Immunotherapy Using 41BB Selected Tumor Infiltrating Lymphocytes for Patients With Metastatic Melanoma
| Status: | Terminated |
|---|---|
| Conditions: | Skin Cancer, Skin Cancer, Cancer |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - 70 |
| Updated: | 7/8/2017 |
| Start Date: | February 21, 2014 |
| End Date: | July 21, 2016 |
A Phase II Study of Cell Transfer Therapy for Metastatic Melanoma Using 41BB Selected Tumor Infiltrating Lymphocytes Plus IL-2 Following a Non-Myeloablative Lymphocyte Depleting Chemotherapy Regimen
Background:
The NCI Surgery Branch has developed an experimental therapy that involves taking white blood
cells from patients' tumors, growing them in the laboratory in large numbers, and then giving
the cells back to the patient. These cells are called Tumor Infiltrating Lymphocytes, or TIL
and we have given this type of treatment to over 100 patients. In this study, we are
selecting a specific subset of white blood cells from the tumor that we think are the most
effective in fighting tumors and will use only these cells in making the tumor fighting
cells.
Objective:
The purpose of this study is to see if these specifically selected tumor fighting cells can
cause melanoma tumors to shrink and to see if this treatment is safe.
Eligibility:
- Adults age 18-70 with metastatic melanoma who have a tumor that can be safely removed.
Design:
- Work up stage: Patients will be seen as an outpatient at the NIH clinical Center and
undergo a history and physical examination, scans, x-rays, lab tests, and other tests as
needed
- Surgery: If the patients meet all of the requirements for the study they will undergo
surgery to remove a tumor that can be used to grow the TIL product.
- Leukapheresis: Patients may undergo leukapheresis to obtain additional white blood
cells. {Leukapheresis is a common procedure, which removes only the white blood cells
from the patient.}
- Treatment: Once their cells have grown, the patients will be admitted to the hospital
for the conditioning chemotherapy, the TIL cells and aldesleukin. They will stay in the
hospital for about 4 weeks for the treatment.
Follow up: Patients will return to the clinic for a physical exam, review of side effects,
lab tests, and scans about every 1-3 months for the first year, and then every 6 months to 1
year as long as their tumors are shrinking. Follow up visits take up to 2 days.
The NCI Surgery Branch has developed an experimental therapy that involves taking white blood
cells from patients' tumors, growing them in the laboratory in large numbers, and then giving
the cells back to the patient. These cells are called Tumor Infiltrating Lymphocytes, or TIL
and we have given this type of treatment to over 100 patients. In this study, we are
selecting a specific subset of white blood cells from the tumor that we think are the most
effective in fighting tumors and will use only these cells in making the tumor fighting
cells.
Objective:
The purpose of this study is to see if these specifically selected tumor fighting cells can
cause melanoma tumors to shrink and to see if this treatment is safe.
Eligibility:
- Adults age 18-70 with metastatic melanoma who have a tumor that can be safely removed.
Design:
- Work up stage: Patients will be seen as an outpatient at the NIH clinical Center and
undergo a history and physical examination, scans, x-rays, lab tests, and other tests as
needed
- Surgery: If the patients meet all of the requirements for the study they will undergo
surgery to remove a tumor that can be used to grow the TIL product.
- Leukapheresis: Patients may undergo leukapheresis to obtain additional white blood
cells. {Leukapheresis is a common procedure, which removes only the white blood cells
from the patient.}
- Treatment: Once their cells have grown, the patients will be admitted to the hospital
for the conditioning chemotherapy, the TIL cells and aldesleukin. They will stay in the
hospital for about 4 weeks for the treatment.
Follow up: Patients will return to the clinic for a physical exam, review of side effects,
lab tests, and scans about every 1-3 months for the first year, and then every 6 months to 1
year as long as their tumors are shrinking. Follow up visits take up to 2 days.
Background:
- Autologous tumor infiltrating lymphocytes (TIL) followed by high dose aldesleukin can
mediate the regression of bulky metastatic melanoma when administered to a patient
following a non-myeloablative but lymphodepleting chemotherapy preparative regimen.
