Immunotherapy of advanced prostate cancer: a phase I/II trial using Mycobacterium vaccae (SRL172) (original) (raw)
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International Journal of Urology, 2013
Abbreviations & Acronyms CRC = colorectal cancer CTL = cytotoxic T lymphocytes DC = dendritic cells IFN = interferon mDC = myeloid dendritic cells MDSC = myeloid-derived suppressor cells PBMC = peripheral blood mononuclear cells PCa = prostate cancer pDC = plasmocytoid dendritic cells PHA = phytohemagglutinin PMA = phorbolmyristate acetate PSA = prostate-specific antigen PSMA = prostate-specific membrane antigen Tregs = regulatory T cells Objectives: A dendritic cell-based cancer vaccine has recently received Food and Drug Administration approval in the USA based on its ability to prolong the survival of prostate cancer patients with advanced disease. However, tumor-mediated immunosuppressive mechanisms might represent an obstacle to optimal performance of this therapy. We have recently shown that monocytes from the blood of prostate cancer patients can fully mature to dendritic cells only after the tumor is removed. Here, we have tested the hypothesis that these tumor-driven monocytes correspond to the recently described subset of CD14 + HLA-DR low immunosuppressor cells. Methods: Prostate cancer patients were studied before and 1 month after prostatectomy. Pre-and postsurgical patients with colorectal cancer were also included for comparison. Flow cytometric analysis was applied to define CD14 -HLA-DR low CD33 + CD11b + (myeloid) and CD14 + HLA-DR low (monocytic) suppressor cells. Interferon-g release was used to assess the immunocompetence of lymphocytes. Results: In both prostate cancer and colorectal cancer patients, the percentage of CD14 + HLA-DR low cells was several-fold higher compared with normal subjects. This was not the case for CD14 -HLA-DR low CD33 + CD11b + cells. Furthermore, postsurgical normalization of CD14 + HLA-DR low cells only occurred in prostate cancer patients. In all patients, the interferon-g response of T lymphocytes to phorbolmyristate acetate-ionomycin was higher compared with normal donors, but it was further increased after tumor ablation only in prostate cancer patients. Conclusions: The direct link between CD14 + HLA-DR low increase and presence of primary tumor suggests a distinguishing immunosuppressive profile of prostate cancer. This observation supports the principle that the appropriate setting for prostate cancer vaccine therapy is a minimal disease status.
Phase I/II Trial of an Allogeneic Cellular Immunotherapy in Hormone-Naive Prostate Cancer
Clinical Cancer Research, 2006
To determine the toxicity, immunologic, and clinical activity of immunotherapy with irradiated, allogeneic, prostate cancer cells expressing granulocyte macrophage colony-stimulating factor (GM-CSF) in patients with recurrent prostate cancer. Patients and Methods: A single-institution phase I/II trial was done in hormone therapy^naI« ve patients with prostate-specific antigen (PSA) relapse following radical prostatectomy and absence of radiologic metastases.Treatments were administered weekly via intradermal injections of1.2 Â 10 8 GM-CSF gene^transduced, irradiated, cancer cells (6 Â 10 7 LNCaP cells and 6 Â 10 7 PC-3 cells) for 8 weeks. Results: Twenty-one patients were enrolled and treated. Toxicities included local injection-site reactions, pruritus, and flu-like symptoms. One patient had a partial PSA response of 7-month duration. At 20 weeks post first treatment, 16 of 21 (76%) patients showed a statistically significant decrease in PSA velocity (slope) compared with prevaccination (P < 0.001). Injection site biopsies showed intradermal infiltrates consisting of CD1a + dendritic cells and CD68 + macrophages, similar to previous clinical trials using autologous GM-CSF-transduced cancer cells. Posttreatment, patients developed new oligoclonal antibodies reactive against at least five identified antigens present in LNCaP or PC-3 cells. A high-titer antibody response against a 250-kDa antigen expressed on normal prostate epithelial cells was induced in a patient with partial PSA remission; titers of this antibody decreased when treatment ended, and subsequent PSA relapse occurred. Conclusions: This non-patient-specific prostate cancer immunotherapy has a favorable safety profile and is immunologically active. Continued clinical investigation at higher doses and with longer boosting schedules is warranted.
Immunotherapy for Prostate Cancer: What's the Future?
