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.

3029 Background: Dendritic cell (DC)-based cryoimmunotherapy (CryoIT) was used to treat metastatic castration-resistant prostate cancer in a Phase I clinical trial. Primary objective was safety of treatment. Secondarily, clinical, radiological and immunological treatment responses were investigated. Methods: In 18 patients cryoablation by a freeze-thaw process under general anesthesia was performed, followed by intratumoral autologous immature DC injection. In the last 9 patients checkpoint inhibition of either CTLA-4 or PD-1 was added. Subjects had minimum 46 weeks follow-up. Adverse events (AEs) and blood analyses were registered at all visits. Disease progression was determined by three imaging modalities according to (i)RECISTv1.1 and progression-free survival (PFS) by Kaplan-Meier method. Circulating tumor cells (CTC/7.5 mL, CellSearch) and ultradeep T-cell receptor (TCR) b-chain sequences (TCRSafe) were enumerated. Patients were separated by CTC into none (n=10), 1-4 (n=4) and ≥ 5 (n=4). Health related quality of life (HRQoL) measured by EORTC-QLQ C30 questionnaire were answered at inclusion, and 10, 22 and 46 weeks post CryoIT. Scores were calculated according to the EORTC manual. Results: Subjects progressing within 22 weeks had higher PSA (p=0.03). AE profile of the total cohort (n=18) was comparable with interim reports (n=13); of 20 possible DC-related AEs one was severe (urinary retention) and 19 mild-to-moderate, and spread independent of treatment regime. Maximum tolerated dose of DC was not reached. By 46 weeks, imaging showed 6 patients partial response or stable disease. Median PFS was 150 days in total cohort. Pretreatment CTC counts ≥5 indicated higher progression rates and recurring CTC. Ultradeep TCR-sequencing showed more prevalent and higher expressed (>5-fold) new TCR clonotypes at 2-6 weeks in men without progression. Participants reported high and stable HRQoL scores throughout the study. However, presence of CTC was associated with worse HRQoL scores at week 10 (p=0.031) and 22 (p=0.005). Conclusions: DC treatment seems safe and well tolerated, also combined with checkpoint inhibitors. Effect is indicated in subjects with moderate pre-treatment PSA levels. Immune responses are suggested by higher number of novel TCR clonotypes in men with non-progressive disease. Clinical trial information: NCT02423928 .

Abstract Interim analysis data are presented for 13 patients with metastatic castration resistant prostate cancer treated with dendritic cell based cryoimmunotherapy (CryoIT) and at least three months follow-up (FU). In CryoIT autologous immature dendritic cells (iDCs) mature in cryoablated tumor tissue and engulf tumor associated antigens and thereafter migrate to lymph nodes to instruct systemic immune attacks on heterogenous cancer cells. Primary endpoint of the trial is to investigate safety of CryoIT while secondary aims include clinical, radiological and immunological responses to treatment. Adverse events (AEs) and blood analyses were registered at all visits and imaging performed before and three months post-treatment. Norwegian regulatory authorities have approved the study. CryoIT of the prostate was performed as a freeze-thaw process under anesthesia and autologous iDCs injected after last thawing cycle. Radiologic responses according to RECISTv1.1 could categorize participants into either Group 1; stable disease (n=5) or Group 2; progressive cancer (n=4). Three patients showed mixed response and one had no follow-up imaging. Hematologic and immunologic values were evaluated according to response group. To identify peripheral blood leukocyte subsets and circulating tumor cells (CTCs), ultradeep T-cell receptor (TCR) β-chain sequences of complementarity-determining region 3, we utilized flow / mass cytometry, Cellsearch System, and TCRSafe Technology, respectively. At inclusion median age was 69 (62-73) years, BMI 25.9 (25-35), ECOG score 0 (0-1) and median PSA 8 (5-11). Group 2 demonstrated higher PSA (p=0.03), median 3.9 (IQR 2.7-6.8) and 74.6 (IQR 47.4-99.0) for Group 1 and Group 2, respectively. In total, 13 possible iDC-related AEs were reported by 10 individuals, whereof one severe and 12 mild-to-moderate, with urinary retention in seven subjects. All but one resolved by use of indwelling urinary catheter for median 8 (1-40) days. Participants with high CTC numbers (>5) before therapy had higher rates of progression, moderate pre-treatment CTC counts (3-5) decreased and no patient acquired CTCs after therapy. Ultradeep TCR-sequencing showed more prevalent and higher expression (>5-fold) of new TCR clonotypes 2-6 weeks after treatment in Group 1. The treatment seems safe and well tolerated. Higher PSA indicates more advanced disease at baseline for Group 2. The data indicate immune responses to treatment with higher increases in TCR clonotypes in radiologic stable disease. Clinical trial ID: NCT02423928. Citation Format: Liv Cecilie V. Thomsen, Alfred Honorè, Bjarte Almås, Lars A. Reisæter, Jannicke Frugård, Einar K. Kristoffersen, Guro Melve, Torjan Haslerud, Jarle Rørvik, Martin Biermann, Svein Inge Helle, Gunnar Kvalheim, Waqas Azeem, Jan Roger Olsen, Ole Johan Halvorsen, Lars Akslen, Duke K. Bahn, Klaus Pantel, Sabine Riethdorf, Haakon Ragde, Bjørn Tore Gjertsen, Anne M. Øyan, Karl-Henning Kalland, Christian Beisland. Dendritic cell based cryoimmunotherapy associates with clinical variables and changes in T-cell receptor expression in a prospective phase I trial of metastatic castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT066.

