Anti-MART-1 F5 Cells Plus ALVAC MART-1 Vaccine to Treat Advanced Melanoma
| Status: | Terminated |
|---|---|
| Conditions: | Skin Cancer, Skin Cancer, Cancer |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 4/21/2016 |
| Start Date: | January 2008 |
| End Date: | March 2011 |
Phase II Study of Metastatic Melanoma Using Lymphodepleting Conditioning Followed by Infusion of Anti-MART-1 F5 TCR-Gene Engineered Lymphocytes and ALVAC Virus Immunization
Background:
- Melanoma antigen recognized by T-cells (MART)-1 is a protein present in melanoma cells.
- An experimental procedure developed for treating patients with melanoma uses the
anti-MART-1 F5 gene and a type of virus to make special cells called anti-MART-1 F5
cells that are designed to destroy the patient's tumor. These cells are created in the
laboratory using the patient's own tumor cells or blood cells.
- The treatment procedure also uses a vaccine called plaque purified canarypox vector
(ALVAC) MART-1, made from a virus that ordinarily infects canaries and is modified to
carry a copy of the MART-1 gene. The virus cannot reproduce in mammals, so it cannot
cause disease in humans. When the vaccine is injected into a patient, it stimulates
cells in the immune system that may increase the efficiency of the anti-MART-1 F5
cells.
Objectives:
-To evaluate the safety and effectiveness of anti-MART-1 F5 and the ALVAC vaccine in
treating patients with advanced melanoma.
Eligibility:
-Patients 18 years of age with metastatic melanoma for whom standard treatments have not
been effective.
Design:
- Patients undergo scans, x-rays and other tests and leukapheresis to obtain white cells
for laboratory treatment.
- Patients have 7 days of chemotherapy to prepare the immune system for receiving the
anti-MART-1 F5.
- Patients receive the ALVAC vaccine, anti-MART-1 F5 cells and interleukin-2 (IL-2) (an
approved treatment for advanced melanoma). The anti-MART-1 F5 cells are given as an
infusion through a vein. The vaccine is given as injections just before the infusion of
anti-MART-1 F5 cells and again 2 weeks later. IL-2 is given as a 15-minute infusion
every 8 hours for up to 5 days after the cell infusion for a maximum of 15 doses.
- After hospital discharge, patients return to the clinic for periodic follow-up with a
physical examination, review of treatment side effects, laboratory tests and scans
every 1 to 6 months.
- Melanoma antigen recognized by T-cells (MART)-1 is a protein present in melanoma cells.
- An experimental procedure developed for treating patients with melanoma uses the
anti-MART-1 F5 gene and a type of virus to make special cells called anti-MART-1 F5
cells that are designed to destroy the patient's tumor. These cells are created in the
laboratory using the patient's own tumor cells or blood cells.
- The treatment procedure also uses a vaccine called plaque purified canarypox vector
(ALVAC) MART-1, made from a virus that ordinarily infects canaries and is modified to
carry a copy of the MART-1 gene. The virus cannot reproduce in mammals, so it cannot
cause disease in humans. When the vaccine is injected into a patient, it stimulates
cells in the immune system that may increase the efficiency of the anti-MART-1 F5
cells.
Objectives:
-To evaluate the safety and effectiveness of anti-MART-1 F5 and the ALVAC vaccine in
treating patients with advanced melanoma.
Eligibility:
-Patients 18 years of age with metastatic melanoma for whom standard treatments have not
been effective.
Design:
- Patients undergo scans, x-rays and other tests and leukapheresis to obtain white cells
for laboratory treatment.
- Patients have 7 days of chemotherapy to prepare the immune system for receiving the
anti-MART-1 F5.
- Patients receive the ALVAC vaccine, anti-MART-1 F5 cells and interleukin-2 (IL-2) (an
approved treatment for advanced melanoma). The anti-MART-1 F5 cells are given as an
infusion through a vein. The vaccine is given as injections just before the infusion of
anti-MART-1 F5 cells and again 2 weeks later. IL-2 is given as a 15-minute infusion
every 8 hours for up to 5 days after the cell infusion for a maximum of 15 doses.
