Renal Cell Carcinoma
Conditions
Keywords
Immunotherapy, Kidney, Genes, Vaccine Therapy, Renal Cell Carcinoma
Brief summary
About 27,000 new cases of renal cell carcinoma (RCC) are diagnosed every year in the United States. 11,000 of these cases will die from the disease. More than half of patients present with advanced or metastatic disease for which chemotherapy plays a very limited role. Therefore, development of another therapeutic approach is needed. Cancers in humans are commonly associated with mutations in dominant and recessive oncogenes. These genes produce mutated proteins that are unique to cancer cells. Von Hipple-Lindau (VHL) gene which is associated with the development of the VHL disease, has been recently mapped and cloned, and it is found to be mutated in 57% of sporadic renal cell carcinomas. Data in mice have shown the generation of major histocompatibility complex (MHC) restricted cytotoxic T lymphocyte (CTL) that are capable of detecting endogenous cytoplasmic peptide derived from mutated oncogenes. In addition, we have recently demonstrated, by conducting different phase I clinical trials in which we vaccinate cancer patients with mutated Ras or p53 peptides corresponding to the abnormality patients harbor in their tumors, that in some patients we can generate immunological responses represented by the generation of lymphocytes (CD4+ and/or CD8+). In the current study, we would like to extend our observations to test whether VHL tumor suppressor protein can be immunologically targeted by vaccination. We have identified specific epitopes along the amino acid sequence of the VHL protein, which represent known specific human leukocyte antigen (HLA) class-I binding motifs. These amino acids stretches in the VHL protein correspond to the area of the point mutation hot spots. Therefore, we propose to treat patients with sporadic RCC who carry VHL mutations in their tumors with corresponding mutant VHL peptide vaccination. This vaccination will be done either by using pulsed-autologous peripheral mononuclear cells with the peptides, or peptides administered subcutaneously alone or in combination with cytokines.
Detailed description
About 27,000 new cases of renal cell carcinoma (RCC) are diagnosed every year in the United States. 11,000 of these cases will die from the disease. More than half of patients present with advanced or metastatic disease for which chemotherapy plays a very limited role. Therefore, development of another therapeutic approach is needed. Cancers in humans are commonly associated with mutations in dominant and recessive oncogenes. These genes produce mutated proteins that are unique to cancer cells. Von Hipple-Lindau gene, which is associated with the development of the VHL disease, has been recently mapped and cloned; it is found to be mutated in 57% of sporadic renal cell carcinomas. Data in mice have shown the generation of MHC restricted CTL that are capable of detecting endogenous cytoplasmic peptide derived from mutated oncogenes. In addition, we have recently demonstrated, by conducting different phase I clinical trials in which we vaccinate cancer patients with mutated Ras or p53 peptides corresponding to the abnormality patients harbor in their tumors, that in some patients we can generate immunological responses represented by the generation of lymphocytes (CD4+ and/or CD8+). In the current study, we would like to extend our observations to test whether VHL tumor suppressor protein can be immunologically targeted by vaccination. We have identified specific epitopes along the amino acid sequence of the VHL protein which represent known specific HLA class-I binding motifs. These amino acids stretches in the VHL protein correspond to the area of the point mutation hot spots. Therefore, this protocol treats patients with sporadic RCC who carry VHL mutations in their tumors with corresponding mutant VHL peptide vaccination.
Interventions
BIOLOGICALincomplete Freund's adjuvant
0.7 ml of ISA-51 (Montanide ISA-51 adjuvant, incomplete Freund's adjuvant) will be mixed with peptide alone and injected subcutaneously every four weeks for a total of four vaccinations.
BIOLOGICALvon Hippel-Lindau peptide vaccine
1000 micrograms administered subcutaneously every four weeks for a total of four vaccinations.
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must be 18 years of age or older. * Histologic diagnosis of renal cell carcinoma. * Tumor tissue availability for determination of Von Hippel-Lindau (VHL) mutation (paraffin block, or fresh tissue). * Patients must carry a VHL mutation in their tumor. * Patients must have metastatic disease for which no further chemotherapy or radiation options, which are known to increase survival, are available. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. * Expected survival more than 3 months. * While measurable disease is preferable, it is not a necessity. * The patient should not have received chemotherapy, radiation therapy, immunotherapy or steroids for at least 4 weeks prior to starting vaccination, and should have recovered from all acute toxicities of previous treatment. * Patients must understand and sign an informed consent document that explains the neoplastic nature of his/her disease, the procedures to be followed, the experimental nature of the treatment, alternative treatments, and potential risks and toxicities.
