Phase 1/2 Study of Metastatic Renal Cancer Using T-Cells Transduced With a T-Cell Receptor Which Recognizes TRAIL Bound to the DR4 Receptor

Background:

- The clinical administration of tumor-reactive T-cells grown in vitro is a highly active
therapy for patients with metastatic melanoma in experimental protocols when they are
combined with preparative lymphodepleting chemotherapy and systemic IL-2.

- We cloned a novel T-cell from the blood of a patient with renal cell cancer (RCC), which
recognizes nearly all human renal cancer lines irrespective of MHC haplotype.

- The alpha sign and beta sign chain of T-cell receptor from this clone, 2G-1, can be
introduced into human lymphocytes by retroviral transduction and confers this same
recognition of RCC.

- This TCR was found to recognize TNF-related apoptosis inducing ligand (TRAIL) bound to
its receptor DR4.

- Both TRAIL and agonist antibodies to DR4 have tumor specificity and are in current
clinical trials for cancer.

- Two amino acid modifications of the native TCR greatly augmented its recognition of RCCs
without altering background reactivity.

Objectives:

- Primary:

- Determine if the administration of T-cells retrovirally transduced with the 2G-1
TCR, with preparative chemotherapy and IL-2, can cause the regression of metastatic
RCC.

- To identify the maximum tolerated dose (MTD) for cells incorporating a TCR in PBL
and in TIL.

- Secondary:

- Determine the toxicities of these T-cells administered in the above fashion.

- Determine TCR and vector presence in the post treatment phase.

Eligibility:

- Patients with measurable metastatic clear cell renal cancer who have previously received
at least one systemic standard care regimen and have progressed or be found to be
intolerant of standard therapies.

- Patients must be eligible for high-dose IL-2.

- Patients must not have active or clinically symptomatic CNS metastases within the
previous 3 months.

- Patients must have acceptable hematopoietic and major organ function as determined by
laboratory and/or functional testing.

Design:

- A phase I-II dose escalating protocol with 2 arms. Patients in Arm A will receive
peripheral blood lymphocytes transduced with the 2G-1 TCR; patients in Arm B will
receive renal TIL transduced with the 2G-1 TCR. Arm B will begin after a safe dose has
been defined in Arm A.

- Once MTD has been established for each arm, up to 24 patients will be enrolled in each
arm of the phase II stage.

- Patients will receive a nonmyeloablative but lymphocyte-depleting preparative regimen
consisting of cyclophosphamide and fludarabine followed in one to four days by IV
infusion of their transduced cells and subsequent IV aldesleukin administration.

- Up to 106 patients may be enrolled over 3-4 years.

- INCLUSION CRITERIA:

1. Measurable metastatic clear cell renal cancer. Histologic diagnosis will be
confirmed by the Laboratory of Pathology at the NCI.

2. Patients must have previously received at least one systemic standard care
regimens and have progressed or be found to be intolerant of standard therapies.

3. Greater than or equal to 18 years of age.

4. Willing to sign a durable power of attorney

5. Able to understand and sign the Informed Consent Document

6. Clinical performance status of ECOG 0 or 1.

7. Life expectancy of greater than three months.

8. Patients of both genders must be willing to practice birth control during and for
four months after receiving the preparative regimen.

9. Serology:

1. 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 immunecompetence, and thus be less
responsive to the experimental treatment and more susceptible to its
toxicities.)

2. Seronegative for hepatitis B antigen and hepatitis C antibody unless antigen
negative.

3. Women of child-bearing potential must have a negative pregnancy test because
of the potentially dangerous effects of the preparative chemotherapy on the
fetus.

10. Hematology:

1. Absolute neutrophil count greater than or equal to 1000/mm3 without the
support of filgrastim.

2. WBC greater than or equal to 3000/mm3.

3. Platelet count greater than or equal to 100,000/mm3.

4. Hemoglobin greater than or equal to 8.0 g/dl.

11. Chemistry:

1. Serum ALT/AST less or equal to 2.5 times the upper limit of normal.

2. Serum creatinine less than or equal to 1.6 mg/dl.

3. Total bilirubin less than or equal to 1.5 mg/dl, except in patients with
Gilbert s Syndrome who must have a total bilirubin less than 3.0 mg/dl.

12. 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 alopecia or skin rash, which must
have recovered to a grade 2 or less).

13. Patients who have previously received anti-CTLA4 antibody 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. 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.)

5. Concurrent 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. Documented LVEF less than or equal to 45%. LVEF will be evaluated in patients with:

1. History of ischemic heart disease, chest pain, or clinically significant atrial
and/or ventricular arrhythmias including but not limited to: atrial fibrillation,
ventricular tachycardia, second or third degree heart block

2. Age greater than or equal to 60 years old

9. Documented FEV1 less than or equal to 60% predicted. Screening pulmonary function
testing will be done in patients with:

1. A prolonged history of cigarette smoking (20 pk/year of smoking, who have not
quit within the past 2 years).

2. Symptoms of respiratory dysfunction

10. Patients who have a history of more than two CNS metastases.

11. Patients who have any CNS lesion that is symptomatic, greater than 1 cm in diameter or
shows significant surrounding edema on MRI scan will not be eligible until they have
been treated and demonstrated no clinical or radiologic CNS progression for at least 2
months.