Gene Therapy Using Anti-Her-2 Cells to Treat Metastatic Cancer
Gene Therapy Using Anti-Her-2 Cells to Treat Metastatic Cancer
Background:

 -  Human epidermal growth factor receptor-2 (Her-2) is a gene found in both normal cells
 and cancer cells. Extra copies of the gene (overexpression) can cause too many Her-2
 proteins (receptors) to appear on the cell surface and cause tumors to grow.

 -  An experimental procedure developed for treating patients with cancer uses blood cells
 found in their tumors or bloodstream. The cells are genetically modified using the
 anti-Her-2 gene and a type of virus. The modified cells (anti-Her-2 cells) are grown in
 the laboratory and then given back to the patient to try to decrease the size of the
 tumors. This is called gene therapy.

 Objectives:

 -  To determine whether advanced cancers that overexpress Her-2 can be treated effectively
 with lymphocytes (white blood cells) that have been genetically engineered to contain an
 anti-Her-2 protein.

 Eligibility:

 -  Patients 18 years of age and older with metastatic cancer (cancer that has spread beyond
 the original site) and for whom standard treatments are not effective.

 -  Patient's tumor overexpresses Her-2.

 Design:

 -  Workup with scans, x-rays and other tests.

 -  Leukapheresis to obtain cells for preparing the anti-Her-2 cells for later infusion.

 -  1 week of chemotherapy to prepare the immune system for receiving the anti-Her-2 cells.

 -  Infusion of anti-Her-2 cells, followed by interleukin-2 (IL-2) treatment. The cells are
 given as an infusion through a vein. IL-2 is given as a 15-minute infusion through a
 vein every 8 hours for a maximum of 15 doses.

 -  Periodic follow-up clinic visits after hospital discharge for physical examination,
 review of treatment side effects, laboratory tests and scans every 1 to 6 months.
Background:

 -  We have constructed a single retroviral vector that contains a chimeric T cell receptor
 (CAR) that recognizes the Her-2 tumor antigen, which can be used to mediate genetic
 transfer of this CAR with high efficiency (greater than 30%) without the need to perform
 any selection.

 -  In co-cultures with Her-2 positive tumors, anti-Her-2 CAR transduced T cells secreted
 significant amount of interferon-gamma (IFN-gamma) (Her-2 high specificity).

 Objectives:

 Primary objectives:

 -  To evaluate the safety of the administration of anti-Her-2 -CAR engineered peripheral
 blood lymphocytes in patients receiving the non-myeloablative conditioning regimen and
 aldesleukin.

 -  Determine if the administration of anti-Her-2 -CAR engineered peripheral blood
 lymphocytes and aldesleukin to patients following a nonmyeloablative but lymphoid
 depleting preparative regimen will result in clinical tumor regression in patients with
 metastatic cancer that expresses the Her-2 antigen.

 Secondary objective:

 - Determine the in vivo survival of CAR gene-engineered cells.

 Eligibility:

 Patients who are 18 years of age or older must have

 -  metastatic cancer whose tumors express the Her-2 antigen;

 -  previously received and have been a non-responder to or recurred after standard care for
 metastatic disease;

 Patients may not have:

 - contraindications for high dose aldesleukin administration.

 Design:

 -  Peripheral blood mononuclear cell (PBMC) obtained by leukapheresis (approximately 5
 times 10^9 cells) 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 approximately 10^8 to 5 times 10^8 cells to
 retroviral vector supernatant containing the anti-Her-2 CAR genes .

 -  Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen
 consisting of cyclophosphamide and fludarabine followed by intravenous (IV) infusion of
 ex vivo tumor reactive, CAR genetransduced PBMC plus IV aldesleukin (720,000 IU/kg q8h
 for a maximum of 15 doses).

 -  Patients will undergo complete evaluation of tumor with physical examination, computed
 tomography (CT) of the chest, abdomen and pelvis and clinical laboratory evaluation four
 to six weeks after treatment. If the patient has stable disease (SD) or tumor shrinkage,
 repeat complete evaluations will be performed every 1-3 months. After the first year,
 patients continuing to respond will continue to be followed with this evaluation every
 3-4 months until off study criteria are met.

