The induction of antigen-specific CTL by in situ Ad-REIC gene therapy.

An adenovirus vector carrying the human Reduced Expression in Immortalized Cell (REIC)/Dkk-3 gene (Ad-REIC) mediates simultaneous induction of cancer-selective apoptosis and augmentation of anticancer immunity. In our preclinical and clinical studies, in situ Ad-REIC gene therapy showed remarkable direct and indirect antitumor effects to realize therapeutic cancer vaccines. We herein aimed to confirm the induction of tumor-associated antigen-specific cytotoxic T lymphocytes (CTLs) by Ad-REIC. Using an ovalbumin (OVA), a tumor-associated antigen, expressing E.G7 tumor-bearing mouse model, we investigated the induction and expansion of OVA-specific CTLs responsible for indirect, systemic effects of Ad-REIC. The intratumoral administration of Ad-REIC mediated clear antitumor effects with the accumulation of OVA-specific CTLs in the tumor tissues and spleen. The CD86-positive dendritic cells (DCs) were upregulated in the tumor draining lymph nodes of Ad-REIC-treated mice. In a dual tumor-bearing mouse model in the left and right back, Ad-REIC injection in one side significantly suppressed the tumor growth on both sides and significant infiltration of OVA-specific CTLs into non-injected tumor was also detected. Consequently, in situ Ad-REIC gene therapy is expected to realize a new-generation cancer vaccine via anticancer immune activation with DC and tumor antigen-specific CTL expansion.

Acute Inflammatory Syndrome Paradoxically Induced by De Novo Purine Inhibitors Synthesis Before Renal Transplantation: A Case Report and Review of the Literature.

BACKGROUND: Mycophenolate mofetil (MMF) and mizoribine (MZR) are increasingly used as immunosuppressive agents for organ transplantation and chronic inflammation. We report a patient with rheumatoid arthritis who had an acute inflammatory syndrome triggered by preoperative immunosuppression therapy with both MMF and MZR. CASE REPORT: A 41-year-old woman with IgA nephropathy was referred to our department for living donor renal transplantation. She had rheumatoid arthritis that was adequately treated with prednisolone 5 mg once a day and salazosulfapyridine 2000 mg once a day. MMF 1000 mg twice a day was started for desensitization therapy. Three days later, the patient developed arthritis in the joints of her left hand and elevated inflammatory markers. On day 7, MMF was switched to MZR 150 mg 3 times a day. However, the symptoms extended to both shoulders and the joints of the right foot; MZR was discontinued. The arthritis and inflammatory markers improved. Two months later, the patient was rechallenged with MMF followed by MZR, resulting in a similar clinical course as previously. Tacrolimus (TAC) 3 mg twice a day and everolimus (EVL) 0.5 mg twice a day were introduced as alternative immunosuppressant therapies. No arthritis occurred. ABO-compatible living donor renal transplantation was successfully performed. The patient received TAC, EVL, prednisolone, rituximab, and basiliximab, and her postoperative course was uneventful without arthritis or rejection. At 9 months postoperatively, the serum creatinine was 0.79 mg/dL. CONCLUSIONS: Acute inflammatory syndrome is an extremely rare complication triggered by preoperative immunosuppression therapy. If antimetabolites cannot be used in immunologically high-risk patients, transplantation becomes very difficult. Clinicians should keep in mind this paradoxical reaction.

Adenovirus vector carrying REIC/DKK-3 gene: neoadjuvant intraprostatic injection for high-risk localized prostate cancer undergoing radical prostatectomy.

As the First-In-Human study of in situ gene therapy using an adenovirus vector carrying the human REIC (reduced expression in immortalized cell)/Dkk-3 gene (Ad-REIC), we conducted neoadjuvant intraprostatic injections in patients with high-risk localized prostate cancer undergoing radical prostatectomy (RP). Patients with recurrence probability of 35% or more within 5 years following RP, as calculated by Kattan's nomogram, were enrolled. Patients received two ultrasound-guided intratumoral injections at 2-week intervals, followed by RP 6 weeks after the second injection. After confirming the safety of the therapeutic interventions with initially planned three escalating doses of 1.0 × 1010, 1.0 × 1011 and 1.0 × 1012 viral particles (vp) in 1.0-1.2 ml (n=3, 3 and 6), an additional higher dose of 3.0 × 1012 vp in 3.6 ml (n=6) was further studied. All four DLs including the additional dose level-4 (DL-4) were feasible with no adverse events, except for grade 1 or 2 transient fever. Laboratory toxicities were grade 1 or 2 elevated aspartate transaminase/alanine transaminase (n=4). Regarding antitumor activities, cytopathic effects (tumor degeneration with cytolysis and pyknosis) and remarkable tumor-infiltrating lymphocytes in the targeted tumor areas were detected in a clear dose-dependent manner. Consequently, biochemical recurrence-free survival in DL-4 was significantly more favorable than in patient groups DL-1+2+3.