Safety evaluation of immune-cell therapy for malignant tumor in the Cancer Immune-cell Therapy Evaluation Group (CITEG).

BACKGROUND AIMS: With the aim of strengthening the scientific evidence of immune-cell therapy for cancer and further examining its safety, in October 2015, our hospital jointly established the Cancer Immune-Cell Therapy Evaluation Group (CITEG) with 39 medical facilities nationwide. METHODS: Medical information, such as patients' background characteristics, clinical efficacy and therapeutic cell types obtained from each facility, has been accumulated, analyzed and evaluated by CITEG. In this prospective study, we analyzed the adverse events associated with immune-cell therapy until the end of September 2022, and we presented our interim safety evaluation. RESULTS: A total of 3839 patients with malignant tumor were treated with immune-cell therapy, with a median age of 64 years (range, 13-97 years) and a male-to-female ratio of 1:1.08 (1846:1993). Most patients' performance status was 0 or 1 (86.8%) at the first visit, and 3234 cases (84.2%) were advanced or recurrent cases, which accounted for the majority. The total number of administrations reported in CITEG was 31890, of which 960 (3.0%) showed adverse events. The numbers of adverse events caused by treatment were 363 (1.8%) of 19661 administrations of αßT cell therapy, 9 of 845 administrations of γδT-cell therapy (1.1%) and 10 of 626 administrations of natural killer cell therapy (1.6%). The number of adverse events caused by dendritic cell (DC) vaccine therapy was 578 of 10748 administrations (5.4%), which was significantly larger than those for other treatments. Multivariate analysis revealed that αßT cell therapy had a significantly greater risk of adverse events at performance status 1 or higher, and patients younger than 64 years, women or adjuvant immune-cell therapy had a greater risk of adverse events in DC vaccine therapy. Injection-site reactions were the most frequently reported adverse events, with 449 events, the majority of which were associated with DC vaccine therapy. Among all other adverse events, fever (228 events), fatigue (141 events) and itching (131 events) were frequently reported. In contrast, three patients had adverse events (fever, abdominal pain and interstitial pneumonia) that required hospitalization, although they were weakly related to this therapy; rather, it was considered to be the effect of treatment for the primary disease. CONCLUSIONS: Immune-cell therapy for cancer was considered to be a safe treatment without serious adverse events.

Prognostic Factors for Endometrial and Cervical Cancers of Uterus Treated With Immune-cell Therapy: A Retrospective Study.

BACKGROUND/AIM: In this retrospective study, we aimed to investigate the efficacy of immune-cell therapy using T lymphocytes activated in vitro with or without dendritic cell vaccination in combination with standard therapies in terms of the survival of patients with advanced or recurrent endometrial and cervical cancers of the uterus. PATIENTS AND METHODS: A total of 187 patients with advanced or recurrent uterine cancer were enrolled in this study. The correlation between overall survival and various clinical factors was examined by univariate and multivariate analyses. RESULTS: Univariate analysis revealed that the prognosis was improved in uterine cancer patients who received immune-cell therapy without prior chemotherapy or without distant metastasis. Multivariate analysis demonstrated that the absence of prior chemotherapy for endometrial cancer and liver/lung metastasis of cervical cancer are indications for immune-cell therapy. CONCLUSION: Survival benefit in uterine cancer patients could be potentially obtained by a combination of immune-cell therapy with other therapies.

Adoptive Immune-Cell Therapy for the Treatment of Neuroendocrine Carcinoma of the Uterine Cervix.

BACKGROUND/AIM: We aimed to investigate the efficacy of immune-cell therapy in terms of the survival of patients with neuroendocrine carcinoma of the uterine cervix (NECC), which lacks standardized therapeutic approaches. PATIENTS AND METHODS: We identified 17 patients who were diagnosed as having NECC and treated with immune-cell therapy. The clinical characteristics of these patients were extracted from their records and their overall survival was measured. RESULTS: Of the 17 patients, two patients with early-stage NECC without recurrence and three patients with less than four treatments were excluded. The median survival times from the time of diagnosis and from the initial administration of immune-cell therapy were 49.7 and 24.4 months, respectively. The overall survival rates at 1, 2, and 5 years were 63.6%, 38.2%, and 25.5%, respectively. Long-term survival was observed in the patients with distant metastases. CONCLUSION: The preliminary results of this retrospective study suggested the potential efficacy of immune-cell therapy for NECC.

Identification of prognostic factors for γδT cell immunotherapy in patients with solid tumor.

