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© 2000 American Society for Clinical Oncology Immunotherapy of Hormone-Refractory Prostate Cancer With Antigen-Loaded Dendritic CellsFrom the Departments of Medicine and Urology, University of California San Francisco Comprehensive Cancer Center, University of California, San Francisco, CA; and Dendreon Corporation, Seattle, WA. Address reprint requests to Eric J. Small, MD, University of California, San Francisco, UCSF Comprehensive Cancer Center, 1600 Divisadero St, 3rd Floor, San Francisco, CA 94115; email smalle{at}medicine.ucsf.edu
PURPOSE: Provenge (Dendreon Corp, Seattle, WA) is an immunotherapy product consisting of autologous dendritic cells loaded ex vivo with a recombinant fusion protein consisting of prostatic acid phosphatase (PAP) linked to granulocyte-macrophage colony-stimulating factor. Sequential phase I and phase II trials were performed to determine the safety and efficacy of Provenge and to assess its capacity to break immune tolerance to the normal tissue antigen PAP. PATIENTS AND METHODS: All patients had hormone-refractory prostate cancer. Dendritic-cell precursors were harvested by leukapheresis in weeks 0, 4, 8, and 24, loaded ex vivo with antigen for 2 days, and then infused intravenously over 30 minutes. Phase I patients received increasing doses of Provenge, and phase II patients received all the Provenge that could be prepared from a leukapheresis product. RESULTS: Patients tolerated treatment well. Fever, the most common adverse event, occurred after 15 infusions (14.7%). All patients developed immune responses to the recombinant fusion protein used to prepare Provenge, and 38% developed immune responses to PAP. Three patients had a more than 50% decline in prostate-specific antigen (PSA) level, and another three patients had 25% to 49% decreases in PSA. The time to disease progression correlated with development of an immune response to PAP and with the dose of dendritic cells received. CONCLUSION: Provenge is a novel immunotherapy agent that is safe and breaks tolerance to the tissue antigen PAP. Preliminary evidence for clinical efficacy warrants further exploration.
PROSTATE CANCER IS the most common type of cancer and the second leading cause of death as a result of cancer in North American men.1 Metastatic disease is initially treated with androgen deprivation, which achieves stabilization or regression of disease in more than 80% of patients.2 However, despite androgen deprivation and secondary hormonal manipulations,3 all patients ultimately develop hormone-refractory prostate cancer (HRPC). The median survival for this group of patients is approximately 1 year. To date, no agent has been shown to prolong survival in HRPC patients,4,5 and prospectively validated palliative interventions are few. Novel therapeutic agents for the treatment of HRPC are urgently required. Active immunotherapy of cancer seeks to induce tumor-specific immunity in the patient and is consequently dependent on a suitable target antigen and effective presentation of that antigen to the patient’s immune system. Antigen-presenting cells (APCs) are responsible for uptake, processing, and presentation of antigens to T cells of the immune system in the context of HLA class I and class II molecules. Dendritic cells are the most potent APCs and the only APCs that can prime an immune response by T cells that have not been exposed to the antigen previously.6,7 Immunotherapy with dendritic cells loaded with specific tumor antigens ex vivo has been studied extensively in animals.8-11 All of these studies found dendritic cells to be effective in treating or preventing tumors in experimental animals in an antigen-specific fashion. Several pilot clinical studies using dendritic cells to deliver antigen for immunotherapy of human malignancies have also shown promise and demonstrate that dendritic-cell therapy can elicit a beneficial immune response.12-18 In many of the preclinical and clinical studies described above, the antigen targets that have proven to be useful in cancer are tissue-specific proteins to which the immune system is normally tolerant. Preclinical studies in rats aimed at eliciting prostate-specific immunity demonstrated that dendritic cells loaded with an engineered antigen-cytokine fusion protein (PA2024) consisting of prostatic acid phosphatase (PAP) and granulocyte-macrophage colony-stimulating factor (GM-CSF) induce strong cellular immune responses in vivo to tissues and tumors that express PAP.19 Delay of tumor development and improved survival were observed in tumor prevention models. In contrast, dendritic cells pulsed with PAP alone elicited significantly weaker immune responses, indicating an important role for the GM-CSF portion of the fusion protein in antigen presentation. Dendritic cells are likewise essential for eliciting cellular immunity in this model, as injections of the PAP-GM-CSF fusion protein alone and injections of PAP in Freund’s adjuvant elicited antibody responses but not cellular immune responses to PAP. Based on these preclinical observations, a dendritic-cell product (Provenge [Dendreon Corp, Seattle, WA], or APC8015) consisting of autologous dendritic cells loaded with the human PAP-GM-CSF fusion protein was developed, and clinical testing of Provenge was undertaken in HRPC patients in a phase I/II trial.
