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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 × 10 8 ) 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., (© 2023. The Author(s).)

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.

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.

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., (Copyright 2002 American Cancer Society.)

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.

Objective: To report 13-year biochemical disease-free survival results on 769 consecutive prostate cancer patients treated with brachytherapy alone., Material and Methods: Seven hundred sixty-nine patients with stage T1-T3, low to high Gleason grade prostate cancer underwent transperineal prostate implants with Iodine-125 (I-125) or Palladium-103 (Pd-103) as the sole treatment between January 1, 1987 and January 1, 1997. Median age was 69 years (range 43-92) and median follow-up was 71 months (range 18-156). Study cohort characteristics are summarized in Tables I and II and Figures 4-6. The patients were divided into two risk groups (low and high risk for extra-prostatic disease) based mainly on clinical stage and Gleason score. Group 1 consisted of 542 patients, who were considered at low risk and were treated with I-125. Group 2 comprised 227 patients, who were considered higher risk and were treated with Pd-103. No patient underwent pathological staging and none received androgen ablative therapy. Treatment failure was based on our modification of the American Society for Therapeutic Radiology and Oncology's (ASTRO) recommended failure criteria, defined as 3 consecutive serum Prostate Specific Antigen (PSA) rises (1). A critical component in our modification is that the value of the third PSA rise be above 0.5 ng/mL., Results: One hundred thirty-seven patients were lost to follow-up. Thirteen patients expired of non-cancer causes within 18 months of the implant. This left 619 patients for evaluation, 441 in Group 1 and 178 in Group 2. The biochemical disease-free survival rates of the 619 patients at 3, 5, 10, and 13 years were 85%, 80%, 77%, and 77%, respectively (Fig. 1). The biochemical disease-free survival rates of the 441 "lower risk" I-125 treated patients at 3, 5, 10, and 13 years were 84%, 79%, 76%, and 76%, respectively (Fig. 2). The biochemical disease-free survival rates of the 178 "higher risk" Pd-103 treated patients at 3, 5, 10, and 13 years were 87%, 82%, 80%, and 80%, respectively (Fig. 3)., Conclusion: The excellent long-term results presented here, as well as the many advantages of prostate brachytherapy over other common treatments, demonstrate that brachytherapy is an effective treatment for clinical organ-confined prostate cancer in the long term.

Background: The purported lack of long term modern prostate brachytherapy outcome data continues to lead many physicians to recommend other, more traditional treatments. This concern for long term results has encouraged the authors to supplement their earlier 10-year follow-up of patients receiving brachytherapy; in the process, an additional 77 patients (> 50%) were added to the original cohort, and the follow-up time was increased by 2 years., Methods: Between January 1987 and September 1989, 229 patients with T1-T3 prostate carcinoma underwent transperineal prostate brachytherapy using iodine-125 (I-125). No patient received adjuvant hormone therapy. The median Gleason sum was 5 (range, 2-10). Of these patients, 147 were determined to have a high probability of organ-confined disease and were treated solely with an I-125 implant. The remaining 82 patients were determined to be at increased risk for extracapsular disease and received pelvic external beam radiation in addition to brachytherapy. All patients were followed continuously. Failure was defined as a positive biopsy, radiographic evidence of metastases, or three consecutive rises in prostate specific antigen (PSA) levels as defined by the American Society for Therapeutic Radiology and Oncology (ASTRO) consensus article., Results: Excluding deaths from intercurrent disease, the median follow-up was 122 months (range, 18-144 months). Fourteen patients were excluded from analysis due to insufficient follow-up. Adopting the ASTRO definition of failure resulted in minimal change in survival when compared with the authors' previous study, which used a PSA level > 0.5 ng/mL as the failure point. Observed 10-year disease free survival (DFS) for the entire cohort was 70%. In the brachytherapy only group, the observed 10-year DFS was 66%, whereas those patients treated with the addition of external pelvic radiation achieved a DFS of 79%. None of the patients who were followed for the full 12 years failed between Years 10 and 12. Only 25% of the failures observed occurred > 5 years after treatment, thus confirming the durability of brachytherapy., Conclusions: Prostate brachytherapy provides excellent long term disease control with few late failures reported in the authors' program. The addition of external beam radiation appears to confer survival advantages in selected patients. Using the ASTRO failure criteria for long term follow-up resulted in no significant difference compared with using a PSA failure point of 0.5 ng/mL., (Copyright 2000 American Cancer Society.)

