A. Stenzl

mRNA vaccine CV9103 and CV9104 for the treatment of prostate cancer

Among currently available vaccine strategies for cancer, nucleotide-based vaccination is an appealing treatment modality. Curevacs’ mRNA containing vaccines (RNActive®) combine the beneficial properties of sufficient antigen-expression, autologous immune-stimulation and a high flexibility with respect to production and application. CV9103 and CV9104 are novel RNActive®-derived anticancer vaccines for the treatment of patients with prostate cancer. After successful phase I/II studies with documentation of good tolerability and favorable immune-activation of CV9103, the vaccine CV9104 is currently undergoing clinical testing in specific clinical settings such as castration resistant prostate cancer and as a neoadjuvant agent in men with high risk prostate cancer prior to surgery. This review discusses the available preclinical and clinical data on the anticancer vaccination treatment with RNActive®-derived anticancer-vaccines CV9103 and CV9104.

Checkpoint modulation--A new way to direct the immune system against renal cell carcinoma.

The introduction of targeted therapies like the tyrosine kinase (TKI) and mammalian target of rapamycin (mTOR) inhibitors has improved patients´ survival in general. Nevertheless the prognosis remains limited. Therapies with a new mode of action are urgently warranted, especially those who would provoke long-term responders or long-lasting complete remissions as observed with unspecific immunotherapy with the cytokines interleukin-2 and interferon-α. In the recent years a deeper understanding of the underlying immunology of T cell activation led to the development of checkpoint inhibitors, which are mainly monocloncal antibodies and which enhances the presence of the co-stimulatory signals needed for T cell activation or priming. This review discusses the clinical data and ongoing studies available for the inhibition of the PD-1 (CD279) and CTLA-4 (CD152) axis in mRCC. In addition, potential future immunological targets are discussed. This approach of T-cell activation or re-activation by immunological checkpoint inhibition holds the inherent promise to directly affect the tumor cell and thereby to potentially cure a subset of patients with mRCC.

Comment on “Epigenetic activation of the drug transporter OCT2 sensitizes renal cell carcinoma to oxaliplatin”

Although the combination of decitabine and platinum drugs may be promising for therapy of renal cell carcinoma, the role of OCT2 needs further investigations. Although the combination of decitabine and platinum drugs may be promising for therapy of renal cell carcinoma, the role of OCT2 needs further investigations.

Results of a Phase 1/2 Study in Metastatic Renal Cell Carcinoma Patients Treated with a Patient-specific Adjuvant Multi-peptide Vaccine after Resection of Metastases

Treatment of metastatic renal cell carcinoma comprises metastasectomy±systemic medical treatment. Specific immunotherapy after metastasectomy could be a complementary option. In this phase 1/2 study, safety and tolerability of an adjuvant multi-peptide vaccine (UroRCC) after metastasectomy was evaluated together with immune response and efficacy, compared with a contemporary cohort of patients (n=44) treated with metastasectomy only. Nineteen metastatic renal cell carcinoma patients received UroRCC via intradermal or subcutaneous application randomized to immunoadjuvants (granulocyte-macrophage colony-stimulating factor or Montanide). Adverse events of UroRCC were mainly grade I and II; frequency of immune response was higher for major histocompatibility complex class II peptides (17/19, 89.5%) than for major histocompatibility complex class I peptides (8/19, 42.1%). Median overall survival was not reached in the UroRCC group (mean: 112.6 mo, 95% confidence interval [CI]: 92.1-133.1) and 58.0 mo (95% CI: 32.7-83.2) in the control cohort (p=0.015). UroRCC was an independent prognosticator of overall survival (hazard ratio=0.19, 95% CI: 0.05-0.69, p=0.012). Adjuvant UroRCC multi-peptide vaccine after metastasectomy was well tolerated, immunogenic, and indicates potential clinical benefit when compared with a contemporary control cohort (NCT02429440). PATIENT SUMMARY The application of a patient-specific peptide vaccine after complete resection of metastases in metastatic renal cell carcinoma patients resulted in favorable tolerability and outcome.

1049 RANKL pathway proteins as risk parameters for biochemical recurrence in patients undergoing radical prostatectomy

INTRODUCTION AND OBJECTIVES: The development of bone metastases from prostate cancer is closely linked to the activity of the receptor activator of the NF-kB Ligand (RANKL) pathway. Recent evidence exists that this pathway might play a role for tumor biology before metastatic disease becomes manifest. We aimed to assess the prognostic impact of proteins of the RANKL pathway in serum samples of patients undergoing radical prostatectomy (RP). METHODS: In total, 178 patients undergoing RP between 2004 and 2006 were included. Serum concentrations of soluble RANKL (sRANKL) and osteoprotegerin (OPG) were determined retrospectively using Enzyme Linked Immunosorbent Assay (ELISA). Results of serum measurements were correlated to clinical and patient follow-up data using the Wilcoxon-Mann-Whitney test, the Kaplan-Maier method, and single variable or multifactorial Cox proportional hazards analysis. RESULTS: Increased sRANKL (p 0.01), decreased OPG (p 0.01) and an increased sRANKL/OPG Ratio (p 0.004) were significant risk factors for biochemical recurrence (BCR). In multifactorial analysis adjusted for classical risk factors for BCR, sRANKL and sRANKL/OPG ratio were confirmed as independent prognostic factors even when considered as continuous variables. Neither sRANKL nor OPG showed a clear association with classical histopathologic factors such as pT, pN, PSA, Gleason score or R status. CONCLUSIONS: Increased activity of the RANKL pathway in the serum of patients with prostate cancer undergoing RP is a risk factor for biochemical recurrence. The RANKL pathway seems to contribute to the biological behavior of prostate cancer already in an organ-confined stage of the disease. Whether serum proteins of this pathway are also able to predict response to RANKL-inhibition in patients without bone metastases remains to be elucidated.

378 DORSAL INLAY SKIN-GRAFT URETHROPLASTY IN PATIENTS OLDER THAN 65 YEARS

Objectives Single-stage dorsal onlay graft urethroplasty is effective for anterior urethral reconstruction. Despite an aging population, the results of this technique in elderly patients have not yet been explicitly reported. We present our experience with dorsal onlay graft urethroplasty in this cohort. Methods We reviewed all urethroplasties performed on males older than 65 years with at least 6 months follow-up. All exhibited extensive anterior urethral strictures precluding anastomotic urethroplasty. Dorsal onlay skin graft urethroplasty was done after stricturotomy using either penile or groin skin grafts. The neourethra was then tubularized in a single stage. Pre- and postoperative urethrograms, urethral ultrasound, and flow measurements were performed in all. Results Forty-two men (mean age 69.25 years) underwent dorsal onlay urethroplasty. Mean graft length was 5.35 cm (range, 3-12). Penile skin was used in 29 and groin skin in 13. Average follow-up was 57.17 months (range, 29-82). Complications occurred in 4 (9.5%), including fistula formation and stricture recurrence. Final success rate was 90.5%. Compared with patients younger than 65 years, there were slightly more failures. Despite prolonged lithotomy position, we did not observe neurovascular lower extremity injuries. Perioperative complications were uncommon. Conclusions Dorsal onlay skin graft urethroplasty can be reliably used in older men with extensive urethral strictures. Although recurrence rates seem to be slightly higher, urethroplasty is generally well tolerated in this cohort of patients. Given the favorable outcome of the dorsal onlay technique, urethral reconstruction should not be withheld solely on the basis of age. Regarding the lifelong benefits of repair, the increased complication rates appear negligible.