Hematology/Oncology Clinics of North America, 2006
rostate cancer is the most common noncutaneous cancer and second leading cause of cancer death among US men. In 2005, 232,090 new cases were estimated to be diagnosed, and 30,350 men were expected to die from prostate cancer in the United States [1]. The identification of tumor-associated and tumor-specific antigens in the 1990s has introduced new excitement for the development of targeted vaccines and monoclonal antibodies for the treatment of prostate cancer. Although clinical outcomes in earlier studies were disappointing, a better understanding of basic immunologic principles has led to a variety of techniques for enhancing tumor-specific immunity. Immunotherapy for prostate cancer is an active field of investigation using a wide variety of approaches. There are two major approaches to cancer immunotherapy: active immunotherapy and passive immunotherapy. Active immunotherapy involves the delivery of a substance designed to elicit an immune reaction. The host's immune system first must recognize and then must respond to the target. Cancer vaccine strategies fall under this category. Passive immunotherapy involves the delivery of a substance with intrinsic immunologic activity, such as an antibody or adoptively transferred activated lymphocytes. Both of these approaches are being studied in prostate cancer clinical trials.
2008
We have previously reported on the safety and immunologic response of a poxvirusbased vaccine encoding prostate-specific antigen (PSA) used in combination with radiation therapy in patients with localized prostate cancer. We hypothesized that a ''metronomic'' dose of interleukin 2 (IL-2) as a biological adjuvant would cause less toxicity while maintaining immunologic response. Experimental Design: Eighteen patients with localized prostate cancer were treated in a singlearm trial using previously established doses of vaccine and radiation therapy. The vaccine used was a recombinant vaccinia virus engineered to encode PSA admixed with a recombinant vaccinia encoding the costimulatory molecule B7.1, followed by booster vaccinations with a recombinant fowlpox vector expressing PSA. Patients received a total of eight planned vaccination cycles, once every 4 weeks, with granulocyte-macrophage colony-stimulating factor given on days 1to 4 and interleukin 2 (IL-2) at a dose of 0.6 MIU/M 2 given from days 8 to 21after each vaccination. Definitive external beam radiation therapy was initiated after the third vaccination cycle. Patients were evaluated for safety and immunologic response. Toxicity and immunologic activity were compared with the previously reported regimen containing a higher dose of IL-2. Results: Seventeen of 18 patients received all eight cycles of vaccine with IL-2. Five of eight HLA-A2 + patients evaluated had an increase in PSA-specific T cells of z3-fold. Toxicities were generally mild, with only seven vaccination cycles of 140 given resulting in grade 3 toxicities possibly attributable to IL-2. Conclusions: Metronomic-dose IL-2 in combination with vaccine and radiation therapy is safe, can induce prostate-specific immune responses, and has immunologic activity similar to low-dose IL-2, with markedly reduced toxicities.
Urology, 1999
Objectives. Prostate cancer recurrence, evidenced by rising prostate-specific antigen (PSA) levels after radical prostatectomy, is an increasingly prevalent clinical problem in need of new treatment options. Preclinical studies have suggested that for tumors in general, settings of minimal cancer volume may be uniquely suitable for recombinant vaccine therapy targeting tumor-associated antigens. A clinical study was undertaken to evaluate the safety and biologic effects of vaccinia-PSA (PROSTVAC) administered to subjects with postprostatectomy recurrence of prostate cancer and to assess the feasibility of interrupted androgen deprivation as a tool for modulating expression of the vaccine target antigen, as well as detecting vaccine bioactivity in vivo. Methods. A limited Phase I clinical trial was conducted to evaluate the safety and biologic effects of vaccinia-PSA administered in 6 patients with androgen-modulated recurrence of prostate cancer after radical prostatectomy. End points included toxicity, serum PSA rise related to serum testosterone restoration, and immunologic effects measured by Western blot analysis for anti-PSA antibody induction. Results. Toxicity was minimal, and dose-limiting toxicity was not observed. Noteworthy variability in time required for testosterone restoration (after interruption of androgen deprivation therapy) was observed. One subject showed continued undetectable serum PSA (less than 0.2 ng/mL) for over 8 months after testosterone restoration, an interval longer than those reported in previous androgen deprivation interruption studies. Primary anti-PSA IgG antibody activity was induced after vaccinia-PSA immunization in 1 subject, although such antibodies were detectable in several subjects at baseline. Conclusions. Interrupted androgen deprivation may be a useful tool for modulating prostate cancer bioactivity in clinical trials developing novel biologic therapies. Immune responses against PSA may be present among some patients with prostate cancer at baseline and may be induced in others through vaccinia-PSA immunization. UROLOGY 53: 260-266, 1999.
