Study of Lymphodepletion Plus Adoptive Cell Transfer With TGF-beta Resistant (DNRII) and NGFR Transduced T-Cells Followed by High Dose Interleukin-2 in Participants With Metastatic Melanoma

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a dose
level of TGFb-DNR and NGFR T-cells based on when you join this study. Up to 5 dose levels of
T-cells may be tested. At least 2 participants will be enrolled at each dose level. The first
group of participants will receive the lowest dose level. Each new group will receive a
higher dose than the group before it, if no intolerable side effects were seen. This will
continue until the highest tolerable dose of TGFb-DNR and NGFR T-cells is found.

All participants will receive the same dose level of cyclophosphamide, fludarabine, and
aldesleukin.

Study Drug Administration:

The days leading up to Day 1 of the study are considered negative days. For example, the day
before Day 0 is Day -1. Day 0 is when you will receive the T-cells, as explained below.

On Days -7 and -6, you will receive cyclophosphamide by vein over about 2 hours. You will
also receive furosemide by vein over about 60 minutes to try to increase the amount of urine
your body makes.

On Day -7, you will receive mesna by vein non-stop over about 24 hours. Mesna is given to
help protect the bladder from side effects of cyclophosphamide.

You will take trimethoprim and sulfamethoxazole (SMX) by mouth 2 times a day, starting on Day
-7 and continuing for at least 6 months after chemotherapy. SMX is given to lower your risk
of side effects.

On Days -5 to -1, you will receive fludarabine by vein over about 15-30 minutes.

On Day 0, you will receive TGFb-DNR and NGFR T-cells through a central venous catheter (CVC)
for up to 4 hours, or possibly more if your doctor thinks it is needed. A CVC is a thin
flexible tube that is inserted into the body. The catheter may be placed into a vein in your
arm or in a large vein in your neck. If the cells need to be given through a large vein in
your upper chest or in your neck, the area will be numbed with anesthetic before the catheter
is put in. Other catheters may be needed in one or both of your arms to give you fluids,
drugs, or extra nutrition. You will sign a separate consent form for the catheter, which will
describe the procedure and the risks in more detail.

Starting on Day 0:

- You will receive levofloxacin with or without food by mouth or by vein over about 60
minutes 1 time a day until your white blood cell count rises. Levofloxacin is designed
to prevent infection caused by bacteria.

- You will take fluconazole by mouth 1 time a day for 6 months after chemotherapy.
Fluconazole is designed to treat fungal infections.

- You will take Valtrex by mouth (or acyclovir by vein over about 60 minutes if you are
unable to take Valtrex by mouth) 1 time a day for 6 months after chemotherapy. These
drugs treat infections caused by the herpes viruses.

On Days 1-5, you will receive aldesleukin by catheter over about 15 minutes every 8-16 hours
for up to 15 doses. On Days 22-26, you will receive aldesleukin by catheter over about 15
minutes every 8-16 hours for up to 15 doses. You will only receive aldesleukin if your
platelet counts are high enough.

You will be in the hospital over the course of about 7 days each time you receive
aldesleukin. You will be expected to stay in the Houston area for at least 14 days in order
to take part in the chemotherapy and cell infusion parts of the study.

You will be given standard drugs to help decrease the risk of side effects and/or to treat
side effects (such as allergic reactions, nausea/vomiting, or low blood cell counts). These
drugs may include Tylenol (acetaminophen), ondansetron, and filgrastim). You may ask the
study staff for information about their risks.

Study Visits:

Every 1-2 days during Days -7 to 26, blood (about 3 teaspoons) will be drawn for routine
tests. Every day during this time, you will have a physical exam.

On Day 0:

Your vital signs will be measured before the TGFb-DNR and NGFR T-cell infusion, every 15
minutes (+/- 10 minutes) during the infusion, and then 1 time an hour (+/- 30 minutes) for 4
hours after the infusion.

On Days 3 and 21 (+/- 7 days) after the T-cell infusion, blood (about 2 teaspoons) sample
will be drawn check for the presence of CMV. The study staff will check your CMV levels at
Day 3 (+/- 24 hours) and Day 21 (+/- 7days) after TIL infusion as an added precaution.

On Day 6 (+/- 3 days) and Day 21 (+/- 7 days) if possible, blood (about 4½ tablespoons) will
be drawn to test the level and activity of the cells.

At about 6 and 12 weeks, the following tests and procedures will be performed:

°You will have a physical exam, including measurement of your vital signs and weight.

Blood (about 4½ tablespoons) will be drawn to test the frequency and activity of the T-cells.

- You will have a CT or PET/CT scan of the chest, abdomen, and pelvis to check the status
of the disease.

- You will have an MRI or CT scan of the brain to check the status of the disease.

- You will have any other tests that the study doctor thinks are needed.

Length of Study Drug Dosing:

You may receive up to 2 rounds of the study drugs (up to 24 weeks total). You will no longer
be able to take the study drugs if the disease gets worse, if intolerable side effects occur,
or if you are unable to follow study directions.

Your participation on the study will be over once you have completed the follow-up visits.

Long-Term Follow-Up:

At about 6 and 12 months after you stop receiving the study drugs and T-cells, blood (about 1
tablespoon) will be drawn to check the activity of the T-cells.

After the first 12 months, you will return to MD Anderson once a year for at least 5 years.
The following tests and procedures will be performed:

- You will have a physical exam.

- Blood (about 4 tablespoons) will be drawn for routine tests.

