Terminally differentiated CD8+ T cells and CD57-FOXP3+CD8+ T cells are highly associated with the efficacy of immunotherapy using activated autologous lymphocytes.

Treatment with activated autologous lymphocytes (AALs) has demonstrated mixed results for cancer treatment. Preliminary results revealed that the proportion of cluster of differentiation (CD)8+CD57+ T cells is significantly increased in AALs, indicating that they are able to determine treatment outcome. Therefore, the role of CD8+CD57+ T cells in AAL efficacy was investigated. T lymphocytes were isolated from 35 patients with stage IV gastric carcinomas (17 men and 18 women; aged 41-84 years) receiving immunotherapy using AALs (IAAL). Using fluorescence activated cell sorting, CD8, CD27, CD57, and forkhead box protein 3 (FOXP3) expression was investigated on CD8+ T cell populations in CD8+ T cell differentiation prior to and following in vitro culture. The association between these populations and progression-free survival (PFS) was analyzed using Cox univariate, and multivariate analyses and Kaplan-Meier survival analysis. CD57 expression was negative in early-differentiated CD8+ T cells (CD27+CD8+CD57-), and positive in intermediate- (CD27+CD8+CD57+) and terminal- (CD27-CD8+CD57+) differentiated CD8+ T cells. Univariate analysis revealed a significant association between terminal-CD8+ T cells and longer PFS times (P=0.035), whereas CD57-FOXP3+CD8+ T cells were associated with shorter PFS times. Multivariate analysis revealed that CD57-FOXP3+CD8+ T cells was an independent poor prognostic factor, whereas CD57+FOXP3+CD8+ T cells were not associated with PFS. Although IAAL increased the proportion of terminal-CD8+ T cells relative to the pre-culture proportions, patients with a high CD57-FOXP3+CD8+ T cell percentage exhibited repressed terminal-CD8+ T cell induction, leading to poor patient prognosis. Terminally differentiated CD27-CD8+CD57+ T cells were responsible for the effectiveness of AALs; however, CD57-FOXP3+CD8+ T cells abrogated their efficacy, possibly by inhibiting their induction.

Therapeutic Efficacy of Adoptive Cell Transfer on Survival of Patients with Glioblastoma Multiforme: Case Reports.

Glioblastoma multiforme (GBM), which occurs mostly in individuals over the age of 40, accounts for 12-15% of all primary brain tumors. Patients with GBM have a poor prognosis, even after aggressive upfront therapies. The present study documents that in 5 of these patients, the use of a novel immunotherapeutic approach combined with standard initial therapies resulted in a prolonged survival of over 3 years, which is significantly longer than the expected survival time with conventional therapies. During the course of intravenous cell-transfer immunotherapy, axial magnetic resonance images of the tumor region were monitored for over 5 years. The discontinuation of adoptive transfer regimens resulted in the rapid deterioration of patients with development of Gd-enhancing regions, indicating the initiation of tumor recurrence. Among patients with recurrence, the reinstatement of adoptive cell regimens with more frequent cell-transfers resulted in an apparent re-regression of tumors. Significantly longer survival times were seen in patients receiving transferred autologous lymphoid cells which were expanded in vitro, and which had a considerable proportion of gammadeltaT cells. We conclude that immunotherapy, combined with standard treatment, plays a significant role in the management of GBM patients and provides patients with a better prognosis.

Novel adopted immunotherapy for mixed chimerism after unrelated cord blood transplantation in Omenn syndrome.

Omenn syndrome is a variant form of severe combined immunodeficiency. It is fatal unless treated by allogeneic stem cell transplantation (SCT), which is the only curative approach. However, both treatment-related complications and graft rejection are major obstacles to treatment success. This report describes a case with Omenn syndrome who developed mixed chimerism after unrelated cord blood transplantation (UCBT). This case was successfully treated by altering the patient's immunosuppression and donor lymphocyte infusion (DLI) with donor cord blood-derived activated CD4+ T cells ex vivo expanded from the cord blood cell residues in an infused bag. This novel development to expand CD4+ T-lymphocytes from the donor cord blood unit for the use of DLI would serve as a useful method to overcome the risk of graft rejection in SCT for primary immunodeficiency disorders with residual cell-mediated immunity without compounding graft-vs.-host disease, especially in the UCBT setting.

Long-term intravenous administration of activated autologous lymphocytes for cancer patients does not induce antinuclear antibody and rheumatoid factor.

The treatment of activated autologous lymphocyte can lead to a potent antitumor effect with destruction of autologous cancer cells, but potential adverse autoimmune effects due to destruction of autologous tissue must also be considered. This study was performed to evaluate whether administration of activated autologous lymphocytes induces autoimmune disease. Patients with advanced cancer, who underwent transfer therapy with activated autologous lymphocytes, were eligible for the study. Informed consent was obtained from 22 patients with hepatocelluler carcinoma, ovarian cancer, gastric cancer, etc. The variation in activated lymphocyte phenotypes was CD3+/HLA-DR+ activated T lymphocytes, 23% to 99%; including CD4+ cells, 4% to 65%; CD8+ cells, 10 to 91%; and CD16+/ICD56+ NK cells, 1% to 59%. Of the 22 patients, levels of antinuclear antibody and/or rheumatoid factor were above normal limits during the study in the following 5 patients: 3 patients showed no marked changes, one patient a slight decrease in rheumatoid factor and one patient a slight increase in antinuclear antibody during the course of treatment, respectively. The values for these markers of the other 17 patients varied within normal limits during treatment. Mild transient fever occurred in several patients as an adverse event. There were no other adverse reactions. No clinical symptoms or signs suggestive of autoimmune disease occurred in any patient during or after treatment. These results suggested that long-term administration of activated autologous lymphocytes does not induce autoimmune disease.

The pilot experience of immunotherapy-combined photodynamic therapy for advanced gastric cancer in elderly patients.

BACKGROUND: Therapeutic efficacy of endoscopic photodynamic therapy (PDT) for advanced gastric cancer is limited. Recent animal studies have clarified the very important role of host immune cells in PDT. We expected a potential cooperative effect of PDT and immunotherapy, and developed immunotherapycombined PDT (I-PDT) for advanced gastric cancer. METHODS AND MATERIALS: We applied I-PDT for two elderly patients with complicated advanced gastric cancer (92- and 89-yr-old males). Tumor bleeding prevented them from leading an ordinary home life. Initial simple PDT was not effective. Patients received over 109 activated T-lymphocyte-predominant autologous immune cells, mainly intravenously, 5x for one course. PDT was performed endoscopically on the day of the third infusion. RESULTS: Two or three courses of I-PDT safely stopped tumor bleeding, and the initial poor prognoses of a few months of survival seemed to be improved (patient 1, over 32 mo; patient 2, 14 mo). CONCLUSIONS: I-PDT was found to be a safe, feasible treatment that could improve symptoms resulting from advanced gastric cancer.