BACKGROUND AIMS: Activated γδT cells have been shown to exhibit cytotoxicity against tumor cells. However, the efficacy of γδT cell immunotherapy for a large number of patients with solid tumors remains unclear. In this study, we examined the efficacy of γδT cell immunotherapy using in vitro-activated γδT lymphocytes in combination with standard therapies in terms of the survival of patients with solid tumors, and determined prognostic factor for γδT cell immunotherapy. METHODS: 131 patients enrolled in this study received γδT cell immunotherapy with or without standard therapies. Their overall survival was analyzed by the Kaplan-Meier with log-rank test and Cox regression methods. Immunological analysis was performed by flow cytometry (FCM) before and after six cycles of γδT cell immunotherapy. RESULTS: Multivariable analysis revealed that patients who showed stable disease (SD) and partial response (PR) to γδT cell immunotherapy showed better prognosis than those with a progressive disease (PD) (P = 0.0269, hazard ratio [HR], 0.410, 95% confidence interval [CI], 0.190-0.901). Furthermore, when immunological parameters were examined by FCM, the high Vγ9/γδT ratio (i.e., the high purity of the Vγ9 cells within the adoptively transferred γδT cells) before treatment was found to be a good prognostic factor for γδT cell immunotherapy (P = 0.0142, HR, 0.328, 95% CI, 0.125-0.801). No serious adverse events were reported during γδT cell immunotherapy. CONCLUSION: Thus, γδT cell immunotherapy might extend the survival of patients with solid tumors.

Prognostic Factors for Colorectal Cancer Patients Treated With Combination of Immune-cell Therapy and First-line Chemotherapy: A Retrospective Study.

BACKGROUND/AIM: In this retrospective study, we aimed to investigate the efficacy of immune-cell therapy using T lymphocytes activated in vitro with or without dendritic cells vaccination (DCs), in combination with 1st-line chemotherapies in terms of the survival of patients with advanced colorectal cancer (CRC). PATIENTS AND METHODS: A total of 198 patients who were diagnosed with advanced CRC and administered 1st-line chemotherapies were enrolled in this study. The correlation between overall survival (OS) and various clinical factors was examined by univariate and multivariate analyses. RESULTS: Univariate analyses revealed that the prognosis was improved in CRC patients who received immune-cell therapy with PS 0, bevacizumab (BV), and capecitabine-including regimens (Cap). Finally, multivariate analysis demonstrated that PS=0, and the combination of immune-cell therapy and Cap provided a survival benefit in patients with advanced CRC. CONCLUSION: The survival benefit could be potentially obtained with better PS by the combination of immune-cell therapy and Cap as a 1st-line setting in patients with CRC.

Prognostic Factors for Pancreatic Cancer Patients Treated with Immune-cell Therapy.

BACKGROUND/AIM: The past 17 years, immune-cell therapy has been administered to 990 patients with advanced or recurrent pancreatic adenocarcinoma and 50 patients with curatively resected pancreatic adenocarcinoma. MATERIALS AND METHODS: The correlation between overall survival (OS) and various factors including sex, age, performance status (PS), distant metastasis, chemotherapy, radiotherapy, and type of immune-cell therapy were evaluated by univariate and multivariate analyses. RESULTS: The median OS of advanced or recurrent pancreatic cancer was 5.8 months, and the prognosis was improved in pancreatic cancer patients who received immune-cell therapy with PS scores of 0-1 [hazard risk (HR)=0.56; 95% confidence interval (CI)=0.46-0.68; p<0.0001], chemotherapy (HR=0.68; 95%CI=0.54-0.87; p=0.002), or radiotherapy (HR=0.76; 95%CI=0.63-0.93; p=0.006). Multivariate analysis demonstrated that distant metastasis indicated a poor prognosis for pancreatic cancer patients that were administered immune-cell therapy (HR=1.62; 95%CI=1.37-1.93; p<0.0001). Additionally, the combined immune-cell therapy with αß T cell and dendritic cell (DC) vaccine provided a survival benefit in advanced or recurrent pancreatic cancer patients (HR=0.69; 95%CI=0.57-0.83; p<0.0001). CONCLUSION: A survival benefit could be potentially obtained with better PS by the combination of αß T cell therapy, DC vaccine therapy, and chemotherapy at an early stage in pancreatic cancer.

Efficacy of Adoptive Immune-cell Therapy in Patients with Advanced Gastric Cancer: A Retrospective Study.