Patients Eligible patients had histologically confirmed adenocarcinoma of the prostate with evidence of disease progression despite androgen deprivation (and if applicable, antiandrogen withdrawal), serum testosterone less than 50 ng/mL, and an expected survival of at least 3 months. Patients with negative bone scan and computed tomography scan were eligible, provided there were at least three climbing prostate-specific antigen (PSA) values, at least 2 weeks apart from each other, and at least 1 month or more after antiandrogen withdrawal. Other eligibility requirements included an Eastern Cooperative Oncology Group performance status of 0 or 1, a serum PAP level  2 times the upper limits of normal, or positive staining for PAP by immunohistochemistry on any prior prostatic cancer specimen. Negative serologic tests for human immunodeficiency virus (HIV), human T-cell leukemia virus type 1, hepatitis B, and hepatitis C were required, as were adequate hematologic, renal, and hepatic function (WBC 2,000/µL, ANC 1,000 µL, platelets 100,000 µL, hemoglobin > 9.0 g/dL, creatinine  2.0 mg/dL, total bilirubin two times upper limit of normal, and ALT and AST five times upper limit of normal). Prior chemotherapy, investigational agents, megestrol acetate or other hormones, or saw palmetto, PC-SPES (Botanic Labs, Brea, CA), or other herbal preparations were allowed, provided they were discontinued at least 1 month before treatment and the patient had recovered adequately. Prior radiation therapy had to have been completed at least 1 month before treatment, and radiopharmaceuticals could not have been administered within 2 months of treatment. Patients who required systemic corticosteroids for any indication were not eligible.
Treatment/Clinical End Points
Preparation and Administration of Provenge
The final Provenge products were transported to the outpatient infusion center at the University of California, San Francisco, Comprehensive Cancer Center at 4°C and infused into the patients within 8 hours of formulation. Provenge and, when appropriate, APC8017 were infused separately, each over 30 minutes, beginning with Provenge. Patients were not routinely premedicated before the infusion. They were observed for 30 minutes after infusion and then discharged to home. PA2024, the target antigen used to prepare Provenge, is a fusion protein consisting of full-length human PAP and full length human GM-CSF. The fusion protein was cloned in a baculovirus system and expressed in Sf21 insect cells adapted to grow in serum-free media. PA2024 was purified by three sequential column chromatography steps to more than 95% homogeneity. Both protein components retained appropriate biologic activity, as demonstrated by enzymatic activity for PAP and growth promotion activity for GM-CSF.
Immune Function Testing T-cell proliferation. Standard T-cell proliferation assays were performed using peripheral-blood lymphocytes isolated from the blood of each patient, obtained at the beginning of each leukapheresis.21 These samples (105 cells/well) were incubated with increasing concentrations of antigen (PA2024 or KLH) for 5 days at 37°C, at which point each well was pulsed with 3H thymidine. Twenty-four hours later, cultures were harvested and mean radioactivity incorporated into proliferating cells was determined. Data are reported as either counts per minute (CPM) or as the stimulation index (SI) (SI = [mean CPM antigen]/mean CPM control).
Allogeneic and Autologous T-Cell Stimulation Activity Before and After Ex Vivo Culture
ELISPOT
Enzyme-Linked Immunoassay (ELISA) for Antibodies and Cytokines
Statistical Design T-cell proliferation data are not normally distributed. To normalize the data for statistical analyses, the data were expressed as the proliferation quotient (PQ) [PQ = (log CPM antigen)–(log CPM control)]. Different patient groups were compared by paired or nonpaired t tests as appropriate.
