Introduction
death, cancers, tumor, cancer, malignancies, tumors, mCRPC, Cancer
CANCERS, TUMOR, CANCER, SOLID TUMORS, MALIGNANCIES, IMMUNE TOLERANCE, RENAL CELL CARCINOMA, METASTATIC PROSTATE CANCER, TUMORS, METASTATIC CASTRATION-RESISTANT PROSTATE CANCER, SKIN MALIGNANT MELANOMA, CANCER
Mortality rates remain high for patients who develop metastatic castration-resistant prostate cancer (mCRPC) [The immunological checkpoint inhibitor therapies, the cytotoxic T-lymphocyte protein 4 (CTLA-4) inhibitor, ipilimumab and programmed cell death protein 1 (PD-1) inhibitor, pembrolizumab, have demonstrated marked effects on progression-free survival (PFS) in malignant melanoma, renal cell carcinoma, and cancers with DNA repair deficiencies [An essential part of the immune response is mediated by dendritic cells (DCs), which are antigen-presenting cells that in their immature state recognize and process tumor-associated antigens. Early-phase trials of DC-based cancer immunotherapies have demonstrated the treatment as safe and feasible with anti-tumor immune activation, but with limited clinical responses [The capacity of malignancies to inactivate DCs and effector T cells and evade the circulating antitumor immune responses is challenging the development of immune-modulating therapies. The T cell subset, regulatory T-lymphocyte (Treg), plays a dual role of mediating immune tolerance and restricting the antitumor immunity [The heterogeneous expression of molecular targets on cells within and between tumors induces different treatment sensitivities and accordingly poses a challenge for targeted therapies. Previously, in vitro matured DCs have been trained to destroy mainly tumor cells expressing preselected antigens, but additionally generate bystander effects, where untreated cells are biologically altered by stress signals from directly treated cells to mirror these by exhibiting similar effects like reduced cell survival and genomic instability [Cancer cell heterogeneity is one of the most fundamental problems of cancer therapy. By combining cryoablation with intratumoral DC injection, cryoimmunotherapy (CryoIT) exposes the entire individualized collection of tumor-associated antigens to immature DCs (iDCs), which consequently are positioned to tackle the cellular heterogeneity. Cryoablation is a process where tissue destruction is initiated by freezing solid tumors to -40 °C in one or several freeze–thaw cycles. Cryoablation has been investigated in localized, locally recurrent, and metastatic prostate cancer [The primary aim of this phase I clinical trial of pre-treated mCRPC was to examine the safety and tolerability of the novel combination of cancer tissue cryoablation and intratumoral injection of autologous iDCs with and without immunological checkpoint inhibitor enhancement. Secondary and explorative endpoints included time to progression, survival, and monitoring of immune responses and circulating tumor cells.