Safety and Effectiveness of a Vaccine for Prostate Cancer That Uses Each Patients' Own Immune Cells.

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety and activity of a type of vaccine as immune therapy for prostate cancer. This vaccine will be made for each participant's own immune cells (called dendritic cells) obtained by blood donation. Dendritic cells are immune cells, whose role is to identify foreign antigens (bacteria, viruses, or tumor cells, for example) in the body and to activate other cells of the immune system to mount an attack on that foreign antigen. Each participant will be randomized into either Arm 1 (experimental treatment only) or Arm 2 (placebo first, then the experimental treatment). Participants will be given the vaccine and three boosters as an injection. After the placebo phase, each participant in Arm 2 will crossover to the treatment phase so that all participants will eventually receive the experimental treatment.

Detailed Description
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This is a Phase I/II dendritic cell vaccine study for patients with prostate cancer. Our laboratory has demonstrated that effective tumor immunity in humans is associated with, and likely mediated at least in part by tumor antigen-specific killer T cells (Albert et al., 1998a; Darnell, 1999; Darnell and Posner, 2003). Moreover, we have demonstrated that apoptotic material derived from dying tumor cells are a potent means of delivering antigen to DCs and subsequently triggering tumor antigen-specific T cell responses ex vivo (Albert et al., 1998a; Albert et al., 1998c). In this study, patients with 3 consecutive rises in PSA measured at least 2 week apart, after definite local therapy (prostatectomy or radiation) will be recruited. Peripheral blood monocytes will be collected by leukapheresis and dendritic cells will be generated in the Cleanroom in the Laboratory of Molecular Neuro-Oncology. These dendritic cells will be pulsed with apoptotic prostate cancer cells from a cell line (LNCaP), harvested, tested for certain release criteria, and then injected as vaccine. When patients are found to be eligible for the study, they will be randomized into either the experimental group or the placebo group for the purposes of comparing adverse events between groups only. Vaccine plus 3 boosters (or placebo) will be given, each two weeks apart. After the third booster, patients will be unblinded. Those receiving the vaccine will when enter the follow up phase which includes a post treatment leukapheresis. Those in the placebo group will cross over and receive the vaccine and boosters. The primary outcomes to be evaluated are toxicity and activity. Patients will be evaluated for both local and systemic toxicity. For activity, we measure both immunological and clinical responses to the vaccine, comparing measures taken before and after vaccination, combining patients in both arms.

Official Title
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A Phase I/II Study of Autologous Dendritic Cells Pulsed With Apoptotic Tumor Cells (DC/LNCaP) Administered Subcutaneously to Prostate Cancer Patients.

Conditions
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Prostate Cancer

Intervention / Treatment
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* Biological: vaccine vehicle only
* Biological: DC/LNCaP