- After hospital discharge, patients return to the clinic for periodic follow-up with a
physical examination, review of treatment side effects, laboratory tests and scans
every 1 to 6 months.
Background:
- We have engineered human PBLs to express an anti-MART-1 T-cell receptor that recognizes
an human leukocyte antigens (HLA-A) 0201 restricted epitope derived from the tumor
infiltrating lymphocytes (TIL) clone DMF5.
- We constructed a single retroviral vector that contains both alpha and infinity chains
and can mediate genetic transfer of this T cell receptor (TCR) with high efficiency
without the need to perform any selection.
- In co-cultures with HLA-A 0201 positive melanoma, anti-MART-1 F5 TCR transduced T cells
secreted significant amount of interferon (IFN)-(but no significant secretion was
observed in control co-cultures with cell lines.
- The anti-MART-1 F5 TCR transduced peripheral blood lymphocytes (PBL) could efficiently
kill HLA-A 0201 positive tumors. There was little or no recognition of normal
fibroblasts cells.
- This TCR is over 10 times more reactive with melanoma cells than the MART-1 TCR that
mediated tumor regression in two patients with metastatic melanoma.
- In this trial we would like to test our hypothesis that the addition of an anti-tumor
ALVAC vaccine will result in clinical tumor regression and persistence of the
transferred cells (as is the case in murine models).
Objectives:
Primary objectives:
-Determine if the administration of anti-MART-1 F5 TCR -engineered peripheral blood
lymphocytes, ALVAC anti-tumor immunization, and aldesleukin to patients following a
nonmyeloablative but lymphoid depleting preparative regimen will result in clinical tumor
regression in patients with metastatic melanoma.
Secondary objectives:
- Determine the in vivo survival of TCR gene-engineered cells.
- Determine the toxicity profile of this treatment regimen.
Eligibility:
Patients who are HLA-A 0201 positive and 18 years of age or older must have:
- metastatic melanoma;
- previously received and have been a non-responder to or recurred after aldesleukin;
- normal values for basic laboratory values.
Patients may not have:
- concurrent major medical illnesses;
- any form of primary or secondary immunodeficiency;
- severe hypersensitivity to any of the agents used in this study;
- contraindications for high dose aldesleukin administration.
- Design:
- peripheral blood mononuclear cells (PBMC) obtained by leukapheresis (approximately 5
times 10^9 cells) will be cultured in the presence of anti-CD3 (OKT3) and aldesleukin
in order to stimulate T-cell growth.
- Transduction is initiated by exposure of approximately 10^8 to 5 X 10^8 cells to
retroviral vector supernatant containing the anti-MART-1 F5 TCR genes. These transduced
cells will be expanded and tested for their anti-tumor activity.
- Once engineered PBMC are demonstrated to be biologically active according to the
strict-criteria outlined in the Certificate of Analysis, patients will receive a
nonmyeloablative but lymphocyte depleting preparative regimen consisting of
cyclophosphamide and fludarabine followed by intravenous infusion of ex vivo tumor
reactive, TCR gene-transduced PBMC plus intravenous (IV) aldesleukin (720,000 IU/kg q8h
for a maximum of 15 doses). Approximately 2 hours prior to cell infusion, patients will
be immunized with ALVAC virus expressing the tumor antigen. ALVAC immunization will be
repeated at 2 weeks.
- Patients will undergo complete evaluation of tumor with physical examination, computed
tomography (CT) of the chest, abdomen and pelvis and clinical laboratory evaluation
four to six weeks after treatment and then monthly for approximately 3 to 4 months or
until off study criteria are met.
- The study will be conducted using a phase II optimal design where initially 21
evaluable patients will be enrolled. If 0 or 1 of the 21 patients experiences a
clinical response, then no further patients will be enrolled but if 2 or more of the
first 21 evaluable patients enrolled have a clinical response, then accrual will
continue until a total of 41 evaluable patients have been enrolled.
