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

Primary Outcome Measures

• Evidence and nature of toxicity based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 6 months after the first T cell infusion ] [ Designated as safety issue: Yes ]
• Feasibility of naive T cell (TN) and central memory T cell (TCM) subsets, measured as the proportion of patients for which T cells are successfully generated and infused and whether only TN or TCM could be generated [ Time Frame: Up to 4 weeks ] [ Designated as safety issue: No ]
  A simple estimate of the proportion along with its 95% confidence interval will be used.
• Persistence of transduced T cells [ Time Frame: Up to 15 years ] [ Designated as safety issue: No ]
  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 TCRbeta 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.

Secondary Outcome Measures

• Frequency of transferred T cells at biopsied tumor sites between the Tn and Tcm groups [ Time Frame: Up to 15 years ] [ Designated as safety issue: No ]
• Functional capacity of transferred cells, measured by production of intracellular cytokines [ Time Frame: Up to 15 years ] [ Designated as safety issue: No ] Tetramer+ cells from peripheral blood, if detectable and available in sufficient number, evaluated for production of intracellular cytokines including interferon-gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and IL-2. Intranuclear Ki-67 expression assessed on recovered tetramer+ T cells. Based on available numbers, ex vivo proliferative capacity after infusion assessed by labeling cells with carboxyfluorescein succinimidyl ester dye and measuring dilution in response to peptide stimulation. Phenotype of tetramer+ antigen-specific cells assessed using established immunophenotyping panels.
• TTP based on RECIST criteria and immune-related response criteria [ Time Frame: 3 months after last infusion ] [ Designated as safety issue: No ]
  The potential efficacy of the infused cells will be assessed and the substrate cell (TN or TCM) that is most effective based on the TTP of patients who have persisting TN cells to that of patients who have persisting TCM cells 3 months after the last infusion will be determined.

DETAILED DESCRIPTION

Primary Objectives

Determine the safety, and potential toxicities associated with treating patients with metastatic NSCLC and mesothelioma with polyclonal autologous central memory and naïve 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).

Determine the feasibility of treating patients with metastatic NSCLC and mesothelioma with polyclonal autologous central memory and naïve CD8+ T cells that have been transduced to express a WT1-specific TCR (Arm 1 and Arm 2).

Determine and compare the in vivo persistence in blood and tumor of transferred polyclonal autologous central memory and naïve CD8+ T cells that have been transduced to express a WT1-specific TCR (Arm 1 and Arm 2).

Secondary Objectives

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.

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).

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).

Evaluate the tumor response and T cell infiltration in tumors of patients with stage IIIA NSCLC treated in the neo-adjuvant setting.

Eligibility

Inclusion Criteria

ELIGIBILITY FOR ENROLLMENT/SCREENING (ARMS 1 AND 2)

Histopathological documentation of NSCLC or mesothelioma

Patients must be able to give informed consent

Patients must be able to provide blood and tumor samples

ELIGIBILITY FOR TREATMENT ON ARM 1

Patients must express human leukocyte antigen (HLA)-A*0201

Evidence of WT1 tumor expression

Patients must have received at least one line of therapy for NSCLC or mesothelioma or previously documented to have declined therapy

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)

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)

Ninety days must have passed since the last doses of radiation or chemoradiation treatment involving lung tissue or thorax prior to T cell infusion

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 3 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

Evidence of WT1 tumor expression

Ninety days must have passed since the last definitive doses of radiation or chemoradiation treatment prior to T cell infusion

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 entry

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):

1. Infection, with or without antibiotic treatment
2. Recent hepatitis exposure (hepatitis B or C antigenemia)
3. Pregnancy or nursing
4. HIV or human T-lymphotropic virus (HTLV) infection
5. 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

Symptomatic and untreated central nervous system (CNS) metastasis; patients must be clinically and radiologically stable for at least 4 weeks and off steroids for a minimum of 2 weeks prior to study treatment

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 × upper limits of normal (ULN)

Bilirubin > 3 × ULN that cannot be attributed to NSCLC metastasis

HIV or HTLV infection