Metastatic Melanoma
Conditions
Keywords
Melanoma
Brief summary
The purpose of this study is to determine what effect using an experimental tumor vaccine (a substance or group of substances meant to cause the immune system to respond to a tumor) made using patients' own tumor cells and blood cells will have on their melanoma.
Detailed description
Historically, metastatic melanoma has been associated with a poor prognosis. Recently, numerous immunotherapeutic agents, particularly checkpoint inhibitors, have moved to the forefront of therapy. Checkpoint inhibitors such as ipilimumab, pembrolizumab, and nivolumab have revolutionized the treatment of melanoma. Despite this, not all patients respond to checkpoint inhibitors, and even patients who initially respond to checkpoint inhibitor therapy often later relapse (median response duration of 2 years); complete responses remain uncommon. Thus, more effective immunotherapies are clearly needed. The concept of administering dendritic cell (DC)-based vaccines to prompt an immune response against tumor cells has shown promise in the treatment of advanced cancers. Sipuleucel-T, now FDA-approved for the treatment of advanced prostate cancer, is one such vaccine that consists of autologous antigen-presenting cell (APC) activated ex vivo by a fusion protein consisting of the antigen prostatic acid phosphatase (PAP) and granulocyte-macrophage colony stimulating factor (GM-CSF). Although response rates to Sipuleucel-T are low, recent studies suggest that DC vaccines have the potential to improve survival by increasing the breadth and diversity of melanoma-specific T cells. It is known that the method of antigen (Ag) delivery is important for the success of DC vaccines, but it remains unclear which method is most effective in producing antitumor responses. Approaches tested clinically include pulsing with HLA-restricted defined peptide Ags, loading with purified proteins, transfecting with mRNA, engineering with Ag-encoding viral vectors, and using autologous tumor cells or allogeneic cell lines directly as sources of Ag. Efficacy can be measured in vivo using surrogate endpoints, such as development of tumor-specific delayed-type hypersensitivity (DTH) reactions. Prolonged survival of vaccinated melanoma patients has been reported to correlate with induction of positive DTH tests. Antitumor activity may also be assessed by ELISpot analysis of the frequency of tumor-Ag specific IFNγ-producing T cells. To assess the quality of the DC vaccines, surrogate markers of DC function including maturation markers, co-stimulatory molecule expression, and IL12p70 production, a critical cytokine in antitumor response, can be measured
Interventions
BIOLOGICALVaccination
Subjects will receive as an outpatient 4 weekly ultrasound-guided intra/peri-lymph nodal administrations of the autologous tumor dendritic cell vaccine. The dose of the autologous tumor cell dendritic cells/vaccine will be 1-5 X 106.
Sponsors
National Institutes of Health (NIH)
National Cancer Institute (NCI)
John Kirkwood
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects must have Stage III-IV melanoma (any tumor thickness and any number of lymph node involvement, and in-transit metastases, or distant metastases) (AJCC). Each diagnosis will be confirmed by pathology review at the Melanoma Center of the University of Pittsburgh Cancer Institute. * All subjects have to be HLA-A2 positive (required for immunologic testing). * Subjects must have recovered fully from surgery. * Availability of resectable or tissue banked tumor cells for autologous tumor dendritic cell vaccine preparation. * Sufficient number of tumor cells available for autologous tumor dendritic cell vaccine preparation (min 2.6 x 10 7). * Sufficient number of DCs of at least 12 X 10 6 for preparation of the autologous tumor dendritic cell vaccine preparation (if less than needed number of cells will be obtained by one course of leukopheresis, the second leukopheresis will be repeated 2 weeks apart). * Subjects must not have received any chemotherapy or immunotherapy within the four weeks preceding vaccination (six weeks for nitrosourea, mitomycin). * Subjects must have an expected survival of greater than or equal to 12 months. * Subjects must have an ECOG performance status 0 or 1. * Subjects must have the following initial and subsequent pretreatment * laboratory parameters: Granulocytes \>=2,500/mm3 Lymphocytes \>=1000/mm3 Platelets \>100,000/mm3 Serum Creatinine \<=1.5 X the ULN AST, ALT, GGT, LDH, Alk phos \<= 2.5 X the ULN Serum Bilirubin \<=1.5 X ULN * Subjects must be \>= 18 years of age and must be able to understand the written informed consent. * No evidence of active infection, regardless of the degree of severity or localization. Subjects with active infections (whether or not they require antibiotic therapy) may be eligible after complete resolution of the infection. Subjects on antibiotic therapy must be off antibiotics for at least 7 days before beginning treatment. * Subjects with measurable disease must have an evaluation for extent of disease (tumor staging) performed within 30 days of start of treatment. * Pretreatment baseline evaluations for laboratory parameters must be obtained within 10 to18 days of subject registration
Exclusion criteria
* Subjects currently treated with anti inflammatory agents including glucocorticoid therapy are ineligible. * Subjects currently on treatment with steroids are ineligible, but may receive the DC autologous tumor dendritic cell vaccine 4 weeks after steroid cessation. Subjects on maintenance steroids because of adrenal insufficiency are eligible. * Subjects with severely abnormal liver function tests \[AST (SGOT), ALT (SGPT), GGT, Alk.Phos, LDH, and total bilirubin greater than 2 X ULN\]. * Subjects with uncontrolled pain. * Subjects with autoimmune disease, HIV, and hepatitis * Subjects with symptomatic brain metastasis. * Subjects with active prior malignancy (with exception of non-melanoma skin cancers and carcinoma in situ of the cervix). * Subjects who have been previously immunized with melanoma vaccine until 10 subjects have been registered in each treatment arm. * Subjects who are pregnant. * Subjects who have sensitivity to drugs to provide local anesthesia.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Delayed Type Hypersensitivity (DTH) Response | 12 mo | Delayed type hypersensitivity (DTH) response to antigen-loaded autologous, dendritic cell vaccine (DC) injected intradermal in vivo |
| ELISpot Response to Melanoma | 12 mo | Peripheral blood CD8+ and CD4+ T cell responses against autologous tumor cells, and HLA-presented melanoma epitopes, using ELISPOT and MHC-peptide tetramer assays. |
Countries
United States
Participant flow
Pre-assignment details
Although 16 subjects were enrolled, one subject was referred to hospice and never began the study.