- The objective will be to determine if the combination of high dose aldesleukin,
lymphocyte depleting chemotherapy, ALVAC immunization and anti-MART-1 F5 TCR-gene
engineered lymphocytes is able to be associated with a clinical response rate that can
rule out 5 percent (p0=0.05) in favor of a modest 20 percent partial response (PR) plus
complete response (CR) rate (p1=0.20).
- We have engineered human PBLs to express an anti-MART-1 T-cell receptor that recognizes
an human leukocyte antigens (HLA-A) 0201 restricted epitope derived from the tumor
infiltrating lymphocytes (TIL) clone DMF5.
- We constructed a single retroviral vector that contains both alpha and infinity chains
and can mediate genetic transfer of this T cell receptor (TCR) with high efficiency
without the need to perform any selection.
- In co-cultures with HLA-A 0201 positive melanoma, anti-MART-1 F5 TCR transduced T cells
secreted significant amount of interferon (IFN)-(but no significant secretion was
observed in control co-cultures with cell lines.
- The anti-MART-1 F5 TCR transduced peripheral blood lymphocytes (PBL) could efficiently
kill HLA-A 0201 positive tumors. There was little or no recognition of normal
fibroblasts cells.
- This TCR is over 10 times more reactive with melanoma cells than the MART-1 TCR that
mediated tumor regression in two patients with metastatic melanoma.
- In this trial we would like to test our hypothesis that the addition of an anti-tumor
ALVAC vaccine will result in clinical tumor regression and persistence of the
transferred cells (as is the case in murine models).
Objectives:
Primary objectives:
-Determine if the administration of anti-MART-1 F5 TCR -engineered peripheral blood
lymphocytes, ALVAC anti-tumor immunization, and aldesleukin to patients following a
nonmyeloablative but lymphoid depleting preparative regimen will result in clinical tumor
regression in patients with metastatic melanoma.
Secondary objectives:
- Determine the in vivo survival of TCR gene-engineered cells.
- Determine the toxicity profile of this treatment regimen.
Eligibility:
Patients who are HLA-A 0201 positive and 18 years of age or older must have:
- metastatic melanoma;
- previously received and have been a non-responder to or recurred after aldesleukin;
- normal values for basic laboratory values.
Patients may not have:
- concurrent major medical illnesses;
- any form of primary or secondary immunodeficiency;
- severe hypersensitivity to any of the agents used in this study;
- contraindications for high dose aldesleukin administration.
- Design:
- peripheral blood mononuclear cells (PBMC) obtained by leukapheresis (approximately 5
times 10^9 cells) will be cultured in the presence of anti-CD3 (OKT3) and aldesleukin
in order to stimulate T-cell growth.
- Transduction is initiated by exposure of approximately 10^8 to 5 X 10^8 cells to
retroviral vector supernatant containing the anti-MART-1 F5 TCR genes. These transduced
cells will be expanded and tested for their anti-tumor activity.
- Once engineered PBMC are demonstrated to be biologically active according to the
strict-criteria outlined in the Certificate of Analysis, patients will receive a
nonmyeloablative but lymphocyte depleting preparative regimen consisting of
cyclophosphamide and fludarabine followed by intravenous infusion of ex vivo tumor
reactive, TCR gene-transduced PBMC plus intravenous (IV) aldesleukin (720,000 IU/kg q8h
for a maximum of 15 doses). Approximately 2 hours prior to cell infusion, patients will
be immunized with ALVAC virus expressing the tumor antigen. ALVAC immunization will be
repeated at 2 weeks.
- Patients will undergo complete evaluation of tumor with physical examination, computed
tomography (CT) of the chest, abdomen and pelvis and clinical laboratory evaluation
four to six weeks after treatment and then monthly for approximately 3 to 4 months or
until off study criteria are met.
- The study will be conducted using a phase II optimal design where initially 21
evaluable patients will be enrolled. If 0 or 1 of the 21 patients experiences a
clinical response, then no further patients will be enrolled but if 2 or more of the
first 21 evaluable patients enrolled have a clinical response, then accrual will
continue until a total of 41 evaluable patients have been enrolled.