Focal ablative therapy may be reasonable for some patients with prostate cancer; selection factors include a variety of clinical and pathologic factors in combination with informed patient choice. Our group evaluated 4 specific pathologic features that may influence this treatment decision. We reviewed the published literature for applicable studies regarding the natural history of prostate cancer, multifocality, cancer volume, and accuracy of cancer detection by current methods. Results were as follows: (1)Latent versus incidental cancer: Is there any utility in separating latent cancer (autopsy- or cystoprostatectomy-detected incidental cancer) from nonlatent cancer (clinically detected cancer)? Prostate cancer is biologically and morphologically heterogeneous, including its malignant potential. We conclude that the ability to detect the biologic potential of prostate cancer in the individual patient is imperfect on the basis of currently available clinical and pathologic data. The best evidence indicates that latent cancer is a medical misnomer, so this separation has no biologic or clinically useful value. We recommend that the term “latent” cancer be abandoned. (2)Multifocality: About 80% of incidental cancers measure <0.5 mL in volume and are assigned a Gleason score of ≤6, indicating low malignant potential. Such microscopic foci do not influence serum prostate-specific antigen (PSA) concentration and likely have minimal effect on survival. However, a small but significant number of microscopic cancers are assigned higher Gleason scores and pose a risk for the patient; 16% of such foci consist of primary Gleason grade 4 cancer. (3)Cancer volume: Cancer volume within the prostate predicts the extent of cancer at autopsy with a reasonable degree of accuracy: 10% risk for extraprostatic extension with 0.5-cm3 cancer; 10% risk for seminal vesicle invasion with 4-cm3 cancer; and 10% risk for lymph node metastases with 5-cm3 cancer. Cancer volume is an important defining factor for both definitions of “clinically insignificant” cancer: (a) cancer <0.5-cm3, Gleason score 7, and organ confined; (b) cancer that will not reach a volume of 20 cm3 by the time of expected death according to patient age, estimated life expectancy, and cancer volume at diagnosis. The volume of cancer in lymph node metastasis is an important predictor of progression in prostate cancer. When systemic progression was predicted with use of the Cox multivariate analysis, only nodal cancer volume added significantly to the model that contained the primary cancer variables (Gleason score, cancer volume, and DNA ploidy). The relative hazard rate for a doubling in nodal cancer volume was 1.6 (95% confidence interval, 1.3 to 2.0; P <0.0001). (4)Cancer detection methods: Multiple factors determine the yield of prostate cancer by biopsy, including uncontrollable patient- and prostate-related risk factors (eg, serum PSA, prostate volume) and factors controllable by the urologist (eg, number of biopsies obtained) or the pathologist (eg, number of tissue slices obtained, expertise of the histotechnologist). It is concluded that multiple pathologic factors influence the choice of focal prostate cancer therapy for select patients, including multifocality, cancer volume, and cancer detection methods.

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.

Widespread prostate-specific antigen screening, coupled with increased public awareness of prostate cancer, has led to a downward stage migration of men presenting with this disease. From the 1980s to the current era, pathologically organ-confined disease has increased from an estimated 42% to 70%. 1 Han M. Partin A.W. Chan D.Y. et al. An evaluation of the decreasing incidence of positive surgical margins in a large retropubic prostatectomy series. J Urol. 2004; 171:: 23-26 Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar Clinically, the pathologic stage can be reasonably predicted given the clinical characteristics at diagnosis, including the serum prostate-specific antigen level, biopsy histologic features, and palpable stage. 2 Khan M.A. Partin A.W. Mangold L.A. et al. Probability of biochemical recurrence by analysis of pathologic stage, Gleason score, and margin status for localized prostate cancer. Urology. 2003; 62:: 866-871 Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar Summary of simultaneous irradiation for prostate cancerUrologyVol. 64Issue 4PreviewAfter our negative experience with retropubic iodine-125 implantation alone for prostate cancer, external beam radiotherapy was added after the implantation. A formal study of this treatment process was started in January 1984. Because the prostate is irradiated at the same time owing to performing an iodine-125 implant first followed by external beam radiotherapy, this method was called simultaneous irradiation (SI). A change from the retropubic to the modern ultrasound-guided transperineal implant technique as a part of SI was begun in 1992. Full-Text PDF

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.

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 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. (C) 2002 American Cancer Society.

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.

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.