Participants by arm
| Arm | Count |
|---|---|
| DCs Co-cultured With Melanoma Cells DCs co-cultured with melanoma cells
Vaccination: Subjects will receive as an outpatient 4 weekly ultrasound-guided intra/peri-lymph nodal administrations of the autologous tumor dendritic cell vaccine. The dose of the autologous tumor cell dendritic cells/vaccine will be 1-5 X 106.
Leukapheresis: All selected subjects will undergo leukapheresis. Two and a half times the subject's blood volume will be processed per procedure. A single 4 hour leukapheresis will be done. | 5 |
| DCs Pulsed With Tumor Cell Lysates DCs pulsed with tumor cell lysates
Vaccination: Subjects will receive as an outpatient 4 weekly ultrasound-guided intra/peri-lymph nodal administrations of the autologous tumor dendritic cell vaccine. The dose of the autologous tumor cell dendritic cells/vaccine will be 1-5 X 106.
Leukapheresis: All selected subjects will undergo leukapheresis. Two and a half times the subject's blood volume will be processed per procedure. A single 4 hour leukapheresis will be done. | 6 |
| DCs Fused With Tumor Cells DCs fused with tumor cells
Vaccination: Subjects will receive as an outpatient 4 weekly ultrasound-guided intra/peri-lymph nodal administrations of the autologous tumor dendritic cell vaccine. The dose of the autologous tumor cell dendritic cells/vaccine will be 1-5 X 106.
Leukapheresis: All selected subjects will undergo leukapheresis. Two and a half times the subject's blood volume will be processed per procedure. A single 4 hour leukapheresis will be done. | 4 |
| Total | 15 |
Baseline characteristics
| Characteristic | DCs Co-cultured With Melanoma Cells | DCs Pulsed With Tumor Cell Lysates | DCs Fused With Tumor Cells | Total |
|---|---|---|---|---|
| Age, Continuous | 66 years | 44.5 years | 54 years | 49 years |
| Sex: Female, Male Female | 4 Participants | 3 Participants | 2 Participants | 9 Participants |
| Sex: Female, Male Male | 1 Participants | 3 Participants | 2 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 11 / 15 |
| serious Total, serious adverse events | 1 / 15 |
Outcome results
Primary
Delayed Type Hypersensitivity (DTH) Response
Delayed type hypersensitivity (DTH) response to antigen-loaded autologous, dendritic cell vaccine (DC) injected intradermal in vivo
Time frame: 12 mo
Population: Patients who met inclusion criteria and received at least 3 doses of the vaccine
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DCs Co-cultured With Melanoma Cells | Delayed Type Hypersensitivity (DTH) Response | 2 participants |
| DCs Pulsed With Tumor Cell Lysates | Delayed Type Hypersensitivity (DTH) Response | 2 participants |
| DCs Fused With Tumor Cells | Delayed Type Hypersensitivity (DTH) Response | 1 participants |
Primary
ELISpot Response to Melanoma
Peripheral blood CD8+ and CD4+ T cell responses against autologous tumor cells, and HLA-presented melanoma epitopes, using ELISPOT and MHC-peptide tetramer assays.
Time frame: 12 mo
Population: Patients who met inclusion criteria and received at least 3 doses of the vaccine
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| DCs Co-cultured With Melanoma Cells | ELISpot Response to Melanoma | 2 participants |
| DCs Pulsed With Tumor Cell Lysates | ELISpot Response to Melanoma | 2 participants |
| DCs Fused With Tumor Cells | ELISpot Response to Melanoma | 1 participants |