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.

Alterations in Hepatocellular Carcinoma-Specific Immune Responses Following Hepatitis C Virus Elimination by Direct-Acting Antivirals.

Direct-acting antivirals (DAAs) have recently revolutionized the eradication of chronic hepatitis C virus (HCV) infection. However, the effects of DAAs on the development of hepatocellular carcinoma (HCC) remain unknown. Therefore, the present study aimed to investigate immune responses to HCC influenced by DAAs in HCV-infected patients and elucidate the underlying mechanisms. We compared immune responses to 19 different HCC-related tumor-associated antigen (TAA)-derived peptides and host immune cell profiles before and 24 weeks after a treatment with DAAs in 47 HLA-A24-positive patients. The relationships between the different immune responses and phenotypic changes in immune cells were also examined. The treatment with DAAs induced four types of immune responses to TAAs and markedly altered host immune cell profiles. Prominently, reductions in the frequencies of PD-1+CD4+ and PD-1+CD8+ T cells by DAAs were associated with enhanced immune responses to TAAs. The HCV F protein was identified as contributing to the increased frequency of PD-1+ T cells, which may be decreased after eradication by DAAs. DAAs altered the immune responses of patients to HCC by decreasing the frequency of PD-1-expressing CD4+ and CD8+ T cells.

Acute kidney injury following vomiting and diarrhea after endoscopy in a duodenal gastrinoma patient.

A 51-year-old woman complaining of weakness in the limbs was diagnosed as having a duodenal gastrinoma on performing a further evaluation. Surgical resection was performed with selective arterial calcium injection for localization. During preoperative hospitalization, she experienced recurrent severe vomiting and diarrhea after endoscopy, leading to acute kidney injury. To our knowledge, this is the first report of gastrinoma with post-endoscopy symptom exacerbation. Although the etiology is unknown, the findings in this case suggest that sufficient fluid replacement, sedation, and high-dose proton pump inhibitor administration should be taken into consideration when performing endoscopy in gastrinoma patients.

Programmed cell death-1 is involved with peripheral blood immune cell profiles in patients with hepatitis C virus antiviral therapy.

Mutations in the non-structural protein regions of hepatitis C virus (HCV) are a cause of a non-sustained virological response (SVR) to treatment with direct-acting antivirals (DAAs) for chronic hepatitis; however, there are non-SVR cases without these mutations. In this study, we examined immune cell profiles in peripheral blood before and after ombitasvir/paritaprevir/ritonavir treatment and screened for genes that could be used to predict the therapeutic effects of DAAs. Fluorescence-activated cell sorting analysis indicated that the median frequencies of programmed cell death-1-positive (PD-1+) effector regulatory T cells (eTregs), PD-1+CD8+ T cells, and PD-1+Helper T cells were decreased significantly in SVR cases, but without significant changes in non-SVR cases. The frequency of PD-1+ naïve Tregs was significantly higher in the SVR group than in the non-SVR group before and after treatment. Similar results were found in patients treated with other DAAs (e.g., daclatasvir plus asunaprevir) and supported an immune response after HCV therapy. RNA-sequencing analysis indicated a significant increase in the expression of genes associated with the immune response in the SVR group, while genes related to intracellular and extracellular signal transduction were highly expressed in the non-SVR group. Therefore, we searched for genes associated with PD-1+ eTregs and CD8+ T cells that were significantly different between the SVR and non-SVR groups and found that T-box transcription factor 21 was associated with the non-SVR state. These results indicate that PD-1-related signaling pathways are associated with a non-SVR mechanism after DAAs treatment separate from mutation-related drug resistance.

Lenvatinib-induced tumor lysis syndrome in a patient with advanced hepatocellular carcinoma: a case report.

Tumor lysis syndrome (TLS) is an oncologic emergency caused by release of intracellular tumor components due to massive tumor lysis and is rare in patients with hepatocellular carcinoma (HCC). We describe a case of TLS with rupture of HCC induced by lenvatinib in a patient with advanced HCC. A 72-year-old man who presented with right upper abdominal pain was diagnosed as having advanced HCC with a high tumor burden by contrast-enhanced computed tomography and percutaneous hepatic tumor biopsy. He was started on lenvatinib 12 mg once daily when his tumor progressed despite one-shot hepatic arterial infusion chemotherapy. On day 2 of treatment with lenvatinib, he developed severe upper abdominal pain and was diagnosed as having TLS with HCC rupture by laboratory tests and contrast-enhanced computed tomography. Urgent treatment with transarterial embolization, hemodialysis, and blood transfusion therapy was successful. The patient was then restarted on oral lenvatinib at a reduced dose without recurrence of TLS. TLS is a rare potential complication of lenvatinib in patients with advanced HCC and a high tumor burden.

Effects of adaptive immune cell therapy on the immune cell profile in patients with advanced gastric cancer.

BACKGROUND: Immunotherapy for cancer patients has been the subject of attention in recent years. In this study, we investigated whether αßT-cell therapy causes changes in the host's immune cell profile, and if so, the effect of these changes on prognosis. METHODS: Peripheral blood mononuclear cells (PBMCs) from 30 gastric cancer patients who had completed one course of αßT-cell therapy were analyzed. The peripheral blood immune cell profile was established using PBMCs by counting the frequency of CD4+ helper T cells, CD8+ killer T cells, regulatory T cells (Tregs), and myeloid-derived suppressor cells and measuring the expression of their surface markers. The changes after treatment and their association with response to treatment were investigated. RESULTS: Immune cell profiles changed greatly after treatment. The frequency of CD4+ helper T cells decreased, but that of CD8+ killer T cells increased. The frequency of programmed cell death 1 (PD-1)+ effector Tregs increased significantly, but only in the non-progressive disease (non-PD) group, in which it was significantly higher compared with the PD group. Patients in whom the frequency of PD-1+ effector Tregs increased had a significantly better prognosis than those in whom it decreased. CONCLUSION: Our results suggested that αßT-cell therapy changes the host's immune cell profile, and an increase in PD-1+ effector Tregs may help improve prognosis.