Genetically Modified T Cells in Treating Patients With Stage III-IV Non-small Cell Lung Cancer or Mesothelioma

Study Overview
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Brief Summary
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This phase I/II trial studies the side effects and best dose of genetically modified T cells in treating patients with stage III-IV non-small cell lung cancer (NSCLC) or mesothelioma. Many types of cancer cells, including NSCLC and mesothelioma, but not most normal cells, have a protein called Wilms tumor (WT)1 on their surfaces. This study takes a type of immune cell from patients, called T cells, and modifies their genes in the laboratory so that they are programmed to find cells with WT1 and kill them. The T cells are then given back to the patient. Cyclophosphamide and aldesleukin may also stimulate the immune system to attack cancer cells. Giving cyclophosphamide and aldesleukin with laboratory-treated T cells may help the body build an immune response to kill tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the safety, and potential toxicities associated with treating patients with metastatic NSCLC and mesothelioma with polyclonal autologous central memory and naive cluster of differentiation (CD)8+ T cells that have been transduced to express a WT1-specific T-cell receptor (TCR) (Arm 1 and Arm 2). II. Determine the feasibility of treating patients with metastatic NSCLC and mesothelioma with polyclonal autologous central memory and naive CD8+ T cells that have been transduced to express a WT1-specific TCR (Arm 1 and Arm 2). III. Determine and compare the in vivo persistence in blood and tumor of transferred polyclonal autologous central memory and naive CD8+ T cells that have been transduced to express a WT1-specific TCR (Arm 1 and Arm 2). EXPLORATORY OBJECTIVES: I. Determine the antitumor efficacy for patients with metastatic NSCLC and mesothelioma (Arm 1), as measured by time to progression (TTP) based on the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. II. Determine the in vivo functional capacity of adoptively transferred polyclonal autologous CD8+ T cells that have been transduced to express a WT1-specific TCR, and assess the acquisition of phenotypic characteristics associated with T cell exhaustion (Arm 1 and Arm 2). III. Determine the migration to tumor sites of adoptively transferred polyclonal autologous CD8+ T cells that have been transduced to express a WT1-specific TCR (Arm 2). IV. Evaluate the tumor response and T cell infiltration in tumors of patients with stage IIIA NSCLC treated in the neo-adjuvant setting. OUTLINE: This is a phase I, dose-escalation study of autologous WT1-TCRc4 gene-transduced CD8-positive Tcm/Tn lymphocytes followed by a phase II study. Patients are assigned to 1 of 3 treatment arms. ARM I, STAGE I: Patients receive autologous WT1-TCRc4 gene-transduced CD8-positive Tcm/Tn lymphocytes intravenously (IV) on days 0 and 14, cyclophosphamide IV on days 11 and 12, and aldesleukin (IL-2) subcutaneously (SC) twice daily (BID) for 14 days. Patients who have received radiation to the chest/lung tissue may receive T lymphocytes 90 days after completion of radiation. ARM I, STAGE II: Patients receive cyclophosphamide IV on days -3 and -2, autologous WT1-TCRc4 gene-transduced CD8-positive Tcm/Tn lymphocytes IV on day 0, and aldesleukin SC BID for 14 days. ARM II: Patients receive autologous WT1-TCRc4 gene-transduced CD8-positive Tcm/Tn lymphocytes IV between 24-96 hours after the last dose of chemotherapy and receive aldesleukin SC BID for 14 days. Patients then undergo surgery within 3-4 weeks after the T-cell infusion. After completion of study treatment, patients are followed up at 3, 6, and 12 months and then annually for 14 years.

Official Title
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Phase I/II Study in WT1-Expressing Non-small Cell Lung Cancer and Mesothelioma, Comparing Cellular Adoptive Immunotherapy With Polyclonal Autologous Central Memory to Naïve CD8+ T Cells That Have Been Transduced to Express a WT1-Specific T-Cell Receptor

Conditions
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Advanced Pleural Malignant Mesothelioma, HLA-A*0201 Positive Cells Present, Recurrent Non-Small Cell Lung Carcinoma, Recurrent Pleural Malignant Mesothelioma, Stage III Non-Small Cell Lung Cancer AJCC v7, Stage III Pleural Malignant Mesothelioma AJCC v7, Stage IIIA Non-Small Cell Lung Cancer AJCC v7, Stage IIIB Non-Small Cell Lung Cancer AJCC v7, Stage IV Non-Small Cell Lung Cancer AJCC v7, Stage IV Pleural Malignant Mesothelioma AJCC v7, WT1 Positive