- You will have a CT or PET/CT scan of the chest, abdomen, and pelvis.

- You will have an MRI or CT scan of the brain.

Inclusion Criteria:

1. Patients must have metastatic melanoma or stage III in-transit, subcutaneous, or
regional nodal disease (turnstile I).

2. Patients must have a lesion amenable to resection for the generation of TIL (Turnstile
I).

3. Patients must receive an MRI/CT/PET of the brain within 6 months of signing informed
consent. If new lesions are present, patient must have definitive treatment. PI or his
designee should make final determination regarding enrollment (Turnstile I).

4. Age greater than or equal to 12 years (Turnstile I).

5. Clinical performance status of ECOG 0-2 within 30 days of signing informed consent
(Turnstile I).

6. Patients previously treated with immunotherapy, targeted therapy, or no therapy
(treatment naive) will be eligible (Turnstile I).

7. Patients receiving cytotoxic agents will be evaluated by the PI or his designee for
eligibility suitability (Turnstile I).

8. Patients with a negative pregnancy test (urine or serum) must be documented within 14
days of screening for women of childbearing potential (WOCBP). A WOCBP has not
undergone a hysterectomy or who has not been naturally postmenopausal for at least 12
consecutive months (i.e. who has not had menses at any time in the preceding 12
consecutive months) (Turnstile I).

9. Patients must have adequate TIL available (Turnstile II). Pre-REP TIL generated in the
similar clinical trial 2004-0069 may also be utilized for Turnstile II.

10. Patients must have at least one biopsiable measurable metastatic melanoma, lesion > or
= to1cm (Turnstile II).

11. Patients may have brain lesions treatment. (Turnstile II)

12. Patients of both genders must practice birth control for four months after receiving
the preparative regimen (lymphodepletion) and continue to practice birth control
throughout the study. Patients must have a documented negative pregnancy test (urine
or serum) for women who have menstruation in the past 12 months and without
sterilization surgery (Turnstile II).

13. Unless surgically sterile by bilateral tubal ligation or vasectomy of partner(s), the
patient agrees to continue to use a barrier method of contraception throughout the
study such as: condom, diaphragm, hormonal, IUD, or sponge plus spermicide. Abstinence
is an acceptable form of birth control (Turnstile II).

14. Patients with negative pregnancy test (urine or serum) must be documented within 14
days of screening for women of childbearing potential (WOCBP). A WOCBP has not
undergone a hysterectomy or who has not been naturally postmenopausal for at least 12
consecutive months (i.e. who has not menses at any time in the preceding 12
consecutive months (Turnstile II).

15. Clinical performance status of ECOG 0-2 within 30 days of signing Informed Consent
(Turnstile II).

16. Absolute neutrophil count greater than or equal to 1000/mm3 (Turnstile II).

17. Platelet count greater than or equal to 100,000/mm3 (Turnstile II).

18. Hemoglobin greater than or equal to 8.0 g/dl (Turnstile II).

19. Serum ALT less than three times the upper limit of normal (Turnstile II).

20. Serum creatinine less than or equal to 1.6 mg/dl (Turnstile II).

21. 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 (Turnstile II).

22. A stress cardiac test (stress thallium, stress MUGA, dobutamine echocardiogram or
other stress test that will rule out cardiac ischemia) within 6 months of
lymphodepletion (Turnstile II).

23. Pulmonary function tests (FEV1>65% or FVC>65%of predicted) within 6 months of
lymphodepletion (Turnstile II).

24. MRI/CT/PET of the brain within 30 days of lymphodepletion (Turnstile II).

Exclusion Criteria:

1. Active systemic infections requiring intravenous antibiotics, coagulation disorders or
other major medical illnesses of the cardiovascular, respiratory or immune system. PI
or his designee shall make the final determination regarding appropriateness of
enrollment (Turnstile I).

2. Primary immunodeficiency and need for chronic steroid therapy, however prednisone is
allowed at < 10 mg/day. (Turnstile I)

3. Patients who are pregnant or nursing (Turnstile I).

4. Presence of a significant psychiatric disease, which in the opinion of the principal
investigator or his designee, would prevent adequate informed consent (Turnstile I).

5. Has had prior systemic cancer therapy within the past four weeks or B-RAF or MEK
inhibitors within 7 days at the time of the start of the lymphodepletion regimen
(Turnstile II).

6. Women who are pregnant will be excluded because of the potentially dangerous effects
of the preparative chemotherapy on the fetus (Turnstile II).

7. Any active systemic infections requiring intravenous antibiotics, coagulation
disorders or other major medical illnesses of the cardiovascular, respiratory or
immune system, such as abnormal stress thallium or comparable test, myocardial
infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease. PI or
his designee shall make the final determination regarding appropriateness of
enrollment (Turnstile II).

8. Any form of primary or secondary immunodeficiency. Must have recovered immune
competence after chemotherapy or radiation therapy as evidenced by lymphocyte counts
(> 500/mm3), WBC (> 3,000/mm3) or absence of opportunistic infections (Turnstile II).

9. Require steroid therapy or steroid-containing compounds, or have used systemic
steroids in the past 4 weeks, or have used topical or inhalational steroids in the
past 2 weeks prior to lymphodepletion; the exception being patients on chronic
physiologic dose of steroid (Turnstile II).

10. Presence of a significant psychiatric disease, which in the opinion of the principal
investigator or his designee, would prevent adequate informed consent or render
immunotherapy unsafe or contraindicated (Turnstile II).