 -  The study will be conducted using a Phase I/II optimal design. The protocol will proceed
 in a phase 1 dose escalation design, with three cohorts. Should a single patient
 experience a dose limiting toxicity (DLT) at a particular dose level, three more
 patients would be treated at that dose to confirm that no greater than 1/6 patients have
 a DLT prior to proceeding to the next higher level. If a level with 2 or more DLTs in
 3-6 patients has been identified, three additional patients will be accrued at the
 next-lowest dose, for a total of 6, in order to further characterize the safety of the
 maximum tolerated dose prior to starting the phase II portion. If a dose limiting
 toxicity occurs in the first cohort, that cohort will be expanded to 6 patients. If 2
 DLTs are encountered in this cohort, the study will be terminated.

 -  Once the maximum tolerated dose (MTD) has been determined, the study then would proceed
 to the phase II portion. Patients will be entered into two cohorts based on histology:
 cohort 1 will include patients with metastatic breast cancer, and cohort 2 will include
 patients with other types of metastatic cancer that express Her-2.

 -  For each of the 2 strata evaluated, the study will be conducted using a phase II optimal
 design where initially 21 evaluable patients will be enrolled. For each of these two
 arms of the trial, if 0 or 1 of the 21 patients experiences a clinical response, then no
 further patients will be enrolled but if 2 or more of the first 21 evaluable patients
 enrolled have a clinical response, then accrual will continue until a total of 41
 evaluable patients have been enrolled in that stratum.

 -  The objective will be to determine if the combination of high dose aldesleukin,
 lymphocyte depleting chemotherapy, and anti-Her-2 CAR-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% partial response (PR) + complete response (CR) rate (p1=0.20).
-  INCLUSION CRITERIA:

 1. Metastatic cancer that expresses Her-2 at greater than or equal to 2+ and
 assessed by immunohistochemistry (IHC) in the clinical laboratory improvement
 amendment (CLIA) approved test in the Laboratory of Pathology, Center for Cancer
 Research (CCR), National Cancer Institute (NCI), National Institutes of Health
 (NIH).

 2. Patients must have previously received systemic standard care (or effective
 salvage chemotherapy regimens) for metastatic disease, if known to be effective
 for that disease, and have been either non-responders (progressive disease) or
 have recurred. Subjects with estrogen receptor-positive or progesterone
 receptor-positive breast cancer must have progressed on or not be a candidate for
 anti-estrogens or aromatase inhibitors and all breast cancer patients must have
 progressed on or not be a candidate for an anthracycline-containing regimen and a
 taxane-containing regimen.

 3. Patients with breast cancer must have previously received trastuzumab. Patients
 will not continue to receive trastuzumab during the trial period.

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

 5. Willing to sign a durable power of attorney

 6. Able to understand and sign the Informed Consent Document

 7. Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1.

 8. Life expectancy of greater than three months.

 9. 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 receiving the
 preparative regimen.

 10. Serology:

 1. Seronegative for human immunodeficiency virus (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.)

 2. 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 reverse transcriptase polymerase chain
 reaction (RT-PCR) and be hepatitis C virus ribonucleic acid (HCV RNA)
 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.

 11. Hematology:

 1. Absolute neutrophil count greater than 1000/mm^3 without the support of
 filgrastim.

 2. White blood cell (WBC) (> 3000/mm^3).

 3. Platelet count greater than 100,000/mm^3.

 4. Hemoglobin greater than 8.0 g/dl.

 12. Chemistry:

 1. Serum alanine aminotransferase (ALT)/aspartate aminotransferase (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.

 13. Left ventricular ejection fraction (LVEF) greater than or equal to 50%.

 14. 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).

 15. Patients who have previously received anti-cytotoxic T-lymphocyte antigen 4
 (CTLA4) antibody therapy 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 forced expiratory volume in 1 second (FEV1) less than or equal to 60%
 predicted tested in patients with:

 1. A prolonged history of cigarette smoking (20 pack/year of smoking within the past
 2 years).

 2. Symptoms of respiratory dysfunction