Patients A total of 31 patients were treated. Twelve men were treated in the phase I portion, with six patients treated at the maximum dose of Provenge. Nineteen men were enrolled onto the phase II trial at the maximum dose (representing an over-accrual of three patients to the phase II portion to account for potentially unassessable patients). Patient characteristics are listed in Table 1. Median age was 69 years (range, 48 to 83 years). Median Eastern Cooperative Oncology Group performance status was 0 (range, 0 to 1).
Median PSA was 41.3 ng/mL (range, 3.4 to 1,007 ng/mL). In the phase I component, all 12 patients had metastatic disease, and the median PSA was 209 ng/mL (range, 26.3 to 1,007 ng/mL). The patients in the phase I trial were more heavily pretreated. All had undergone androgen deprivation with combined androgen blockade, followed by antiandrogen withdrawal. Eleven (92%) of 12 patients had received a second-line hormonal manipulation, such as ketoconazole, and eight patients (66%) had also received chemotherapy, suramin, or some other investigational agent. By contrast, the patients in the phase II portion had less extensive disease. None of these patients had metastases identified on bone scan or computed tomography. An increasing PSA was the only evidence of disease progression, and the median PSA level was much lower (14.5 ng/mL; range, 3.4 to 216 ng/mL). All 19 phase II patients had undergone combined androgen deprivation followed by antiandrogen withdrawal. Twelve (63.2%) had received a second-line hormone, and only one had received prior therapy with an investigational agent (hydrazine sulfate).
Preparation of PAP-Loaded Dendritic Cells (Provenge)
Adverse Events Overall treatment was well tolerated. Most patients had no treatment-related adverse events. Other than minor discomfort, there were no adverse events associated with leukapheresis. Fifteen infusions (14.7%) were associated with febrile reactions that developed within 2 hours. Two febrile reactions were scored as grade 3 using National Cancer Institute common toxicity criteria, and 13 were grade 1 or 2. Similarly, mild myalgias (grade 1) occurred 1 or 2 days after Provenge infusions in two patients, and mild fatigue occurred in one patient. Five patients experienced mild urinary complaints, including obstructive voiding symptoms, incontinence, urgency, and nocturia. There was no treatment-related hematologic, hepatic, or renal toxicity.
Stimulation of Antigen-Specific Immune Responses
To exclude the possibility that Provenge stimulates T-cell responses nonspecifically, the patients’ T-cell proliferation responses to the recall antigen influenza and to the naive antigen KLH were measured before treatment and every 4 weeks thereafter. The 12 phase I patients’ T-cell stimulation index to influenza did not change with treatment. The median stimulation index was 5.5 at week 0 and 4.7 at week 8 for the lowest in vitro antigen dose (0.4 µg/mL) and 9.2 at week 0 and 9.7 at week 8 for the highest dose (50 µg/mL). Five patients received KLH-loaded dendritic cells (APC8017). None had pre-existing T-cell proliferation responses to KLH and, as expected, all developed responses after treatment with APC8017. By contrast, nine patients who did not receive APC8017 were tested for KLH immune responses after treatment with PAP-loaded dendritic cells (Provenge), and none developed a response to KLH. Thus, Provenge stimulated antigen-specific immune responses. PA2024 consists of PAP fused to the targeting element GM-CSF. T-cell responses to each of these components were examined. No patient had pre-existing T-cell responses to PAP isolated from human seminal fluid; whereas after treatment with Provenge, 10 (38%) of 26 patients developed a T-cell response to PAP. Pre-existing T-cell proliferation responses to GM-CSF (Leukine; Immunex, Seattle, WA) were observed in 15 patients (57%), of whom three had been treated previously with GM-CSF on a different immunotherapy protocol. After treatment with Provenge, T-cell proliferation responses to GM-CSF were observed in an additional four patients for a total of 19 (70%) of 27 patients.
