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

Abstract

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.

Modern Methods of Obtaining Immune Dendritic Cells With Anti-Tumor Potential

“…При проведенні пацієнтам, хворим на рак простати, кріоаблації та внутрішньопухлинному введенні 2,010 8 аутологічних незрілих ДК було показано, що така терапія добре переноситься пацієнтами і в 33 % випадків дає тривалий (46 тижнів) клінічний ефект із середнім показником загального виживання 40,7 місяця [8].…”

“…Однак, як свідчать численні клінічні випробування, вакцини на основі ДК поки що мають низьку ефективність при лікуванні солідних пухлин і гематологічних онкозахворювань [6]. Проте ці вакцини можуть стати інструментом, спрямованим на індукцію розвитку специфічної протипухлинної Т-клітинної відповіді в поєднанні з іншими методами протипухлинної терапії [7,8]. Багато в чому успіх лікування онкозахворювань із використанням ДК залежить як від біологічних характеристик пухлини, так і від вихідного імунного статусу пацієнта [9].…”

Dendritic cell subsets and implications for cancer immunotherapy

“…The performance of Sipleucel-T as a monotherapy ultimately was never widely adopted due to high cost for limited benefit. It is however currently being investigated for use as combination therapy with checkpoint blockade, chemotherapy, radiation, and cryoablation (120,121). Again, clinical benefit has been unclear.…”