- In animal models, mixing irrelevant (non-reactive) cells with tumor-reactive cells
negatively impacts on tumor treatment possibly by competing for cytokines, suggesting
that enrichment for tumor-reactive cells could enhance clinical efficacy. Additionally,
preclinical animal models and clinical investigation have demonstrated that prolonged in
vitro culture negatively impacts on tumor treatment.
- The current method for enrichment of tumor-reactive TIL requires screening of multiple
independent TIL cultures for anti-tumor specificity using gamma-interferon production by
TIL. However, in vitro screening depends on autologous tumor reagents that are often
unavailable, and IFN gamma release in vitro may not be the best effector function to
evaluate tumor recognition. The screen increases the length of in vitro culture times (
30 days), which results in shorter telomere lengths and more differentiated cells.
Additionally, selection of a few highly reactive cultures for further expansion may
reduce the diversity of CD8+ repertoire recognizing the tumor.
- 4-1BB is a co-stimulatory molecule up-regulated on the cell surface of T cells upon TCR
engagement. Pre-clinical studies in the Surgery Branch have evaluated a fast and
simplified method to select and expand a diverse tumor-reactive repertoire, regardless
of knowledge of the specific antigen recognized, based on selection of 4-1BB expressing
TIL from the fresh tumor digest.
Objectives:
- To determine the safety and objective response rate of patients with metastatic melanoma
receiving ACT using 4-1BB selected TIL plus aldesleukin treatment following a
chemotherapy preparative regimen.
- To determine the survival of patients receiving this treatment regimen.
Eligibility:
Patients who are 18 years or older must have:
- Evaluable metastatic melanoma;
- Metastatic melanoma lesion suitable for surgical resection for the preparation of TIL;
- No contraindications to high-dose aldesleukin administration;
- No concurrent major medical illnesses or any form of immunodeficiency
Design:
- Patients with metastatic melanoma will have a lesion resected and 4-1BB expressing tumor
infiltrating lymphocytes will be isolated using a FACS sorter approved for clinical use.
The 4-1BB selected cells will be rapidly expanded in vitro and administered plus
aldesleukin following a non-myeloablative chemotherapy preparative regimen.
- The study will be conducted using a stage 2 optimal design to determine if this
treatment is able to be associated with a clinical response rate that can rule out 10%
(p0=0.10) in favor of a modest 30% PR + CR rate (p1=0.30).
- Up to 35 patients may be enrolled over 2 years.
- Autologous tumor infiltrating lymphocytes (TIL) followed by high dose aldesleukin can
mediate the regression of bulky metastatic melanoma when administered to a patient
following a non-myeloablative but lymphodepleting chemotherapy preparative regimen.
- In animal models, mixing irrelevant (non-reactive) cells with tumor-reactive cells
negatively impacts on tumor treatment possibly by competing for cytokines, suggesting
that enrichment for tumor-reactive cells could enhance clinical efficacy. Additionally,
preclinical animal models and clinical investigation have demonstrated that prolonged in
vitro culture negatively impacts on tumor treatment.
- The current method for enrichment of tumor-reactive TIL requires screening of multiple
independent TIL cultures for anti-tumor specificity using gamma-interferon production by
TIL. However, in vitro screening depends on autologous tumor reagents that are often
unavailable, and IFN gamma release in vitro may not be the best effector function to
evaluate tumor recognition. The screen increases the length of in vitro culture times (
30 days), which results in shorter telomere lengths and more differentiated cells.
Additionally, selection of a few highly reactive cultures for further expansion may
reduce the diversity of CD8+ repertoire recognizing the tumor.
- 4-1BB is a co-stimulatory molecule up-regulated on the cell surface of T cells upon TCR
engagement. Pre-clinical studies in the Surgery Branch have evaluated a fast and
simplified method to select and expand a diverse tumor-reactive repertoire, regardless
of knowledge of the specific antigen recognized, based on selection of 4-1BB expressing
TIL from the fresh tumor digest.