Prostate brachytherapy is an effective treatment option for clinically organ-confined prostate carcinoma. Observed 5- and 10-year follow-up have documented prostate-specific antigen (PSA) levels that were comparable to published radical prostatectomy series and were better than several published external-beam radiation series. Between January 1987 and June 1988, a total of 152 consecutive patients with Stage T1 to T3 low to high Gleason grade prostate cancer were studied at Northwest Hospital in Seattle, Washington. Patients' median age was 70 years (range, 53 to 92 years). All patients received Iodine-125 prostate brachytherapy with or without a 45 Gy dose of external-beam radiation. The average preoperative PSA, clinical stage, and prostate needle biopsy Gleason sum were 11 ng/ml, T2, and (5), respectively, and were known in all but five patients. PSA follow-up, clinical examination, and biopsy results judged disease-free survival at 5 and 10 postoperative years. Elevation of PSA above 0.5 ng/ml or a positive biopsy or a positive bone scan was considered treatment failure. The authors provide an historical review of prostate brachytherapy in conjunction with up-to-date implant techniques and long-term outcome results., (Copyright 2000 Wiley-Liss, Inc.)

Background: Prostate-specific antigen (PSA) cannot differentiate benign prostatic hyperplasia (BPH), from prostatitis, or prostate cancer in the range of 4.0-10 ng/ml. An accurate cytologic or histologic assessment is necessary to confirm the proper diagnosis. The nature of a biopsy tends to make it a selective test not frequently repeated. We are reporting a technique employing semen as a source for the differential diagnosis of prostate epithelial cells., Methods: Eleven vasectomized and nonvasectomized prostate cancer patients provided semen samples (stage T1 to T2). Two patients provided repeat samples. In addition, 15 vasectomized or nonvasectomized individuals without evidence of disease provided semen samples. Three million cells fixed with 50% ethanol were stained by an antibody (7E11.C5) to prostate-specific membrane antigen (PSMA), Hybritech Antibody (399) to PSA, and cytokeratin 8 and 18. In addition to the antibodies described, a DNA stain To-Pro 3 was used to identify 2n-4n DNA containing cells. A dual laser, Becton Dickinson FACSCaliber cytometer, was used to analyze the samples., Results: All semen specimens contained diploid, cytokeratin 18-positive epithelial cells regardless of disease status. A clear difference between prostate cancer and normal prostate cell samples was observed using staining with 7E11.C5. The ratio of prostatic cells in the total epithelial cell population (PSMA:cytokeratin ratios) was calculated for each specimen. A retrospective study of sixteen semen samples from 11 prostate cancer patients had a mean PSMA:cytokeratin ratio of 0.57, whereas the samples from 15 patients without evidence of cancer had a mean PSMA:cytokeratin ratio of 0.11. This difference was significant. PSA staining was variable and inconsistent., Conclusions: This report demonstrates that human semen contains prostate cells that can be characterized and used in the clinical diagnosis of prostate cancer.

Background: In this paper we describe our program for the immune monitoring of phase II participants given dendritic cell (DC)/prostate-specific membrane antigen (PSMA)-based immunotherapy, and we also present some initial findings., Methods: Phase II subjects received six administrations of autologous dendritic cells exogenously pulsed with two peptides derived from PSMA. Prior to the initial infusion, and following each treatment, peripheral blood mononuclear cells (PBMC) were collected for the generation of dendritic cells as well as for comprehensive immune monitoring., Results: Thus far, an increase in PSMA-peptide-specific as well as overall cellular reactivity has been observed in several patients receiving DC plus PSM-P1 and -P2, as measured by delayed-type hypersensitivity (DTH) test and enzyme-linked immunosorbant assay (ELISA)., Conclusions: Our initial observations using an ELISA and DTH test indicate that we are enhancing cellular immunity in prostate cancer patients following infusion with DC plus PSMA-derived peptides. Several methods are underway to comprehensively monitor both cell-mediated and humoral immune responsiveness, including: determining anti-PSMA serum antibody titers, testing immunogen-restricted responder-cell proliferation and cytotoxicity, assessing aberrations in signal transduction, antigen processing, and presentation, and measuring soluble factors that may promote tumor outgrowth.

Background: Stored serum from clinical trial cases undergoing ProstaScint (CYT-356) scanning were available for Prostate Specific Membrane Antigen (PSMA) assay. Prostate Specific Antigen (PSA) levels had already been determined. This provided an opportunity to see what correlations existed between the serum markers and the ProstaScint scan. A group of patients had the studies preprostatectomy, whereas another group had the studies postprostatectomy., Methods: The scan results, serum PSA, serum PSMA, and clinical data were separately analyzed. PSMA serum levels were determined by Western blot., Results: Preoperatively, radical prostatectomy patients showed a correlation between serum PSA or PSMA levels and the ProstaScint scan in the total group (n = 86), or in an untreated group (n = 38). Preoperatively, PSMA correlated with the pathological stage, whereas PSA correlated with the scan. Postoperatively, only PSMA serum levels correlated with the scan in an untreated group (n = 40)., Conclusions: Preoperatively or postoperatively, Western blot PSMA serum levels predict the stage of disease or local, regional, or distant metastases, as shown by ProstaScint scan. Both the scan and the serum tests provide prognostic information and evaluate the extent of disease to a more significant degree than previously possible.