Folliculotropic mycosis fungoides treated with electron beam therapy that evolved into fatal, tumor-stage mycosis fungoides and erythroderma with multiple ulcerations

　A 71-year-old woman diagnosed with mycosis fungoides with multiple erythematous plaques and follicular papules on the scalp, trunk, and thigh was referred to our institution. Folliculotropic mycosis fungoides was histologically diagnosed, and the erythematous papules and plaques regressed temporarily after total-skin electron beam therapy. The patient then developed tumors and erythroderma. The area of painful erosion spread, and her condition rapidly worsened. The patient died 3 years and 4 months after the first examination due to multiple organ failure caused by sepsis. The cause of rapid evolution into erythroderma remains elusive and requires further investigation in similar cases

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

ハンキョウジセイタイニオケルマグノンソクタイノネツテキナフルマイ

京都大学0048新制・課程博士理学博士甲第1157号理博第230号新制||理||150(附属図書館)3158UT51-47-A368京都大学大学院理学研究科化学専攻(主査)教授 山本 常信, 教授 高木 秀夫, 教授 辻川 郁二学位規則第5条第1項該当Kyoto UniversityDA