Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic Melanoma
| Status: | Terminated |
|---|---|
| Conditions: | Skin Cancer, Cancer |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - 70 |
| Updated: | 4/21/2016 |
| Start Date: | September 2011 |
| End Date: | June 2018 |
A Pilot Study of the Administration of Young Tumor Infiltrating Lymphocytes Following a Non-Myeloablative Lymphocyte Depleting Chemotherapy Regimen in Metastatic Melanoma
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 with aldesleukin (IL-2) a drug that keeps the
white blood cells active. These cells are called Tumor Infiltrating Lymphocytes, or TIL
and we have given this type of treatment to over 200 patients with melanoma.
- This study will use chemotherapy to prepare the immune system before this white blood
cell treatment. Our prior studies indicate that aldesleukin may not be required for
cell transfer.
Objectives:
- To see if chemotherapy and white blood cell therapy without aldesleukin is a safe and
effective treatment for metastatic melanoma.
Eligibility:
- Individuals at least 18 years of age and less than or equal to 70 years of age with
metastatic melanoma.
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 will 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 with aldesleukin (IL-2) a drug that keeps the
white blood cells active. These cells are called Tumor Infiltrating Lymphocytes, or TIL
and we have given this type of treatment to over 200 patients with melanoma.
- This study will use chemotherapy to prepare the immune system before this white blood
cell treatment. Our prior studies indicate that aldesleukin may not be required for
cell transfer.
Objectives:
- To see if chemotherapy and white blood cell therapy without aldesleukin is a safe and
effective treatment for metastatic melanoma.
Eligibility:
- Individuals at least 18 years of age and less than or equal to 70 years of age with
metastatic melanoma.
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 will take up
to 2 days.
BACKGROUND:
- Tumor Infiltrating Lymphocytes (TIL) can mediate the regression of bulky metastatic
melanoma when administered to the autologous patient along with high-dose aldesleukin
(IL-2) following a non-myeloablative lymphodepleting chemotherapy preparative regimen.
- IL-2 administration has been shown to increase the number of T regulatory cells and in
our trials we have found a direct relationship between the number of IL-2 doses and the
reconstitution of patients at one week with CD4+ Foxp3+ T regulatory cells.
- In our analysis of factors that relate to the ability of this treatment to mediate
objective responses, we have found a highly significant inverse correlation between
reconstitution of CD4+ Foxp3+ T regulatory cells and the likelihood of achieving an
objective response.
- In our prior clinical trials of cell transfer using TIL after lymphodepletion with or
without
2Gy total body irradiation, patients who experienced an objective response received
fewer doses of IL-2 compared to non-responders (p=0.007 and 0.03 respectively).
- High levels of the homeostatic T cell growth factor, IL-15, are present in patient
serum after the lymphodepleting regimen at the time of cell transfer.
- These factors raise the possibility that IL-2 administration is not required after cell
transfer.
OBJECTIVES:
- The primary objective of this trial is to determine whether objective responses can be
mediated in patients with metastatic melanoma who have received a lymphodepleting
chemotherapy regimen and adoptive transfer of young tumor infiltrating lymphocytes and
no IL-2 administration.
- The secondary objective involves the determination of the level of transferred cells in
the blood that persist at about 1 week and 1 month after transfer.
ELIGIBILITY:
- Patients greater than or equal to 18 years old with pathologically confirmed diagnosis
of metastatic melanoma.
- Patients with measurable disease, absolute neutrophil count greater than 1000/mm(3) and
platelet count greater than 100,000/mm(3).
- Patients not eligible to receive IL-2.
DESIGN:
- Patients with metastatic melanoma will undergo resection to obtain tumor for generation
of autologous TIL cultures.
- Patients will receive a non-myeloablative lymphodepleting preparative regimen
consisting of cyclophosphamide and fludarabine followed by the administration of young
autologous TIL.
- Patients will be evaluated for objective clinical response and for persistence of the
transferred cells.
- Tumor Infiltrating Lymphocytes (TIL) can mediate the regression of bulky metastatic
melanoma when administered to the autologous patient along with high-dose aldesleukin
(IL-2) following a non-myeloablative lymphodepleting chemotherapy preparative regimen.