Objectives:
- To determine the safety and objective response rate of patients with metastatic melanoma
receiving ACT using 4-1BB selected TIL plus aldesleukin treatment following a
chemotherapy preparative regimen.
- To determine the survival of patients receiving this treatment regimen.
Eligibility:
Patients who are 18 years or older must have:
- Evaluable metastatic melanoma;
- Metastatic melanoma lesion suitable for surgical resection for the preparation of TIL;
- No contraindications to high-dose aldesleukin administration;
- No concurrent major medical illnesses or any form of immunodeficiency
Design:
- Patients with metastatic melanoma will have a lesion resected and 4-1BB expressing tumor
infiltrating lymphocytes will be isolated using a FACS sorter approved for clinical use.
The 4-1BB selected cells will be rapidly expanded in vitro and administered plus
aldesleukin following a non-myeloablative chemotherapy preparative regimen.
- The study will be conducted using a stage 2 optimal design to determine if this
treatment is able to be associated with a clinical response rate that can rule out 10%
(p0=0.10) in favor of a modest 30% PR + CR rate (p1=0.30).
- Up to 35 patients may be enrolled over 2 years.
-INCLUSION CRITERIA:
1. Measurable metastatic melanoma with at least one lesion that is resectable for TIL
generation. The lesion must be at least 1 cm in diameter that can be surgically
removed with minimal morbidity (defined as any operation for which expected
hospitalization
2. Confirmation of diagnosis of metastatic melanoma by the Laboratory of Pathology of the
NCI.
3. Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and
asymptomatic are eligible. Lesions that have been treated with stereotactic
radiosurgery must be clinically stable for 1 month after treatment for the patient to
be eligible.
4. Greater than or equal to 18 years of age and less than or equal to age 70.
5. Able to understand and sign the Informed Consent Document
6. Willing to sign a durable power of attorney
7. Clinical performance status of ECOG 0 or 1
8. Oxygen saturation of greater than or equal to 90% on room air
9. Life expectancy of greater than three months
10. Patients of both genders must be willing to practice birth control from the time of
enrollment on this study and for up to four months after treatment.
11. Serology:
- Seronegative for 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 seronegative for hepatitis C antibody.
If hepatitis C antibody test is positive, then patient must be tested for the
presence of antigen by RT-PCR and be HCV RNA negative.
12. Women of child-bearing potential must have a negative pregnancy test because of the
potentially dangerous effects of the treatment on the fetus.
13. Hematology
- Absolute neutrophil count greater than 1000/mm3 without the support of filgrastim
- WBC greater than or equal to 3000/mm (3)
- Platelet count greater than or equal to 100,000/mm (3)
- Hemoglobin > 8.0 g/dl
14. Chemistry:
- Serum ALT/AST less than 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).
Patients must have progressing disease after prior treatment.
Note: Patients may have undergone minor surgical procedures within the past 3 weeks,
as long as all toxicities have recovered to grade 1 or less or as specified in the
eligibility criteria in Section 2.1.1.
16. Six weeks must have elapsed from the time of any antibody therapy that could affect an
anti cancer immune response, including anti-CTLA4 antibody therapy at the time the
patient receives the preparative regimen to allow antibody levels to decline.
Note: Patients who have previously received ipilimumab and have documented GI toxicity must
have a normal colonoscopy with normal colonic biopsies.
EXCLUSION CRITERIA:
1. Prior treatment with an anti-4-1BB antibody.
2. Women of child-bearing potential who are pregnant or breastfeeding because of the
potentially dangerous effects of the treatment on the fetus or infant.
3. Active systemic infections, coagulation disorders or other active major medical
illnesses of the cardiovascular, respiratory or immune system, as evidenced by a
positive stress thallium or comparable test, myocardial infarction, cardiac
arrhythmias, obstructive or restrictive pulmonary disease.
4. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency
Disease).
5. Concurrent 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).
6. Concurrent systemic steroid therapy.
7. History of severe immediate hypersensitivity reaction to any of the agents used in
this study.
8. History of coronary revascularization or ischemic symptoms.
9. Documented LVEF of less than or equal to 45%, testing is required 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
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
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