BACKGROUND: Conventional therapy for advanced gastric cancer (GC) has limited survival benefits. In this retrospective study, we aimed to investigate the efficacy of immune-cell therapy, using in vitro-activated T-lymphocytes with and without dendritic cells (DCs), in combination with standard therapies in terms of the survival of patients with advanced GC. PATIENTS AND METHODS: A total of 242 patients who were diagnosed as having stage-IV GC were enrolled in this study to receive immune-cell therapy with or without standard therapies, such as chemotherapy, surgery, or radiation therapy. Overall survival was analyzed by the Kaplan-Meier with log-rank test and Cox regression methods. RESULTS: Immune-cell therapy increased median survival time (21.5 months) in patients with advanced GC. The patients who underwent surgery with or without chemotherapy as a prior treatment showed better prognosis than those who received other therapies (p<0.001). Patients who showed stable disease or a partial response to immune-cell therapy had a better prognosis than those with progressive disease (p<0.001). Multivariate analysis revealed that performance status, the type of immune-cell therapy, and prior treatment were independent prognostic factors for patients with GC. No serious adverse event was reported in immune-cell therapy. CONCLUSION: Immune-cell therapy might extend the survival of patients with advanced GC.

Immunohistochemical Analysis of WT1 Antigen Expression in Various Solid Cancer Cells.

For a peptide-pulsed dendritic cell (DC) vaccine to work effectively in cancer treatment, it is significant that the target protein is expressed in cancer cells. Wilms' tumor 1 (WT1) has been identified as a molecular target for immune cell therapy of cancer. We evaluated the protein expression levels of WT1 in various solid tumors, as well as mucin 1 (MUC1) or major histocompatibility complex (MHC) class l molecules. Seven hundred and thirty-eight patients whose tissue samples were examined by immunohistochemical analysis agreed to undergo DC vaccine therapy. The positive staining of WT1 in tumor cells was observed in 25.3% of patients, with only 8.5% of them showing moderate to strong expression; moreover, WT1 tended to localize in the nucleus and cytoplasm. A positive staining of tumor cells by an anti-MHC class l monoclonal antibody was observed in 98.6% and by an anti-MUC1 monoclonal antibody in 76.8% of the patients. In relation to the application of cancer-specific immunotherapy, these findings provide useful information for determining the efficacy of MUC1- and WT1-targeted therapy.

Improvement of Impaired Immunological Status of Patients with Various Types of Advanced Cancers by Autologous Immune Cell Therapy.

We evaluated the immunological status of patients with various solid tumors by flow cytometry of immune cell populations and their frequencies in peripheral blood samples. The change in immunological status was also analyzed in patients given autologous immune cell therapy, such as αßT cell, γδT cell, NK cell or DC vaccine therapy. The frequency of regulatory T-cells (Tregs) was shown to be high in patients with cancers of the lung (squamous carcinoma cells), head and neck, esophagus and uterus, although there were no significant differences in effector cell population or Th1/2 ratio between various types of cancers except for a few. The cellular immunological status was impaired in most patients with advanced solid tumors before immune cell therapy and the impaired T-cell immune status was restored by infusion of effector cells, such as αßT cells or γδT cells, although the number of NK cells in the peripheral blood did not always increase after autologous NK cell therapy. The concurrent αßT cell therapy and DC vaccine therapy could successfully increase the number of CD8(+) T-cells in the peripheral blood of patients with various types of cancers. Two or three injections of αßT cells could potentially reduce Tregs frequency prior to DC vaccine, as well as the concurrent αßT cell and DC vaccine therapy. However, an increase in the Tregs frequency was observed in some patients who received NK cell therapy. These findings suggest that it is necessary to include or combine certain types of immune cell therapy when the Tregs frequency of cancer patients is high before or after autologous immune cell therapy.

Case report: A breast cancer patient treated with GcMAF, sonodynamic therapy and hormone therapy.

BACKGROUND: Gc protein-derived macrophage-activating factor (GcMAF) occurs naturally in the human body. It has various functions, such as macrophage activation and antitumor activities. Recently, immunotherapy has become an attractive new strategy in the treatment of cancer. GcMAF-based immunotherapy can be combined with many other therapies. Sonodynamic therapy (SDT) using low-intensity ultrasound is a novel therapeutic modality. Ultrasound has been demonstrated to activate a number of sonosensitive agents allowing for the possibility of non-invasive targeted treatment for both superficial and deep-seated tumors. The current case study demonstrates that GcMAF and SDT can be used in combination with conventional therapies in patients with metastatic cancer, especially where treatment options are limited due to factors such as toxicity. This case study also suggests a new concept of cancer treatment using local destruction of cancer tissue, in this case conducted with SDT, to be used in combination with GcMAF immunotherapy as a systemic treatment.

