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.

Chemotherapy followed by syngeneic dendritic cell injection in the mouse: findings and implications for human treatment.

A growing number of studies have described an apparent synergy between systemic chemotherapy administration and the intratumoral injection of dendritic cells (DCs) in the successful treatment of murine tumors. A review of several of these studies is undertaken here and possible combinations of DC therapy and conventional cancer therapies are discussed with the goal of contemplating the exploitation of current findings and theory toward the treatment of human patients with cancer. The methods and results of several murine studies are described in detail and additional reference is made to other relevant murine studies. Hypothetical routes of synergy between DC therapy, chemotherapy, and ablative therapies are explored, and the potentially significant role played by the regulatory immune system is discussed. Given the results of preclinical studies and the current understanding of cancer immunity, it is possible to consider a human treatment that calls for focal ablation of cancer followed by intratumoral DC injection, in the setting of chemotherapy-based regulatory T-cell depletion.

Dendritic cell based vaccines: progress in immunotherapy studies for prostate cancer.

PURPOSE: No effective treatment is currently available for metastatic prostate cancer. Dendritic cell (DC) based cancer vaccine research has emerged from the laboratories to human clinical trials. We describe progress in the development of DC based prostate cancer vaccine. MATERIALS AND METHODS: The literature was reviewed for major contributions to a growing number of studies that demonstrate the potential of DC based immunotherapeutics for prostate cancer. Background topics relating to DC based immunotherapy theory and practice are also addressed. RESULTS: DCs have been recognized as the most efficient antigen presenting cells that have the capacity to initiate naive T cell response in vitro and in vivo. During their differentiation and maturation pathways, dendritic cells can efficiently capture, process and present antigens for T cell activation. These characteristics make DC an attractive choice as the cellular adjuvant for cancer vaccines. Advances in DC generation, loading, and maturation methodologies have made it possible to generate clinical grade vaccines for various human trials. More than 100 DC vaccine trials, including 7 studies of patients with advanced prostate cancer have been reported to date. These vaccines were generally well tolerated with no significant adverse toxicity reported. Clinical responders have been identified in these studies. CONCLUSIONS: The new prospects opened by DC based vaccines for prostate cancer are fascinating. When compared to conventional treatments, DC vaccinations have few side effects. Improvements in patient selection, vaccine delivery strategies, immune monitoring and vaccine manufacturing will be crucial in moving DC based prostate cancer vaccines closer to the clinics.

Adjuvant chemohormonal therapy of high risk prostate carcinoma. Ten year results.

BACKGROUND: Patients with T3 and/or N1 prostate carcinoma have poor cure rates. The authors sought to improve the relapse free, cancer specific survival of these patients by adding chemohormonal therapy to radiation. METHODS: Twenty-five men with clinical Stage III positive seminal vesicles or positive nodes received six courses of vinblastine, doxorubicin, and mitomycin with simultaneous radiation and permanent androgen deprivation. Prostate specific antigen (PSA) testing was the sole criterion for relapse. Median followup was 10.5 years. RESULTS: Treatment was well tolerated. Patients received 91-95% of each drug and all planned radiation. At 10 years the cumulative relapse free rate determined by continuously undetectable PSA levels was 73%, and the cumulative cancer specific survival was 81%. Of node-positive patients, 82% were relapse-free at 10 years. CONCLUSIONS: The addition of chemotherapy to hormonal and radiation therapy is feasible and is accepted by most men when they are openly informed of their prognosis with conventional therapy. Results in the current small series appear excellent and may be superior to radiation plus hormones alone. Larger randomized studies are warranted.

An interinstitutional and interspecialty comparison of treatment outcome data for patients with prostate carcinoma based on predefined prognostic categories and minimum follow-up.

BACKGROUND: The optimal management of patients with clinically localized prostate carcinoma remains undefined due in part to the absence of well-designed, prospective, randomized trials. The current study was conducted to compare and contrast outcomes with different forms of therapy for patients with prostate carcinoma who were treated at several institutions using predefined prognostic categories. METHODS: A retrospective study of 6877 men with prostate carcinoma who were treated between 1989 and 1998 at 7 different institutions with 6 different types of therapy was conducted. Five-year actuarial rates of prostate specific antigen (PSA) failure were calculated based on predefined prognostic categories, which included combinations of pretreatment PSA level, tumor stage, and Gleason score. In addition, outcome was calculated using consistent biochemical failure definitions and a minimum, median length of follow-up. RESULTS: Substantial differences in outcome were observed for the same type of treatment and at the same institution, depending on the number of prognostic variables used to define treatment groups. However, estimates of 5-year PSA outcomes after all forms of therapy for low-risk and intermediate-risk patient groups were remarkably similar (regardless of the type of treatment) when all three pretreatment variables were used to define prognostic categories. For patients in high-risk groups, the 5-year PSA outcomes were suboptimal, regardless of the treatment technique used. CONCLUSIONS: The current data suggest that interinstitutional and interspecialty comparisons of treatment outcome for patients with prostate carcinoma are possible but that results must be based on all major prognostic variables to be meaningful. Analyzed in this fashion, 5-year PSA results were similar for patients in low-risk and intermediate-risk groups, regardless of the form of therapy. Findings from prospective, randomized trials using survival (cause specific and overall) as the end point for judging treatment efficacy and longer follow-up will be needed to validate these findings and to identify the most appropriate management option for patients with all stages of disease.