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Disease Characteristics Histologically confirmed prostate carcinoma Progressive, disease required, i.e.: elevated PSA documented to be rising on 3 occasions, either despite castrate testosterone levels (below 50 ng/dl), or after definitive local therapy (prostatectomy or radiation). Prior/Concurrent Therapy -Biologic therapy: Recovered from toxicity of any prior therapy -Chemotherapy: At least 4 weeks since chemotherapy -Endocrine evaluation/therapy 3 rising PSA values at least 2 weeks apart At least 2 weeks since concurrent corticosteroids (other than for replacement therapy for adrenal insufficiency) Medical hormonal therapy to maintain castrate testosterone levels permitted -Radiotherapy: At least 4 weeks since radiotherapy -Surgery: Prior surgery allowed Patient Characteristics Age: 18 and over, able to give written informed consent. Individuals unable to provide informed consent must have consent provided by the legal guardian, or person designated by the subject to give consent on his behalf. Performance status: Karnofsky 70-100% Life expectancy: At least 1 year Hematopoietic: obtained twice, once within 45 days prior to study entry, and again within 72 hours of study entry. WBC greater than 3,800 Absolute neutrophils greater than 1,500 Absolute lymphocytes greater than 500 Platelets greater than 120,000 Hb at least 10 g/dl Hepatic: --Bilirubin less than 2.0 mg/dl OR --SGOT less than 2 x ULN Renal: Creatinine no greater than 2.0 mg/dl OR Creatinine clearance at least 40 ml/min Rheumatologic: --ANA no greater than upper limit of normal, or ANA abnormal in absence of clinical signs of autoimmunity. Rheumatoid factor (RF) no greater than upper limit of normal, or RF abnormal in absence of clinical signs of autoimmunity. Anti-ds DNA no greater than upper limit of normal, or anti ds DNA abnormal in absence of clinical signs of autoimmunity. Immunologic: Influenza serology (assessment made at time of screening). Assessment of DTH response to a standard anergy panel (to include candida, trichophyton and tetanus) or to a Multitest CMI (a disposable kit for DTH testing with standardized preloaded antigens). Endocrine: --TSH, T3, and T4 no greater than upper limit of normal Radiographic: Baseline bone scan Baseline CT or MRI of abdomen and pelvis Exclusion Criteria: Disease Characteristics -No active CNS metastases Prior/Concurrent Therapy Biologic therapy: No prior autologous or allogeneic tumor vaccines No concurrent other immunotherapy Chemotherapy --Not previously treated with more than 2 chemotherapy regimens No concurrent chemotherapy Radiotherapy --No concurrent radiotherapy Patient Characteristics -Cardiovascular: No NYHA class III/IV status No active angina, clinically significant cardiac arrythmia, recent (6 months) myocardial infarction Pulmonary: --No severe debilitating pulmonary disease Other: No active infection requiring antibiotics No active pain requiring chronic opioid analgesics. Not HIV, hepatitis B or hepatitis C virus positive; anti-HIV, HbsAg and Hep C antibody negative No history of hypersensitivity to vaccine components No serious uncontrolled medical illness No currently active second malignancy other than non-melanoma skin cancer (note: a patient is NOT considered to have currently active malignancy if they have completed therapy and are now considered by their physician to be at less than 30% risk for relapse) No history of total lymph node irradiation No history of vasculitis, including but not limited to systemic necrotizing vasculitides (polyarteritis nodosa group), hypersensitivity vasculitis, Wegener's granulomatosis. No history of autoimmune disease. No use of hydroxyurea within 45 days of study entry No receipt of immune modulators or suppressors within 30 days prior to study entry, including but not limited to interferons and thalidomide. No active requirement for corticosteroids; prior use is acceptable. No psychiatric illness or social condition that, in the opinion of the investigator, would interfere with adherence to study requirements. No alcohol or drug use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>12 patients in the placebo Arm for 8 weeks followed by DC/LNCAP, DC/LNCaP-M1 and DC/KLH immunizations over 8 weeks. | Biological: vaccine vehicle only<br>* Subcutaneous injection of vaccine vehicle only (5% DMSO in normal saline), followed by cross-over to Arm 1 design.<br>|
| Experimental: DC/LNCaP<br>12 patients, receiving DC/LNCaP, DC/LNCaP-M1 and DC/KLH immunizations over 8 weeks | Biological: DC/LNCaP<br>* Subcutaneous injection of DC/LNCaP, DC/LNCaP-M1, DC/KLH<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Event | Occurrence of adverse events (AE) was compared between the placebo and vaccine groups during the blinded phase (the 1st 9 weeks). At the end of this phase, all were unblinded, and those who received placebo crossed over to now receive vaccine. All serious AEs and any other AEs that occurred 5 times or more are reported. The exact binomial test was used to compare the occurrence of each AE between groups. | End of blinded phase (wk 9) | 
| Immunogenicity of the DC/LNCaP Vaccine. Pre- vs Post-vaccination Bulk T Cell Proliferation (3H Thymidine Incorporation) by Type of Antigen. The Number Indicated is the Median Difference of Post-Pre, of Each Antigen Group. | The difference between post minus pre-vaccination bulk T cell proliferation was calculated for each antigen. | pre- vs post-vaccination. Pre-vaccination T cells were collected at Wk 0 and post-vaccination T cells were collected at Wk 13 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in PSA Slope, Pre- vs Post-vaccination. | To model the evolution of PSA (in log-scale) during the three study phases (pre-vaccine, vaccine, and post-vaccine phases), a mixed linear spline model was used. Two knots (one at the start of the vaccine phase and the other at the start of the post-vaccine phase) were used to directly quantify the differences in slopes between each phase. To account for the heterogeneous treatment effect and the repeated measures structure, random effects are incorporated into the model. For the general model, random effects for the intercept, slope and the first knot were considered. | pre- vs post- vaccination PSA slopes. |