T cells can be separated into two distinct groups based on the type of cytokines the cells secrete. Th1 cells secrete IFN Antibodies to PAP and GM-CSF were evaluated by specific ELISA on serum samples obtained at baseline and then every 4 weeks. None of the patients had pre-existing antibodies to PAP (isolated from human seminal fluid); whereas after treatment, 16 (52%) of 31 patients had antibodies. The median antibody titer was 1/240 (range, 1/40 to 1/5120). Similar to the T-cell experience, 10 patients (33%) had pre-existing antibodies to GM-CSF, and after treatment, 25 (80.6%) of 31 patients had antibodies. The baseline immune function of all patients was assessed by in vitro T-cell proliferation responses to the recall antigen influenza. There was no difference in baseline immune response to influenza between patients who did or did not subsequently develop an immune response to PAP. Similarly, there was no difference in baseline immune responses to influenza between patients who received an average dose of more than 100 x 106 cells and those who received fewer cells.
Responses to Treatment The relationship between development of a T-cell or B-cell immune response to PAP (seminal fluid-derived) and the time to disease progression was evaluated (Fig 5). The median time to disease progression was 34 weeks for patients who developed an immune response (n = 20) compared with 13 weeks for patients who did not (n = 11) (P < .027).
The relationship between the time to disease progression and the average dose of dendritic cells received by each patient was also examined. Inspection of the data revealed that all patients who experienced disease progression more than 24 weeks after registration received average cell doses above 100 x 106cells/infusion. The median time to disease progression was 31.7 weeks for patients who received more than 100 x 106 cells/infusion compared with 12.1 weeks for patients who received fewer cells (Fig 6). The difference between the two groups was statistically significant (P = .013).
This phase I/II trial demonstrates that treatment of men with HRPC with Provenge induced specific immune responses in all patients, with the response being apparent after a single treatment. Specificity of this therapy is suggested by the fact that treatment with Provenge did not increase the patients’ response to the recall antigen influenza. In addition, none of the patients who received Provenge alone developed immune responses to the control antigen KLH. Cytokine production by T cells responding to the target antigen was analyzed by ELISA in some of the patients. The profile of cytokines produced indicates that the patients’ T cells released IFN  but not IL-4. These data suggest that the T-cell response was of the Th-1 type, which is thought to be important for host immunity to tumors. The baseline immune function of all patients was assessed by in vitro T-cell proliferation responses to the recall antigen influenza. There was no difference in baseline immune response to influenza between patients who did or did not subsequently develop an immune response to PAP. Similarly, there was no difference in baseline immune responses to influenza between patients who received an average dose of more than 100 x 106 cells and those who received fewer cells.24 ELISPOT assays in two patients confirmed the Th-1 cytokine profile and revealed substantial increases in T-cell precursor frequency. The GM-CSF element in our prostate antigen is essential to in vitro antigen processing, but there are several reasons why we believe that GM-CSF does not otherwise contribute to Provenge’s in vivo effects. First, the cells are washed extensively before infusion, and the quantity of residual GM-CSF is negligible. Secondly, most investigators use dendritic cells prepared in the presence of GM-CSF, and there is, to our knowledge, no evidence that the in vivo activity of those dendritic cells is caused by an adjuvant effect of GM-CSF. Thirdly, our preclinical studies compared infusions of dendritic cells pulsed with the fusion protein with injections of the fusion protein itself. Unlike the antigen-pulsed dendritic cells, the PAP-GM-CSF fusion protein did not elicit T-cell responses to PAP. Finally, we have performed a clinical trial that involved subcutaneous injections of the fusion protein and observed that the injections did not stimulate T-cell or antibody responses.25 Several groups have reported pilot trials of antigen-loaded dendritic cells for solid and hematologic malignancies and for HIV infection.17 Hsu et al12 treated four B-cell lymphoma patients with immunoglobulin idiotype-pulsed dendritic cells and observed two complete remissions. Treatment with idiotype-pulsed dendritic cells has resulted in disease regression in 25% of low–tumor burden myeloma patients13 and in disease stabilization of high–tumor burden myeloma patients.14 Peptide-pulsed or tumor-lysate pulsed dendritic cells have yielded clinical regressions in patients with advanced melanoma.15 Similarly, fusion