[A malignant lymphoma (non-hodgkin lymphoma, follicular type) patient who achieved complete remission by radiochemotherapy].

A 54-year-old female patient visited our hospital as an outpatient in August 2008 for her growing mass thigh, without pain, redness or fever. She had suffered discomfort from that swelling since she had been diagnosed with erysipelas by a dermatologist she had visited 6 months before and received some medication. Suspicious of a subcutaneous soft tissue tumor, we performed a biopsy, and histological examination of the lesion indicated malignant lymphoma (follicular lymphoma grade 2). PET-CT (as of September, 2008) showed abnormal migration at the right inguinocrural and right external iliac lymph nodes. In view of her age and the that rapid exacerbation, we considered chemotherapy (rituximab, cyclophosphamide, adriamycin, vincristine and prednisolone: R-CHOP) and involved field radiotherapy (IFRT) better to perform than 'watchful wait'. PET-CT (as of November, 2008) after 3 courses of R-CHOP therapy showed abnormal migration had been significantly improved (complete remission on PET-CT) and completely disappeared in the right external iliac lymph nodes. For long-term prognosis and prophylaxis of recurrence, we then added 2 courses of chemotherapy (rituximab alone) and IFRT (30 Gy/20 Fr) as radical therapy. She is now doing well and visits our hospital once a month for follow-up after achieving CR with RECIST guideline.

[A recurrent gastric cancer patient with multiple organ metastasis who achieved partial remission by multidisciplinary therapy (radiochemotherapy plus hyperthermia)].

A 77-year-old male patient visited our hospital for postoperative gastric cancer in September of 2007. He suffered from serious appetite loss, general fatigue, nausea and some other side effects since he was taking S-1(100 mg/day) for the postoperative adjuvant therapy. Chest enhanced CT(as of September, 2007)revealed right mediastinum lymph node metastases and multiple liver metastases that had been diagnosed at the operation were evaluated as remission. He re-started S-1 with a lower dose(80 mg/day)soon after he visited our hospital as an outpatient. That side-effect was slightly improved. However, PET-CT(as of May, 2008)showed another metastasis of left supraclavicular lymph nodes(Virchow lymph nodes). Multidisciplinary therapy, chemotherapy(docetaxel 60 mg/m2, every 3 weeks), radiotherapy and hyperthermia were performed and PET-CT(as of July, 2008)showed left supraclavicular lymph node metastases were evaluated as complete remission, and as to right mediastinum lymph node metastases, we achieved partial remission. Thus, overall partial remission was achieved with the RECIST guideline.

[Intratumoral injection of immature dendritic cells (DC) for cancer patients].

We proceeded with DC immunotherapy for 21 cancer patients. Immature dendric cells were injected intratumorally to the 16 patients, and three good and effective cases were obtained: case 1: A 69-year-old male patient with papilla-vater carcinoma, case 2: A 49-year-old female patient with gastric cancer, case 3: A 66-year-old male patient with malignant melanoma.

Reduced-intensity stem cell transplantation in two cases of metastatic renal cell carcinoma.

Allogeneic hematopoietic stem-cell transplantation can induce curative graft-versus-leukemia reactions in patients with hematological malignancies. There is also evidence of such an effect in patients with solid tumors. We report two patients with metastatic renal cell carcinoma who underwent RIST. In both patients, disease progression was observed 6 months after transplantation. However, one patient had transient symptoms of tumor progression after the occurrence of acute graft-versus-host disease, consistent with graft-versus-tumor effects.

[Successful treatment with foscarnet for disseminated varicella-zoster infection after reduced intensity stem cell transplantation in a case of relapsed refractory central nervous system lymphoma].

Visceral disseminated varicella-zoster virus (VZV) infection occurred with acute graft-versus-host disease in a 33-year-old Japanese male with non-Hodgkin lymphoma who had undergone allogeneic stem cell transplantation from an HLA-identical sibling after reduced intensity conditioning chemotherapy. Although ganciclovir and acyclovir treatment was effective temporarily, the number of VZV-DNA copies in the blood remained at a high level, and the hepatitis was prolonged. The patient was treated with foscarnet, which led to improvement of the VZV viremia and the hepatic dysfunction. Foscarnet therapy should be considered for acyclovir-resistant VZV infection in the setting of allogeneic hematopoietic stem cell transplantation.

