Treating Cancer With Anti-mesothelin Modified Lymphocytes

Detailed Description

Background:

• We have constructed a single retroviral vector that contains a chimeric T cell receptor (CAR) that recognizes mesothelin, which can be used to mediate genetic transfer of this CAR with high efficiency (> 50%) without the need to perform any selection.
• In co-cultures with mesothelin expressing cells, anti-mesothelin transduced T cells secreted significant amounts of IFN-gamma with high specificity.

Objectives:

Primary Objectives:

• To evaluate the safety of the administration of anti-mesothelin CAR engineered peripheral blood lymphocytes in patients receiving a non- myeloablative conditioning regimen, and aldesleukin.
• Determine if the administration anti-mesothelin 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.

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 or unresectable cancer that expresses mesothelin;
• Previously received and have been a non-responder to or recurred after standard care;

Patients may not have:

• -Contraindications for low dose aldesleukin administration.

Design:

• 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 108 to 5 times 108 cells to retroviral vector supernatant containing the anti-mesothelin CAR.
• Patients will receive a nonmyeloablative but lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of ex vivo CAR gene-transduced PBMC plus IV aldesleukin (72,000 IU/kg q8h for a maximum of 15 doses).
• Patients will undergo complete evaluation of tumor with physical examination, CT of the chest, abdomen and pelvis and clinical laboratory evaluation four to six weeks after treatment. If the patient has 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. Initially, the protocol will enroll 3 patients in each dose cohort unless one patient experiences a dose limiting toxicity (DLT). Should a single patient experience a dose limiting toxicity at a particular dose level, additional 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 dosing is escalated to cohort 10, 6 patients will be accrued to this cohort in order to further characterize the safety of the maximum tolerated dose prior to starting the phase II portion. 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 cell dose will be reduced for two de-escalation cohorts. Once the 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 mesothelioma, and cohort 2 will include patients with other types of cancer that express mesothelin.
• 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 low dose aldesleukin, lymphocyte depleting chemotherapy, and anti-mesothelin 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% PR + CR rate (p1=0.20).

Primary Outcome Measures:

• Evaluate safety of anti-mesothelin CAR engineered PBL in patients receiving the protocol regimen.
• Determine if anti-mesothelin CAR engineered PBL and aldesleukin to patients following the protocol regimen will result in clinical tumor regression.

Secondary Outcome Measures:

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

Eligibility Criteria

Inclusion Criteria:

1. Metastatic or unresectable measurable cancers that express mesothelin. Epithelial mesotheliomas and pancreatic cancers do not need to be assessed for mesothelin expression since all of these tumors have been shown to express mesothelin.
2. Patients must have previously received at least one systemic standard care (or effective salvage chemotherapy regimens) for metastatic or unresectable disease, if known to be effective for that disease, and have been either non-responders (progressive disease) or have recurred.
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 from the time of enrollment on this study and for up to four months after receiving the preparative regimen.
9. 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 immunecompetence 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.
   • 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:
    • Absolute neutrophil count greater than 1000/mm(3) without the support of filgrastim.
    • WBC (> 3000/mm(3)).
    • Platelet count greater than 100,000/mm(3).
    • Hemoglobin greater than 8.0 g/dl.
11. Chemistry:
    • Serum ALT/AST less or equal to 2.5 times the upper limit of normal.
    • 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 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 toxicities such as alopecia or vitiligo).

Exclusion Criteria:

1. Patients with sarcomatoid mesothelioma as mesothelin is not expressed in this type of mesothelioma.
2. 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.
3. Patients with known brain metastases.
4. Patients receiving full dose anticoagulative therapy.
5. 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.
6. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
7. 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).
8. Patients with diabetic retinopathy.
9. Concurrent Systemic steroid therapy.
10. History of severe immediate hypersensitivity reaction to any of the agents used in this study.
11. History of coronary revascularization or ischemic symptoms.
12. Documented FEV1 less than or equal to 60% predicted tested in all patients.
13. In patients over 60 years of age, LVEF of less than 45%