Intervention / Treatment
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* Biological: Aldesleukin
* Biological: Autologous WT1-TCRc4 Gene-transduced CD8-positive Tcm/Tn Lymphocytes
* Drug: Cyclophosphamide
* Other: Laboratory Biomarker Analysis
* Procedure: Therapeutic Conventional Surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ELIGIBILITY FOR ENROLLMENT/SCREENING (ARMS 1 AND 2): Histopathological documentation of NSCLC or mesothelioma ELIGIBILITY FOR ENROLLMENT/SCREENING (ARMS 1 AND 2): Patients must be able to give informed consent ELIGIBILITY FOR ENROLLMENT/SCREENING (ARMS 1 AND 2): Patients must be able to provide blood and tumor samples and undergo the procedures required for this protocol Arm 2 ONLY: Surgically operable NSCLC or mesothelioma ELIGIBILITY FOR TREATMENT ON ARM 1: Patients must express human leukocyte antigen (HLA)-A*0201 ELIGIBILITY FOR TREATMENT ON ARM 1: Evidence of WT1 tumor expression ELIGIBILITY FOR TREATMENT ON ARM 1: Patients must have received at least one line of therapy for NSCLC or mesothelioma or previously documented to have declined therapy ELIGIBILITY FOR TREATMENT ON ARM 1: NSCLC patients with a mutation in epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) must have demonstrated progression or intolerance to at least one of the corresponding targeted therapies (for example erlotinib or crizotinib) ELIGIBILITY FOR TREATMENT ON ARM 1: Bi-dimensionally measurable disease by palpation, clinical exam, or radiographic imaging (X-ray, computed tomography [CT] scan, positron emission tomography [PET] scan, magnetic resonance imaging [MRI], or ultrasound) ELIGIBILITY FOR TREATMENT ON ARM 1: Ninety days must have passed since the last doses of radiation or chemoradiation treatment involving lung tissue or thorax prior to T cell infusion (to avoid confounding pneumonitis) ELIGIBILITY FOR TREATMENT ON ARM 1: Patients treated with prior immunotherapy including and not limited to vaccines, cytokines, T cell stimulating agents, cytotoxic T lymphocyte antigen 4 (CTLA4) inhibitors and programmed death (PD)-1 check point inhibitors are allowed on therapy provided they did not have any severe grade 4 toxicities due to prior therapy and any toxicities due to prior therapy should have resolved, if resolvable to less than or equal to grade 1 ELIGIBILITY FOR TREATMENT ON ARM 2: Patients must express HLA-A*0201 ELIGIBILITY FOR TREATMENT ON ARM 2: Evidence of WT1 tumor expression ELIGIBILITY FOR TREATMENT ON ARM 2: Ninety days must have passed since the last definitive doses of radiation or chemoradiation treatment prior to T cell infusion (to avoid confounding pneumonitis) Exclusion Criteria: EXCLUSION FOR ENROLLMENT/SCREENING (ARMS 1 AND 2) Eastern Cooperative Oncology Group (ECOG) performance status >= 2 Active autoimmune disease (e.g., systemic lupus erythematosus, vasculitis, infiltrating lung disease, inflammatory bowel disease) in which possible progression during treatment would be considered unacceptable by the investigators Any condition or organ toxicity deemed by the principal investigator (PI) or the attending physician to place the patient at unacceptable risk for treatment on the protocol Men or women of reproductive ability who are unwilling to use effective contraception or abstinence; women of childbearing potential must have a negative urine pregnancy test within 2 weeks prior to first infusion Pregnant women and nursing mothers will be eligible for screening only to test HLA type by saliva or buccal swab and WT1 expression from previously collected tissue sample Clinically significant and ongoing immune suppression including, but not limited to, systemic immunosuppressive agents such as cyclosporine or corticosteroids, chronic lymphocytic leukemia (CLL), uncontrolled human immunodeficiency virus (HIV) infection, or solid organ transplantation EXCLUSION FOR TREATMENT (ARMS 1 AND 2) Exclusions for the leukapheresis procedure (this can be performed at a later time of symptoms resolve): Infection, with or without antibiotic treatment Recent hepatitis exposure (hepatitis B or C antigenemia) Pregnancy or nursing HIV or human T-lymphotropic virus (HTLV) infection Positive result on standard test for syphilis (STS) Unable to generate antigen-specific WT1-specific CD8+ T cells for infusions; however, the patient will have the option to receive WT1-specific T-cells if a lower than planned number of cells is available Documented infections or known oral temperature > 38.2 degrees Celsius (C) fewer than 72 hours prior to receiving study treatment or systemic infection requiring chronic maintenance; the start of treatment may be delayed Systemic steroids should be stopped 2 weeks before the start of treatment; topical and inhaled steroids are allowed Untreated central nervous system (CNS) metastasis that are > 1 cm or symptomatic are not allowed; (patients with CNS metastases > 1 cm or symptomatic that have been treated and demonstrated to be radiologically and clinically stable for at least 4 weeks are allowed) White blood cells (WBC) < 2,000/ul Hemoglobin (Hb) < 8 g/dL Absolute neutrophil count (ANC) < 1,000/ul Platelets < 50,000/ul New York Heart Association functional class III-IV heart failure, symptomatic pericardial effusion, stable or unstable angina, symptoms of coronary artery disease (CAD), congestive heart failure, clinically significant hypotension or history of an ejection fraction of =< 30% (echocardiogram or multi-gated acquisition scan [MUGA]) Clinically significant pulmonary dysfunction, as determined by medical history and physical exam; patients so identified will undergo pulmonary functions testing and those with forced expiratory volume in 1 second (FEV1) < 2.0 L or diffusion capacity of the lungs for carbon monoxide (DLCO) (corrected for Hb) < 50% will be excluded Creatinine > 1.5 x the upper limit of normal Aspartate aminotransferase/alanine aminotransferase (AST/ALT) > 5 x upper limits of normal (ULN) Bilirubin > 3 x ULN that cannot be attributed to NSCLC metastasis HIV or HTLV infection