[An XXX female with essential thrombocythemia].

We describe an XXX female patient accompanied with essential thrombocythemia. To our knowledge this is the first case ever to have been reported. The patient was asymptomatic, but her platelet count had increased to 111.2 x 10(4)/microliter, and she was diagnosed as having essential thrombocythemia based on the diagnostic criteria of the Polycythemia Vera Study Group. At the same time, chromosome analysis of bone marrow cells revealed that she was an XXX female. The patient remained asymptomatic throughout the course of treatment.

[Analysis of factors for poor mobilization after administration of recombinant human granulocyte stimulating factor (rHuG-CSF) in healthy donors].

Allogeneic hematopoietic stem cell transplantation is an effective treatment for hematological malignancies. Peripheral blood stem cells (PBSCs) are increasingly used as an alternative to bone marrow for allogeneic transplantation. However, predictive factors for the response to recombinant human granulocyte stimulating factor (rHuG-CSF) in healthy donors have not been extensively studied. We analyzed the side effects, laboratory test results after administration of rHuG-CSF and the factors influencing mobilization of peripheral blood stem cells in 30 healthy donors. Bone pain, fever and headache were observed with high frequency after administration of rHuG-CSF. WBCs and reticulocytes increased, and RBCs and platelets decreased significantly after administration rHuG-CSF. Biochemical examination revealed significant elevations of LDH, CRP, ALP and UA. Univariate analysis showed the age of donors (< 50 vs. > 50, p = 0.041) and the lymphocyte counts before administration of rHuG-CSF (p = 0.032) to be correlated with the number of CD34 positive cells. From a multivariate analysis, the tendency for good mobilization with a twice daily dose of rHuG-CSF (p = 0.065) was observed. The rHuG-CSF schedule may be the most important factor affecting peripheral blood stem cell mobilization and collection in healthy donors.

Development of chronic myelocytic leukemia after chemotherapy for malignant fibrous histiocytoma.

At the age of 28, a 33-year-old male was diagnosed with malignant fibrous histiocytoma (MFH) with a primary lesion in the right maxillary sinus. Although arterial infusion chemotherapy (pirarubicin hydrochloride and carboplatin) was given, no tumor shrinkage was observed, and surgery was therefore performed to remove the tumor. Thereafter, the patient received autologous peripheral blood stem cell transplantation with high-dose chemotherapy (combination of ifosphamide, carboplatin and etoposide) as pretreatment. An increase in the peripheral leukocyte count was noted 56 months after the diagnosis of MFH was made. Cytogenetic study showed translocation (9;22)(q34;q11). Chronic myelocytic leukemia (CML) was therefore diagnosed. MFH was in a state of complete remission. The clinical course of this patient strongly suggests that this was a case of treatment-related CML that developed after chemotherapy for MFH. Treatment-related malignant blood diseases are known to include acute myelocytic leukemia and myelodysplastic syndrome, but reports of treatment-related CML are rare, although there have been some cases of treatment-related CML occurring several years after pretreatment.

[Chronic myelogenous leukemia treated with non-myeloablative stem cell transplantation after discontinuing myeloablative stem cell transplantation due to mental aberrations].

A 54-year-old woman with chronic myelogeneous leukemia was admitted to our hospital on February 15th, 2001 to undergo allogeneic bone marrow transplantation (BMT). We started the transplantation preconditioning with busulfan and high-dose cyclophosphamide on February 22nd, 2001. However, symptoms of a psychiatric nature, such as hallucination, persecution complex, auditory hallucination and sleeplessness, occurred by the third day of treatment with busulfan. Thus, we decided to discontinue conditioning and stopped the administration of BMT at that point. However, pancytopenia persisted for more than 20 days. She finally underwent BMT followed by reduced-intensity conditioning with fludarabine and ATG from a sex-mismatched, HLA-identical sibling donor on April 19th, 2001. To prevent any exacerbation of the psychotic symptoms, the patient was hospitalized in a laminar flow instead of a bio-free room. Graft-versus-host disease occurred on the 32nd hospital day, and was brought under control by steroid treatment. Achievement of complete chimeras was confirmed on the 54th hospital day. Her mental condition was kept stable with antidepressant drugs and tranquilizers, although minor changes in the combination of drugs were required to treat transient exacerbation of psychosis after a short period at home. She was discharged on September 1st, 2001. We think that non-myeloablative stem cell transplantation is a useful treatment for patients with hematological malignancy complicated with psychiatric disorders.