of patients receiving care at Designated Cancer Care (DCC) hospitals could be obtained. RESULTS: We found that an estimated 56,143 cancer patients who have 87,017 dependent children are diagnosed with cancer every year in Japan. The proportion of children in Japan who had a parent newly diagnosed with cancer in 2010 was approximately 0.38%. We estimated that in 2011 there were on average about 82 cancer patients with minor children and 128 minor children who have at least one parent diagnosed with cancer in every DCC hospital in Japan. CONCLUSION: Parental cancer is common. We have identified that many adults diagnosed with cancer have the double burden of coping with the diagnosis and treatment as well as supporting their children through this experience. Additional data on socioeconomic characteristics and needs assessment of these patients are required to understand how best to help children and families cope with cancer.

Mismatched human leukocyte antigen class II-restricted CD8⁺ cytotoxic T cells may mediate selective graft-versus-leukemia effects following allogeneic hematopoietic cell transplantation.

Partial human leukocyte antigen (HLA)-mismatched hematopoietic stem cell transplantation (HSCT) is often performed when an HLA-matched donor is not available. In these cases, CD8(+) or CD4(+) T cell responses are induced depending on the mismatched HLA class I or II allele(s). Herein, we report on an HLA-DRB1*08:03-restricted CD8(+) CTL clone, named CTL-1H8, isolated from a patient following an HLA-DR-mismatched HSCT from his brother. Lysis of a patient Epstein-Barr virus-transformed B cell line (B-LCL) by CTL-1H8 was inhibited after the addition of blocking antibodies against HLA-DR and CD8, whereas antibodies against pan-HLA class I or CD4 had no effect. The 1H8-CTL clone did not lyse the recipient dermal fibroblasts whose HLA-DRB1*08:03 expression was upregulated after 1 week cytokine treatment. Engraftment of HLA-DRB1*08:03-positive primary leukemic stem cells in non-obese diabetic/severe combined immunodeficient/γc-null (NOG) mice was completely inhibited by the in vitro preincubation of cells with CTL-1H8, suggesting that HLA-DRB1*08:03 is expressed on leukemic stem cells. Finally, analysis of the precursor frequency of CD8(+) CTL specific for recipient antigens in post-HSCT peripheral blood T cells revealed a significant fraction of the total donor CTL responses towards the individual mismatched HLA-DR antigen in two patients. These findings underscore unexpectedly significant CD8 T cell responses in the context of HLA class II.