Mycobacterium vaccae (SRL172): a potential immunological adjuvant evaluated in rat prostate cancer
BJU International, 1998
Objective To evaluate the potential of heat-killed Results SRL172 was eCective as an adjuvant to autologous whole tumour cell vaccination in the prevention Mycobacterium vaccae (SRL172) as a nonspecific immunostimulant and as an adjuvant to whole tumour cell of MAT-LyLu tumours and the survival benefit was equivalent to that provided when the adjuvant was vaccination in the rat model of prostate cancer. Materials and methods SRL172 was used as a vaccine live-attenuated BCG. SRL172 alone did not reduce tumour take or tumour growth in this model and in the prevention and treatment of subcutaneous tumours in rats. Prevention experiments were conduc-neither strategy was eCective in delaying the growth of established MAT-LyLu tumours. In the Lobund-ted using subcutaneous MAT-LyLu tumours in Copenhagen rats, comparing vaccination with Wistar rat vaccination with autologous whole tumour cells and SRL172 significantly delayed the growth of SRL172 alone, SRL172 plus autologous cells, and bacille Calmette-Guèrin (BCG) plus autologous cells established tumours. Conclusion Mycobacterium vaccae deserves further evalu-before tumour implantation. Treatment experiments were conducted using subcutaneous MAT-LyLu ation as an adjuvant to whole tumour cell vaccination in a phase I clinical trial in patients with prostate tumours in the Copenhagen rat and subcutaneous PAIII tumours in the Lobund-Wistar rat. Tumours cancer. Keywords Prostate cancer, immunotherapy, Myco-were induced by subcutaneous injection with tumour cells. Animals were then vaccinated with autologous bacterium vaccae, vaccine, rat model cells, autologous cells plus SRL172, or SRL172 alone. or by the co-injection of adjuvant [5]. In animal models
The Journal of Urology, 2000
Purpose: Several immune based therapies targeting prostate cancer associated proteins are currently undergoing clinical investigation. In general, however, little is known about the immunogenicity of prostate cancer or which prostate cancer associated proteins elicit immune responses. We determine whether patients with prostate cancer have antibody immunity to known prostate cancer associated proteins, what the prevalence of this immunity is and whether immunity to individual proteins is associated with the stage of disease. Materials and Methods: We evaluated the inherent humoral immune response against prostate specific antigen (PSA), prostatic acid phosphatase, p53 and HER-2/neu, all known prostate cancer associated proteins, in 200 patients with various stages of disease and male controls. Results: Antibody immunity to PSA was significantly different between the patient (11%, 22 of 200) and control populations (1.5%, 3 of 100, p ϭ 0.02), and titers 1:100 or greater were particularly prevalent in the subgroup of patients with androgen independent disease (11%, 6 of 56). Antibody immunity to prostatic acid phosphatase and p53 was detected (5.5%, 11 of 200 and 6%, 12 of 200), and was not different from the control population (4%, 4 of 100, p ϭ 0.57 and 7%, 7 of 100, p ϭ 0.74). Antibody immunity to HER-2/neu was significantly higher in patients with prostate cancer (15.5%, 31 of 200) compared to controls (2%, 2 of 100, p ϭ 0.0004), and titers 1:100 or greater were most prevalent in the subgroup of patients with androgen independent disease (16%, 9 of 56). Conclusions: These findings suggest that prostate cancer is an immunogenic tumor. Moreover, for PSA and HER-2/neu the prevalence of antibody immunity was higher in patients with androgen independent disease, indicating that even patients with advanced stage prostate cancer can have an immune response to their tumor.
Immunostaging in carcinoma of prostate
Urology, 1976
Immunostaging is a new method of assessing patients immunologically before and after immunotherapy. Twenty-eight patients with adenocarcinoma of the prostate were immunostaged independently by two investigators. There was a positive correlation between both immunostagings. There was also a positive correlation between the patient's immunostage and the clinical stage of his cancer.