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.

Braquiterapia en el tratamiento del cáncer de próstata localizado: estudio de supervivencia a trece años de 769 pacientes consecutivos tratados con implantes radiactivos como única medida terapéutica y libres de enfermedad en seguimiento bioquímico / Brachytherapy for clinically localized prostate cancer: thirteen-year disease-free survival of 769 consecutive prostate cancer patients treated with permanent implants alone

OBJETIVOS: Comunicar nuestros resultados de 13 años de seguimiento de nuestros pacientes libres de enfermedad seguidos por métodos bioquímicos en un total de 769 casos consecutivos tratados con braquiterapia como única medida terapéutica. MÉTODOS: Setecientos sesenta y nueve pacientes con cáncer de próstata, T1-T3, con Gleason altos y bajos, fueron sometidos a implante transperineal de Yodo 125 o Paladio 103, como único tratamiento en el periodo de 1 de Enero de 1987 a 1 de Enero de 1997. La edad media fue de 69 años (43-92) y el seguimiento medio fue de 71 meses (18-156). Se detallan las características de los pacientes en las Tablas I y II y figuras 4-6. Los pacientes se dividieron en dos grupos de riesgo (alto y bajo por enfermedad extraprostática) basándonos fundamentalmente en el estadio clínico y en el grado de Gleason. El grupo I lo constituyen 542 pacientes, considerados de bajo riesgo que fueron tratados con I-125. El grupo II, de alto riesgo compuesto por 227 pacientes, fue tratado con Pd-103. A ninguno de los pacientes se les hizo seguimiento con biopsia y ninguno fue sometido a terapéutico con antiandrógenos. El fallo del tratamiento se determinó con el criterio modificado de la Sociedad Americana de Radiología y de Oncología (ASTRO), definido como criterios de fracaso al incremento consecutivo de 3 determinaciones de PSA (1). Un componente crítico de nuestra modificación es que el valor del tercer PSA debe superar los 0,5 ng/ml. RESULTADOS: 137 pacientes se perdieron para control*. Trece pacientes fallecieron de causas no imputables a su cáncer de próstata, antes de los 18 meses de seguimiento. Esto nos deja con 619 pacientes para evaluación, 441 en el grupo I y 178 en el grupo II. La tasa de pacientes bioquímicamente libres de enfermedad del grupo de los 619 pacientes fue a los 3, 5, 10 y 13 años de 85 por ciento, 80 por ciento, 77 por ciento y 77 por ciento respectivamente (Fig. 1). La misma tasa libre de enfermedad para los pacientes de "bajo riesgo", es decir los 441 pacientes tratados con I-125, fue a los 3, 5, 10 y 13 años de 84 por ciento, 79 por ciento, 76 por ciento y 76 por ciento respectivamente (Fig. 2).La misma tasa libre de enfermedad para los pacientes de "alto riesgo", es decir 178 pacientes tratados con Pd103, fue a los 3, 5, 10 y 13 años de 87 por ciento, 82 por ciento, 80 por ciento y 80 por ciento respectivamente (Fig. 3).CONCLUSIONES: Los excelentes resultados a largo plazo presentados aquí así como las múltiples ventajas de la braquiterapia prostática sobre otros tratamientos que se utilizan comúnmente, demuestran la efectividad de este tratamiento a largo plazo en patología organoconifnada .Alrededor del 50 por ciento eran residentes en otros estados o extranjeros (AU)