- The objective will be to determine if the combination of high dose aldesleukin,
lymphocyte depleting chemotherapy, ALVAC immunization and anti-MART-1 F5 TCR-gene
engineered lymphocytes is able to be associated with a clinical response rate that can
rule out 5 percent (p0=0.05) in favor of a modest 20 percent partial response (PR) plus
complete response (CR) rate (p1=0.20).
-INCLUSION CRITERIA:
1. Metastatic melanoma with measurable disease.
2. Previously received high dose interleukin-2 (IL-2) and have been either
non-responders (progressive disease) or have recurred.
3. Positive for MART-1 by immunohistochemistry (IHC) which will be reviewed by the
Laboratory of Pathology at National Cancer Institute (NCI).
4. Tumor infiltrating lymphocytes (TIL) cells not available for treatment on other
Surgery Branch protocols.
5. Greater than or equal to 18 years of age.
6. Willing to sign a durable power of attorney.
7. Able to understand and sign the Informed Consent Document.
8. Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1.
9. Life expectancy of greater than three months.
10. Patients of both genders must be willing to practice birth control for four months
after receiving the preparative regimen.
11. Patients must be human leukocyte antigens (HLA-A) 0201 positive.
12. Serology:
- Seronegative for human immunodeficiency virus (HIV) antibody. (The experimental
treatment being evaluated in this protocol depends on an intact immune system.
Patients who are HIV seropositive can have decreased immune -competence and thus
be less responsive to the experimental treatment and more susceptible to its
toxicities.)
- Seronegative for hepatitis B antigen and hepatitis C antibody unless antigen
negative.
13. Hematology:
- Absolute neutrophil count greater than 1000/mm^3 without the support of
filgrastim.
- White blood cell (WBC) (greater than 3000/mm^3.
- Platelet count greater than 100,000/mm^3.
- Hemoglobin greater than 8.0 g/dl.
14. Chemistry:
- Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less or
equal to 2.5 times the upper limit of normal.
- Serum creatinine less than or equal to 1.6 mg/dl.
- Total bilirubin less than or equal to 2.0 mg/dl, except in patients with
Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dl.
15. More than four weeks must have elapsed since any prior systemic therapy at the time
the patient receives the preparative regimen, and patients' toxicities must have
recovered to a grade 1 or less (except for toxicities such as alopecia or vitiligo).
16. Six weeks must have elapsed since prior MDX-010 therapy to allow antibody levels to
decline.
17. Patients who have previously received MDX-010 or ticilimumab must have a normal
colonoscopy with normal colonic biopsies.
EXCLUSION CRITERIA:
1. Women of child-bearing potential who are pregnant or breastfeeding because of the
potentially dangerous effects of the preparative chemotherapy on the fetus or infant.
2. Active systemic infections, coagulation disorders or other major medical illnesses of
the cardiovascular, respiratory or immune system, myocardial infarction, cardiac
arrhythmias, obstructive or restrictive pulmonary disease.
3. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency
Disease).
4. Ongoing opportunistic infections (The experimental treatment being evaluated in this
protocol depends on an intact immune system. Patients who have decreased immune
competence may be less responsive to the experimental treatment and more susceptible
to its toxicities).
5. Systemic steroid therapy.
6. History of severe immediate hypersensitivity reaction to any of the agents used in
this study.
7. History of coronary revascularization or ischemic symptoms.
8. Any patient known to have an left ventricular ejection fraction (LVEF) less than or
equal to 45 percent.
9. Documented LVEF of less than or equal to 45 percent tested in patients with:
- Clinically significant atrial and/or ventricular arrhythmias including but not
limited to: atrial fibrillation, ventricular tachycardia, second or third degree
heart block.
- Age greater than or equal to 60 years old.
10. Documented forced expiratory volume in 1 second (FEV1) less than or equal to 60
percent predicted tested in patients with:
- A prolonged history of cigarette smoking (20 pk/yrs of smoking).
- Symptoms of respiratory dysfunction.
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
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