of autologous renal cell carcinoma cells with allogeneic dendritic cells has resulted in complete regression of tumor in some renal cell carcinoma patients.26 Carcinoembryonic antigen peptide-pulsed dendritic cells stimulated immune responses but did not elicit clinical responses in a mixed group of patients with tumors that express carcinoembryonic antigen.16 Similarly, HIV peptide–pulsed allogeneic dendritic cells elicited strong cytolytic T-lymphocyte immune responses but did not affect HIV viral load.17 These trials all demonstrated that antigen-loaded dendritic cells are effective for stimulating antigen-specific T-cell immune responses. In contrast, Salgaller et al18 reported that dendritic cells loaded with peptide fragments of prostate membrane–specific antigen stimulated antigen-specific immunity in only two of 82 men with HRPC. The low frequency of immune responses to prostate membrane–specific antigen in that study may result from weak immunogenicity of the selected antigen epitopes or poor functionality of the dendritic cells. It has been noted previously that dendritic cells pulsed with a whole protein may be more effective than dendritic cells pulsed with HLA class I–restricted peptides for eliciting antigen-specific immune responses in patients with HIV infection.17 Protein-pulsed dendritic cells may be more effective than single peptide-pulsed dendritic cells for stimulating immunity because of the larger repertoire of antigens present in the protein and the resulting ability to elicit both CD4+ helper cells and CD8+ effector cells. There was evidence of clinical activity with single-agent Provenge therapy, as revealed by unambiguous PSA declines in some patients. The utility of a decrease of more than 50% in PSA as a marker of response and clinical outcome for men with HRPC remains debated.27-29 Nevertheless, a decrease in PSA of more than 50% has been accepted as a reasonable screen for anticancer activity.30 The fact that men with overtly HRPC who had received no other treatment had a sufficient immune response to decrease their PSA levels is provocative. The observation that time to disease progression correlated with development of an immune response to PAP and to the dose of Provenge is intriguing, but caution is warranted in interpreting these results. The differences in time to disease progression as a function of immune response and cell dose cannot be unambiguously attributed to treatment. It is possible that a lower cell yield or a lower innate immune response to antigens presented by dendriticcells is a function of greater disease burden or increased aggressiveness of disease, so that it would not be surprising that these patients had a shorter time to disease progression. However, many of the patients who received low dendritic-cell doses were part of the phase I dose escalation trial, and the low dose was because of prospectively planned dose levels and not because of an intrinsic defect in the patients’ number of dendritic cells. Similarly there were no apparent differences in the baseline immune function among the different patient groups as assessed by T-cell proliferation responses to the recall antigen influenza. The relationships between clinical benefit and the dose of dendritic cells and the extent of immune response clearly warrant further investigation. Finally, Provenge seems to be safe and well tolerated. There was no evidence for development of an autoimmune disease caused by cross-reactivity between the PAP antigen and a normal tissue component. This lack of cross-reactivity with normal tissue antigens was predicted from the lack of PAP expression by normal tissues other than the prostate31 and from review of gene banks for proteins that express potentially cross-reactive epitopes. An immune response to PAP expressed by normal prostate tissue could result in prostatitis. Although five men had urinary symptoms, none of these were clearly caused by treatment-induced prostatitis. The absence of prostatitis in men with immune responses to PAP is not unexpected as 20 of 31 men had undergone prior local therapy and all men had undergone hormone ablative therapy as well. In conclusion, active immunotherapy with autologous dendritic cells that were loaded ex vivo with a fusion protein containing PAP is a novel approach to prostate cancer immunotherapy. This clinical trial demonstrates that this therapeutic approach is feasible, that treatment is safe and immunologically active, and that clinical activity seems to be present, although proof of clinical benefit will require completion of ongoing controlled randomized trials. This trial establishes the groundwork for future refinements, including optimization of dosing schedule, use in patients with less extensive disease, and possibly in combination with other therapeutic agents or modalities.
Presented in part at the Thirty-Fourth Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, May 16–19, 1998.
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INTRODUCTION