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I, Stage I (T lymphocytes, cyclophosphamide, IL-2)<br>Patients receive autologous WT1-TCRc4 gene-transduced CD8-positive Tcm/Tn lymphocytes IV on days 0 and 14, cyclophosphamide IV on days 11 and 12, and aldesleukin SC BID for 14 days. Patients who have received radiation to the chest/lung tissue may receive gene-transduced T lymphocytes 90 days after completion of radiation. | Biological: Aldesleukin<br>* Given SC<br>* Other names: Recombinant Human Interleukin-2;Biological: Autologous WT1-TCRc4 Gene-transduced CD8-positive Tcm/Tn Lymphocytes<br>* Given IV<br>Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|
| Experimental: Arm I, Stage II (T lymphocytes, cyclophosphamide, IL-2)<br>Patients receive cyclophosphamide IV on days -3 and -2, autologous WT1-TCRc4 gene-transduced CD8-positive Tcm/Tn lymphocytes IV on day 0, and aldesleukin SC BID for 14 days. | Biological: Aldesleukin<br>* Given SC<br>* Other names: Recombinant Human Interleukin-2;Biological: Autologous WT1-TCRc4 Gene-transduced CD8-positive Tcm/Tn Lymphocytes<br>* Given IV<br>Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|
| Experimental: Arm II (T lymphocytes, IL-2, surgery)<br>Patients receive autologous WT1-TCRc4 gene-transduced CD8-positive Tcm/Tn lymphocytes IV between 24-96 hours after the last dose of chemotherapy and receive aldesleukin SC BID for 14 days. Patients then undergo surgery within 3-4 weeks after the T-cell infusion. | Biological: Aldesleukin<br>* Given SC<br>* Other names: Recombinant Human Interleukin-2;Biological: Autologous WT1-TCRc4 Gene-transduced CD8-positive Tcm/Tn Lymphocytes<br>* Given IV<br>Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Procedure: Therapeutic Conventional Surgery<br>* Undergo surgical resection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | Based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. | Up to 6 months after the first T cell infusion | 
| Count of Patients for Which T Cells Are Successfully Generated and Infused and Whether Only TN or TCM Could be Generated | There were products generated for 11 participants and 10 participants were treated on the study. 8 participants received an infusion with Tn and Tcm cells. 1 participant received infusions with only Tn cells. 1 participant received their last infusion with only Tcm cells. The one participant that was not treated did successfully have Tn and Tcm cells generated but they were not treated due to their condition worsening. | Up to 4 weeks | 
| Persistence of Transduced T Cells | In vivo persistence of cells generated from the TN subset with cells generated from the TCM subset will be directly compared within each patient by high throughput T-cell receptor (TCR) beta sequencing. The one-sample T test will be used to assess the difference in mean persistence between groups, in which the outcome for each patient is the time to disappearance of infused cytotoxic T lymphocytes. | Up to 100 days after the last T cell infusion |