A phase I prospective, non-randomized trial of autologous dendritic cell-based cryoimmunotherapy in patients with metastatic castration-resistant prostate cancer

Metastatic castration-resistant prostate cancer (mCRPC) is an immunologically cold disease with dismal outcomes. Cryoablation destroys cancer tissue, releases tumor-associated antigens and creates a pro-inflammatory microenvironment, while dendritic cells (DCs) activate immune responses through processing of antigens. Immunotherapy combinations could enhance the anti-tumor efficacy. This open-label, single-arm, single-center phase I trial determined the safety and tolerability of combining cryoablation and autologous immature DC, without and with checkpoint inhibitors. Immune responses and clinical outcomes were evaluated. Patients with mCRPC, confirmed metastases and intact prostate gland were included. The first participants underwent prostate cryoablation with intratumoral injection of autologous DCs in a 3 + 3 design. In the second part, patients received cryoablation, the highest acceptable DC dose, and checkpoint inhibition with either ipilimumab or pembrolizumab. Sequentially collected information on adverse events, quality of life, blood values and images were analyzed by standard descriptive statistics. Neither dose-limiting toxicities nor adverse events > grade 3 were observed in the 18 participants. Results indicate antitumor activity through altered T cell receptor repertoires, and 33% durable (> 46 weeks) clinical benefit with median 40.7 months overall survival. Post-treatment pain and fatigue were associated with circulating tumor cell (CTC) presence at inclusion, while CTC responses correlated with clinical outcomes. This trial demonstrates that cryoimmunotherapy in mCRPC is safe and well tolerated, also for the highest DC dose (2.0 × 108) combined with checkpoint inhibitors. Further studies focusing on the biologic indications of antitumor activity and immune system activation could be considered through a phase II trial focusing on treatment responses and immunologic biomarkers.publishedVersio

Impact of positive surgical margins on secondary treatment, palliative radiotherapy and prostate cancer‐specific mortality. A population‐based study of 13 198 patients

Background The results of studies evaluating the impact of positive surgical margins on prostate cancer‐specific mortality have been inconsistent. We, therefore, evaluated the impact of surgical margin status on subsequent secondary treatment, palliative radiotherapy, and prostate cancer‐specific mortality. Methods A total of 14 837 men treated with radical prostatectomy (RP) during the period 2001 to 2015 were identified from the Cancer Registry of Norway. Of those, 13 198 (89%) patients had complete data on the preoperative prostate‐specific antigen level, pathological T‐category, Gleason score in the prostatectomy specimen, and margin status. Multivariable Cox proportional hazards models were used to evaluate the risk, and flexible parametric models for the cumulative incidence were fitted to predict the probabilities of secondary treatment (salvage radiotherapy or prophylactic breast radiation), palliative radiotherapy, and prostate cancer‐specific mortality. Results After a median follow‐up time of 5.2 years (3591 patients with ≥8 years of follow‐up), positive surgical margins (PSMs) were independently predictive of secondary treatment (hazard ratio [HR] = 2.43, 95% confidence interval [CI] = 2.21‐2.66) and palliative radiotherapy (HR = 1.45, 95% CI = 1.03‐2.05). After 10 years, the absolute increased risk for palliative radiotherapy in patients with PSMs after RP varied between 0.1% in pT2 tumors with a Gleason score of 6, to 12% for pT3b tumors with a Gleason score of 9 to 10. PSMs were not independently associated with prostate cancer‐specific mortality (HR = 1.14, 95% CI = 0.82‐1.59). Conclusion PSMs were associated with increased application of secondary treatment and palliative radiotherapy but were not predictive of prostate cancer‐specific mortality. As the use of palliative radiotherapy was only marginally increased in patients with PSMs and the lowest‐risk disease characteristics, avoiding PSMs may be of greatest prognostic relevance in patients with higher‐risk disease characteristics