Of all the treatment options available for men with organ-confined prostate cancer, brachytherapy—permament implantation of radioactive seeds into the prostate gland—is the least disruptive for the patient, both physiologically and practically. Early brachytherapy represents the oldest technique for delivering radiation to the prostate gland, preceding external beam therapy of the prostate by several decades. Although there have not been, and are not likely to be, any definitive randomized studies comparing radical prostatectomy, external beam radiotherapy, and brachytherapy, treatment decisions will continue to be made on the basis of patient and physician preferences in conjunction with clinical probabilities. Long-term results in this series show that monotherapy with seed implants achieved disease-free survival of 66%; moreover, 79% of patients with higher grade disease who were treated with a combination of brachytherapy and external beam radiation also experienced long-term disease-free survival. The following article provides a brief historical review of prostate brachytherapy, rationale for treatments, patient selection criteria, up-to-date implant techniques, and long-term (12-year) outcome results.

A phase II trial was conducted to assess the efficacy of infusions of dendritic cells (DC) and two HLA‐A2‐specific PSMA peptides (PSM‐P1 and ‐P2). This report describes thirty three subjects with hormone‐refractory metastatic prostate cancer without prior vaccine therapy history who were evaluated and reported as a group.

BACKGROUND. A phase IT trial was conducted to assess the efficacy of infusions of dendritic cells (DC) and two HLA-A2-specific prostate-specific membrane antigen (PSMA) peptides (PSM-P1 and -P2). This report describes the evaluation of 37 subjects admitted with presumed local recurrence of prostate cancer after primary treatment failure.METHODS. All subjects received six infusions of DC pulsed with PSM-P1 and -P2 at 6-week intervals. Clinical monitoring was conducted pre-, during, and post-phase II study. Data included: complete blood count, bone and total alkaline phosphatase, prostate markers, physical examination, performance status, bone scan, ProstaScint(R) scan, and chest X-ray, as well as other assays to monitor cellular and humoral immune responses.RESULTS. One complete and 10 partial responders were identified from this group based on National Prostate Cancer Project criteria, or on a 50% reduction of prostate-specific antigen (PSA), or on a significant resolution in lesions (biopsy-proven when possible) on ProstaScint(R) scan.CONCLUSIONS. About 30% of study participants in this group showed a positive response at the conclusion of the trial. This study suggests that DC-based cancer vaccines may provide an alternative therapy for prostate cancer patients whose primary treatment failed. (C) 1999 Wiley-Liss, Inc.

BACKGROUND:Recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF; Leukine [sargramostim], Immunex Corp., Seattle, WA) was administered to a subgroup of 44 patients in a phase II clinical trial for prostate cancer using DC pulsed with HLA-A2-specific prostate-specific membrane antigen (PSMA) peptides. Our purpose was to determine if GM-CSF caused any enhancement of patients' immune responses, including enhancement of clinical response to the DC-peptide treatment. This report compares the clinical responses to DC-peptide infusions with and without systemic GM-CSF treatment. METHODS:GM-CSF was administered by subcutaneous injection at a dose of 75 microg/m2/day for 7 days with each of six infusion cycles. Prefilled syringes were supplied to the patients for self-administration. RESULTS:One complete and 8 partial responders were identified among 44 patients who received GM-CSF, as compared to 2 complete and 17 partial responders among 51 patients who did not receive GM-CSF. For patients who received GM-CSF and were tested by delayed-type hypersensitivity (DTH) skin test, 3 cases of improved immune response were identified, compared to 5 cases of improvement in patients who did not receive GM-CSF. The main GM-CSF side effects reported were local reactions at the site of injection, fatigue, pain, and fever. Most reported side effects were of mild severity, with some cases of moderate severity leading to discontinuation of GM-CSF. CONCLUSIONS:Our results suggest GM-CSF as employed in this trial did not detectably enhance clinical response to DC-peptide infusions, or significantly enhance the measured immune response.

BACKGROUND A phase II trial, involving infusions of autologous dendritic cells (DC) and two human histocompatibility antigen (HLA-A2)-specific prostate-specific membrane antigen (PSMA) peptides, was recently completed. Thirty percent of the participants, including subjects with hormone-refractory metastastic disease, and those with suspected local recurrence of prostate cancer, were identified as clinical responders. This report describes the follow-up evaluation of 19 responders in the two study groups. METHODS After conclusion of the study, study participants were subjected to follow-up evaluations at 6–8-week intervals. Each responder was reevaluated for response status, and duration of response was determined. RESULTS Subjects were observed for an average of 291 days (metastastic group, group A-2) and 557 days (local recurrence group, group B), which included the treatment and follow-up periods. The average duration of response was 149 days for group A-2, and 187 days for group B. A majority of responders (11/19; 58%) were still responsive at the end of the current follow-up. CONCLUSIONS The responses observed may be significant and relatively durable. This study suggests that DC-based cancer vaccines in the future may provide an additional therapy for advanced prostate cancer. Prostate 40:125–129, 1999. © 1999 Wiley-Liss, Inc.