Exclusion criteria
* Any condition that does not fit with the inclusion criteria. * Any of the following: White blood cells (WBC) less than 2000/mm(3); Platelets less than 100K/mm * (3); Creatinine greater than 2.0 mg/dl; Serum Bilirubin greater than 2.0 mg/dl, Serum glutamic oxaloacetic transaminase (SGOT), or Serum glutamic pyruvic transaminase (SGPT) greater than 4x normal. * Human Immunodeficiency virus (HIV) or active Hepatitis B or C (i.e. detectable Hepatitis B surface (HBS) Antigen or Heteroconjugate (HC) antibodies). * Pregnant women or nursing mothers are ineligible. Women with reproductive potential must have negative urine pregnancy test. Women of reproductive potential must use adequate contraception. * Patients with active ischemic heart disease (i.e. Class III or IV cardiac disease)-New York Heart Association), a recent history of myocardial infarction (within the last 6 months), history of congestive heart failure, ventricular arrhythmias or other arrhythmias requiring therapy, or any other medical conditions that the principal investigators sees to be unfit for such therapy. * History of Central Nervous System (CNS) metastases. * Patients with history of autoimmune disease e.g. (autoimmune neutropenia, thrombocytopenia, or hemolytic anemia; systemic lupus erythematosus, Sjogren syndrome, or scleroderma; myasthenia grave's; Good pasture syndrome; Addison's disease, Hashimoto's thyroiditis, rheumatoid arthritis, multiple sclerosis, or active Graves' disease). * If, in the opinion of the principal or associate investigators, it is not in the best medical interest of the patient to enter this study, the patient will be ineligible.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Generated an Immune Response | 30 months | The immunological response was assessed by in-vitro T cell cytokine production enzyme-linked immunosorbent spot (ELISPOT). From each patients, post-vaccination peripheral blood mononuclear cells (PBMC) were compared to pre-vaccination as a baseline. A positive ELISPOT result for the patients was defined as a total number of experimental spots in the post-vaccination sample of more than twofold above the total spots in the pre-vaccination sample. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Participants With Adverse Events. | 88 months | Here are the total number of participants with adverse events. For the detailed list of adverse events see the adverse event module. |
Countries
United States
Participant flow
Recruitment details
Between 40-60 total patients may be required for this protocol. Between 2-3 years would be required to enter all necessary patients.
Participants by arm
| Arm | Count |
|---|---|
| Group A-VHL Peptide and ISA-51 Adjuvant Patients are vaccinated with 1000 micrograms of the mutant Von Hippel-Lindau (VHL) peptide administered subcutaneously along with Montanide ISA-51 adjuvant. | 6 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | No evidence of disease | 1 |
| Overall Study | progressed disease | 2 |
| Overall Study | recurrent disease | 2 |
Baseline characteristics
| Characteristic | Group A-VHL Peptide and ISA-51 Adjuvant |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants |
| Age, Continuous | 62 years STANDARD_DEVIATION 11.31 |
| Region of Enrollment United States | 6 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 5 / 6 |
| serious Total, serious adverse events | 5 / 6 |
Outcome results
Primary
Percentage of Participants Who Generated an Immune Response
The immunological response was assessed by in-vitro T cell cytokine production enzyme-linked immunosorbent spot (ELISPOT). From each patients, post-vaccination peripheral blood mononuclear cells (PBMC) were compared to pre-vaccination as a baseline. A positive ELISPOT result for the patients was defined as a total number of experimental spots in the post-vaccination sample of more than twofold above the total spots in the pre-vaccination sample.
Time frame: 30 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A-VHL Peptide and ISA-51 Adjuvant | Percentage of Participants Who Generated an Immune Response | 80 percentage of participants |
Secondary
The Number of Participants With Adverse Events.
Here are the total number of participants with adverse events. For the detailed list of adverse events see the adverse event module.
Time frame: 88 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A-VHL Peptide and ISA-51 Adjuvant | The Number of Participants With Adverse Events. | 5 participants |