Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing Human Thyroglobulin to People With Thyroglobulin Expressing Thyroid Cancer
Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing Human Thyroglobulin to People With Thyroglobulin Expressing Thyroid Cancer
Background

 The NCI Surgery Branch has developed an experimental therapy for treating patient with
 metastatic thyroid cancer that involves taking white blood cells from the patient, growing
 them in the laboratory in large numbers, genetically modifying these specific cells with a
 type of virus (retrovirus) to attack only the tumor cells, and then giving the cells back to
 the patient. This type of therapy is called gene transfer. In this protocol, we are modifying
 the patient s white blood cells with a retrovirus that has the gene for anti-thyroglobulin
 incorporated in the retrovirus.

 Objectives:

 The purpose of this study is to see if these tumor fighting cells (genetically modified
 cells) that express the receptor for the thyroglobulin molecule on their surface can cause
 thyroid tumors to shrink and to see if this treatment is safe.

 Eligibility:

 <TAB>Adults 18 and older with thyroid cancer that has the thyroglobulin molecule on tumor
 surfaces

 Design:

 <TAB>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

 <TAB>Leukapheresis: If the patients meet all of the requirements for the study they will
 undergo leukapheresis to obtain white blood cells to make the anti- thyroglobulin cells.
 {Leukapheresis is a common procedure, which removes only the white blood cells from the
 patient.}

 <TAB>Treatment: Once their cells have grown, the patients will be admitted to the hospital
 for the conditioning chemotherapy, the anti-thyroglobulin 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 take up to 2 days.
Background:

 -  We generated a murine T-cell receptor (mTCR) that recognizes human thyroglobulin (hTG)
 in the context of HLA-A0201 and constructed a single retroviral vector that contains its
 alpha and beta chains and will confer hTG recognition to HLA-A0201+ PBL on transduction.

 -  In co-cultures with HLA-A0201+, hTG+ target cells, anti-TG mTCR transduced T cells
 secrete significant amounts of IFN- >= with high specificity.

 Objectives:

 Primary objectives:

 -  To determine the safety of administering PBL transduced with this anti-TG mTCR in
 concert with preparative lymphodepletion and high dose interleukin-2 (IL-2;
 aldesleukin).

 -  Determine if these mTCR-transduced PBL can mediate the regression of TG-expressing
 tumors.

 Eligibility:

 Patients who are HLA-A*0201 positive and 18 years of age or older must have

 -Advanced TG-expressing thyroid cancer (including those with bone-only disease) which has
 progressed after surgery (if indicated) and radioiodine ablation

 Patients may not have:

 -Contraindications for high dose aldesleukin administration.

 Design:

 -  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-TG mTCR.

 -  All patients will receive a non-myeloablative lymphocyte depleting preparative regimen
 of cyclophosphamide and fludarabine.

 -  On day 0 patients will receive their PBL transduced with the anti-TG mTCR and then begin
 high dose aldesleukin.

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

 -  The study will be conducted using a Phase I/II optimal design.

 -  The objective will be to determine if the combination of high dose aldesleukin,
 lymphocyte depleting chemotherapy, and anti-TG mTCR-gene engineered lymphocytes is able
 to be associated with a clinical response rate that can rule out 5% (p0=0.05) in favor
 of a modest 20% PR + CR rate (p1=0.20).

 -  A total of up to 68 patients may be required; approximately 25 patients in the phase I
 portion of the study and 43 (41, plus an allowance of up to 2 non-evaluable) patients in
 the phase II portion of the study.
-  INCLUSION CRITERIA:

 1. Unresectable thyroid cancer expressing TG as assessed by one of the following
 methods: RT-PCR on tumor tissue, or by immunohistochemistry of resected tissue.

 2. Recurrent/metastatic radioiodine refractory disease that has progressed within
 the past 6 months with at least 1 lesion increasing by 0.5cm in diameter or with
 increasing bone metastases.

 3. Confirmation of diagnosis of thyroid cancer by the Laboratory of Pathology of the
 NCI.

 4. PET avid disease with SUV >5.

 5. Patients must have previously received standard systemic therapy for advanced
 thyroid cancer (to include radioactive iodine for iodine-avid tumors and surgery
 (if indicated)) and have been either non-responders (progressive disease) or have
 recurred.

 6. 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.

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

 8. Willing to sign a durable power of attorney

 9. Able to understand and sign the Informed Consent Document

 10. Clinical performance status of ECOG 0 or 1

 11. Life expectancy of greater than three months

 12. Patients must be HLA-A*0201 positive

 13. 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 treatment.

 14. 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.

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

 p. Hematology

 -  Absolute neutrophil count greater than 1000/mm3 without the support of filgrastim

 -  WBC less than or equal to 3000/mm3

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

 -  Hemoglobin greater than 8.0 g/dl

 q. 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.

 r. 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.

 EXCLUSION CRITERIA:

 1. Women of child-bearing potential who are pregnant or breastfeeding because of the
 potentially dangerous effects of the treatment on the fetus or infant.

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

 Immunodeficiency Disease).

 3. Active systemic infections (e.g. : requiring anti-infective treatment), coagulation
 disorders or other major medical illnesses of the cardiovascular, respiratory or
 immune system, myocardial infarction, cardiac arrhythmias, obstructive or restrictive
 pulmonary 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 cyclophosphamide or
 fludarabine.

 7. History of coronary revascularization or ischemic symptoms

 8. Documented LVEF of less than or equal to 45%. Testing is required in patients with:

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

 -  Age greater than or equal to 60 years old