- IL-2 administration has been shown to increase the number of T regulatory cells and in
our trials we have found a direct relationship between the number of IL-2 doses and the
reconstitution of patients at one week with CD4+ Foxp3+ T regulatory cells.
- In our analysis of factors that relate to the ability of this treatment to mediate
objective responses, we have found a highly significant inverse correlation between
reconstitution of CD4+ Foxp3+ T regulatory cells and the likelihood of achieving an
objective response.
- In our prior clinical trials of cell transfer using TIL after lymphodepletion with or
without
2Gy total body irradiation, patients who experienced an objective response received
fewer doses of IL-2 compared to non-responders (p=0.007 and 0.03 respectively).
- High levels of the homeostatic T cell growth factor, IL-15, are present in patient
serum after the lymphodepleting regimen at the time of cell transfer.
- These factors raise the possibility that IL-2 administration is not required after cell
transfer.
OBJECTIVES:
- The primary objective of this trial is to determine whether objective responses can be
mediated in patients with metastatic melanoma who have received a lymphodepleting
chemotherapy regimen and adoptive transfer of young tumor infiltrating lymphocytes and
no IL-2 administration.
- The secondary objective involves the determination of the level of transferred cells in
the blood that persist at about 1 week and 1 month after transfer.
ELIGIBILITY:
- Patients greater than or equal to 18 years old with pathologically confirmed diagnosis
of metastatic melanoma.
- Patients with measurable disease, absolute neutrophil count greater than 1000/mm(3) and
platelet count greater than 100,000/mm(3).
- Patients not eligible to receive IL-2.
DESIGN:
- Patients with metastatic melanoma will undergo resection to obtain tumor for generation
of autologous TIL cultures.
- Patients will receive a non-myeloablative lymphodepleting preparative regimen
consisting of cyclophosphamide and fludarabine followed by the administration of young
autologous TIL.
- Patients will be evaluated for objective clinical response and for persistence of the
transferred cells.
- INCLUSION CRITERIA:
- Measurable metastatic melanoma with available autologous TIL.
- 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. Patients with surgically resected brain metastases are eligible.
- Greater than or equal to 18 years of age and less than or equal to 70 years of age.
- Able to understand and sign the Informed Consent Document
- Clinical performance status of ECOG 0 or 1.
- Life expectancy of greater than three months
- 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 receiving the treatment.
- 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.
- Women of child-bearing potential must have a negative pregnancy test because of the
potentially dangerous effects of the treatment on the fetus.
- Hematology
- Absolute neutrophil count greater than 1000/mm(3) 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
- Chemistry:
- Serum ALT/AST less than or equal to to 2.5 times the upper limit of normal
- Serum Creatinine less than or equal to to 1.6 mg/dl
- Total bilirubin less than or equal to to 1.5 mg/dl, except in patients with Gilbert s
Syndrome who must have a total bilirubin less than 3.0 mg/dl.
- 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).
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.
- Six weeks must have elapsed since any prior antibody therapy including anti-CTLA4
antibody therapy that could affect any anti-cancer immune response, at the time the
patient receives the preparative regimen to allow antibody levels to decline. NOTE:
patients who have previously received ipililumab and have documented GI toxicity must
have a colonoscopy with normal colonic biopsies.)
- Patients must be ineligible to receive IL-2 based on evidence that may include
ischemic heart disease, or arrhythmias, or poor ventricular ejection fraction (<
50%), or respiratory compromise (FEV1 < 60%), or clinically significant patient
history which in the judgment of the investigator would compromise the patient s
ability to tolerate aldesleukin.
EXCLUSION CRITERIA:
- Women of child-bearing potential who are pregnant or breastfeeding because of the
potentially dangerous effects of the treatment on the fetus or infant.
- Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency
Disease).
- 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).
- Concurrent systemic steroid therapy.
- History of severe immediate hypersensitivity reaction to any of the agents used in
this study.
- Patients with a ventricular ejection fraction (less than or equal to 30%), or
respiratory compromise (FEV1 less than or equal to 40%).
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
Phone: 866-820-4505
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