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

TY - JOUR

T1 - A phase I prospective, non-randomized trial of autologous dendritic cell-based cryoimmunotherapy in patients with metastatic castration-resistant prostate cancer

AU - Thomsen, Liv Cecilie Vestrheim

AU - Honoré, Alfred

AU - Reisæter, Lars Anders Rokne

AU - Almås, Bjarte

AU - Børretzen, Astrid

AU - Helle, Svein Inge

AU - Førde, Kristina

AU - Kristoffersen, Einar Klæboe

AU - Kaada, Silje Helland

AU - Melve, Guro Kristin

AU - Haslerud, Torjan Magne

AU - Biermann, Martin

AU - Bigalke, Iris

AU - Kvalheim, Gunnar

AU - Azeem, Waqas

AU - Olsen, Jan Roger

AU - Gabriel, Benjamin

AU - Knappskog, Stian

AU - Halvorsen, Ole Johan

AU - Akslen, Lars Andreas

AU - Bahn, Duke

AU - Pantel, Klaus

AU - Riethdorf, Sabine

AU - Ragde, Haakon

AU - Gjertsen, Bjørn Tore

AU - Øyan, Anne Margrete

AU - Kalland, Karl-Henning

AU - Beisland, Christian

N1 - © 2023. The Author(s).

PY - 2023/7

Y1 - 2023/7

N2 - 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.

AB - 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.

KW - Humans

KW - Male

KW - Dendritic Cells

KW - Ipilimumab/therapeutic use

KW - Prospective Studies

KW - Prostatic Neoplasms, Castration-Resistant/therapy

KW - Quality of Life

KW - Tumor Microenvironment

U2 - 10.1007/s00262-023-03421-7

DO - 10.1007/s00262-023-03421-7

M3 - SCORING: Journal article

C2 - 36939854

VL - 72

SP - 2357

EP - 2373

JO - CANCER IMMUNOL IMMUN

JF - CANCER IMMUNOL IMMUN

SN - 0340-7004

IS - 7

ER -