Administering Peripheral Blood Lymphocytes Transduced With a CD70-Binding Chimeric Antigen Receptor to People With CD70 Expressing Cancers

Background:

- We generated a chimeric antigen receptor (CAR) that engages CD70 using its natural
ligand CD27, as the binding moiety. Transducing peripheral blood lymphocytes (PBL) with
this CAR conveys major histocompatibility complex (MHC)-independent recognition of
CD70-expressing target cells, which include renal cell carcinoma and other cancers.

- In co-cultures with CD70+ target cells, anti-hCD70 CAR transduced T cells secrete
significant amounts of IFN-gamma with high specificity.

Objectives:

Primary objectives:

- Phase I: Determine the safety of administering PBL transduced with anti-hCD70 CAR in
concert with preparative lymphodepletion and high dose interleukin-2 (IL-2;
aldesleukin).

- Phase II: Determine if anti-hCD70 CAR-transduced PBL can mediate the regression of CD70
expressing tumors.

Eligibility:

- Patients must be/have:

- Age greater than or equal to 18 years and less than or equal to 70 years

- CD70-expressing tumors

- Measurable metastatic disease that has progressed after standard therapy

- Patients may not have:

- Allergies or hypersensitivities to high-dose aldesleukin, cyclophosphamide, or
fludarabine.

Design:

- This is a phase I/II, single center study of PBL transduced with anti-hCD70 CAR in
patients with measurable, unresectable cancer expressing CD70.

- PBMC obtained by leukapheresis 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 these cells to retroviral vector supernatant
containing replication-incompetent virus encoding the anti-hCD70 CAR.

- All patients will receive a non-myeloablative, lymphodepleting preparative regimen of
cyclophosphamide and fludarabine.

- On day 0, patients will receive PBL transduced with the anti-hCD70 CAR and will then
begin high-dose aldesleukin.

- A complete evaluation of lesions will be conducted approximately 4-6 weeks after
treatment.

- The study will be conducted using a Phase I/II optimal design, with two separate cohorts
for the Phase II component: Cohort 1 - clear cell renal cell carcinoma (RCC): Cohort 2 -
non-RCC malignancies (solid tumors only).

- A total of up to 113 patients may be required; approximately 27 patients in the Phase I
portion of the study and 43 (41, plus an allowance of up to 2 non-evaluable) patients in
each cohort of the Phase II portion of the study.

- INCLUSION CRITERIA:

- Measurable, unresectable cancer expressing CD70 as assessed by immunohistochemistry of
resected tissue (> 2+ CD70 positive on > 50% of cancer cells, or >1+ CD70 positive on
>75% of cancer cells).

- Confirmation of the diagnosis of cancer by the NCI Laboratory of Pathology.

- Patients must have previously received at least one standard therapy for their cancer
(if available) and have been either non-responders (progressive disease) or have
recurred.

- Patients with 3 or fewer brain metastases that are less than or equal to 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.

- Age greater than or equal to 18 years and less than or equal to 70 years.

- Clinical performance status of ECOG 0 or 1

- Patients of both genders must be willing to practice birth control from the time of
enrollment on this study and for four months after 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 may 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.

-Hematology

- ANC 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. Subjects may be transfused to reach this cut-off.

-Chemistry

- Serum ALT/AST less than or equal to 2.5 times ULN

- Serum creatinine less than or equal to 1.6 mg/dL

- 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 or equal to 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.

Note: Patients may have undergone minor surgical procedures within the past three weeks, as
long as all toxicities have recovered to grade 1 or less.

- Ability of subject to understand and the willingness to sign a written informed
consent document.

- Willing to sign a durable power of attorney.

- Subjects must be co-enrolled on the NCI-SB cell harvest protocol 03-C-0277 (Cell
Harvest and Preparation for Surgery Branch Adoptive Cell Therapy Protocols).

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.

- Concurrent systemic steroid therapy.

- Active systemic infections requiring anti-infective treatment, coagulation disorders,
or any other active or uncompensated major medical illnesses.

- Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency
Disease).

- History of major organ autoimmune 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).

- History of severe immediate hypersensitivity reaction to cyclophosphamide,
fludarabine, or aldesleukin.

- History of coronary revascularization or ischemic symptoms.

- Documented LVEF less than or equal to 45% tested in patients:

- Age greater than or equal to 65 years

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

- Who have had prior treatment with significant exposure to anthracyclines or
cyclophosphamide.

- Documented FEV1 less than or equal to 60% predicted tested in patients with:

- A prolonged history of cigarette smoking (greater than or equal to 20 pack-year
smoking history, with cessation within the past 2 years).

- Symptoms of respiratory dysfunction

- Patients who are receiving any other investigational agents.