E7 TCR T Cells for Human Papillomavirus-Associated Cancers

Background:

- Metastatic or refractory/recurrent human papillomavirus (HPV)-16+ cancers (cervical,
vulvar, vaginal, penile, anal, and oropharyngeal cancers) are incurable and poorly
palliated by standard therapies.

- HPV-16+ cancers constitutively express the HPV-16 E7 oncoprotein, which is absent from
healthy human tissues.

- Administration of T cell receptor (TCR) gene engineered T cells can induce objective
tumor responses in certain malignancies including HPV-16+ cancers.

- T cells genetically engineered with a TCR targeting HPV-16 E7 (E7 TCR) display specific
reactivity against HLA-A2+, HPV-16+ target cells.

Objectives:

Phase I Primary Objective

- To determine a safe dose for E7 TCR cells plus aldesleukin for the treatment of metastatic
HPV-16+ cancers.

Phase II Primary Objective

-To determine safety and efficacy of E7 TCR cells plus aldesleukin for the treatment of
metastatic HPV-16+ cancers.

Eligibility:

- Patients greater than or equal to 18 years old and less than or equal to 70 years old
with metastatic or refractory/recurrent HPV-16+ cancer.

- Prior first line systemic therapy is required unless the patient declines standard
treatment.

- Patients must be HLA-A*02:01-positive.

Design:

- This is a phase I/II clinical trial that will test the safety and efficacy of E7 TCR
cells.

- All patients will receive a non-myeloablative lymphocyte-depleting preparative regimen
of cyclophosphamide and fludarabine followed by a single infusion of E7 TCR cells. Cell
infusion will be followed by high-dose aldesleukin.

- Re-enrollment will be allowed for a small number of subjects.

- INCLUSION CRITERIA:

1. Measurable metastatic or refractory/recurrent HPV-16+ cancer (determined by in
situ hybridization (ISH) or a polymerase chain reaction (PCR)-based test).

2. Patients must be HLA-A*02 by low resolution typing, and HLA-A*02:01 by one of the
high resolution type results.

3. All patients must have received prior first line standard therapy or declined
standard therapy.

4. Patients with three or fewer brain metastases that have been treated with surgery
or stereotactic radiosurgery are eligible. Lesions that have been treated with
stereotactic radiosurgery must be clinically stable for one month before protocol
treatment. Patients with surgically resected brain metastases are eligible.

5. Greater than or equal to 18 years of age and less than or equal to 70 years of
age.

Note: This age range is consistent with the age of patients with the disease
being studied.

6. Able to understand and sign the Informed Consent Document.

7. Clinical performance status of ECOG 0 or 1.

8. Patients of both genders must be willing to practice birth control from the time
of enrollment on this study up to four months after treatment. Patients must be
willing to undergo testing for HPV-16 prior to becoming pregnant after this
period.

9. Women of childbearing potential must have a negative pregnancy test because of
the potentially dangerous effects of the treatment on the fetus. Women of
childbearing potential are defined as all women except women who are
postmenopausal or who have had a hysterectomy. Postmenopausal will be defined as
women over the age of 55 who have not had a menstrual period in at least one
year. Because there is a potential risk for adverse events in nursing infants
secondary to treatment of the mother with E7 TCR transduced PBL, breastfeeding
should be discontinued if the mother is treated with E7 TCR transduced PBL. These
potential risks may also apply to other agents used in this study.

10. 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 are 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 the patient must be tested for the
presence of antigen by RT-PCR and be HCV RNA negative.

a. 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

b. Chemistry:

- Serum ALT/AST less than or equal to 2.5 times the upper limit of normal

- Calculated creatinine clearance (CCr) greater than or equal to 50 mL/min/1.73^2 using
the Cockcroft-Gault equation

- 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

c. More than four weeks must have elapsed since any prior systemic therapy at the time
the patient receives the E7 TCR cells.

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.

EXCLUSION CRITERIA:

1. Active systemic infections (for e.g.: requiring anti-infective treatment), 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, severe obstructive or restrictive
pulmonary disease. Patients with abnormal pulmonary function tests but stable
obstructive or restrictive pulmonary disease may be eligible.

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

3. 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).

4. Patients with autoimmune diseases such as Crohn s disease, ulcerative colitis,
rheumatoid arthritis, autoimmune hepatitis or pancreatitis, and systemic lupus
erythematosus. Hypothyroidism, vitiligo and other minor autoimmune disorders are not
exclusionary.

5. Concurrent systemic steroid therapy.

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

7. History of coronary revascularization or ischemic symptoms.

8. Documented LVEF of less than or equal to 45% tested. The following patients will
undergo cardiac evaluations

1. Clinically significant atrial and/or ventricular arrhythmias including but not
limited to: atrial fibrillation, ventricular tachycardia, second or third degree
heart block or

2. Age greater than or equal to 60 years old

9. Subjects with baseline screening pulse oxygen level of < 95% on room air will not be
eligible. If the underlying cause of hypoxia improves, then they may be reevaluated