Phase I/II Study to Assess the Safety and Activity of Enhanced TCR Transduced Autologous T Cells in Metastatic Melanoma

• Clinical Activity of TCR gene therapy [ Time Frame: every 4 weeks until month 5 and then every other month through month 11 ] [ Designated as safety issue: No ]
  To determine the clinical activity TCR gene therapy as assessed by RECIST criteria and progression-free survival.
• Persistence of modified T cells in the peripheral blood [ Time Frame: Days: 1, 5-9, 12-6, then weekly for 10 weeks ] [ Designated as safety issue: No ]
  To determine the persistence of modified T cells in the peripheral blood and at tumor sites.
• T cell function [ Time Frame: Weeks 4 and 8 post T cell infusion ] [ Designated as safety issue: No ]
  To determine the functional properties and phenotype of modified T cells from peripheral blood and tumor sites. T cell function is essential to document the activity (or inactivity) of TCR positive T cells isolated from each patient at certain time points after adoptive transfer. We hypothesize that functional TCR positive T cells as assessed by our ex vivo analysis will be associated with clinical response and improved outcomes. In contrast, anergic T cells will be associated with disease progression.

• Clinical Activity TCR gene therapy as assessed by RECIST criteria and progression-free survival [ Time Frame: every 4 weeks while on study up 12 week ] [ Designated as safety issue: No ]
  To determine the clinical activity TCR gene therapy as assessed by RECIST criteria and progression-free survival. Tumor measurements will be repeated q4weeks using RECIST criteria. Progression free survival will be calculated.
• Persistence of modified T cells in the peripheral blood [ Time Frame: Days: 1, 5-9, 12-6, then weekly for 10 weeks ] [ Designated as safety issue: No ]
  To determine the persistence of modified T cells in the peripheral blood and at tumor sites.
• T cell function [ Time Frame: Weeks 4 and 8 post T cell infusion ] [ Designated as safety issue: No ]
  To determine the functional properties and phenotype of modified T cells from peripheral blood and tumor sites. T cell function is essential to document the activity (or inactivity) of TCR positive T cells isolated from each patient at certain time points after adoptive transfer. We hypothesize that functional TCR positive T cells as assessed by our ex vivo analysis will be associated with clinical response and improved outcomes. In contrast, anergic T cells will be associated with disease progression.

The purpose of this early (phase I/II) clinical trial is to assess the effects (both good and bad) of genetically modified T cells after chemotherapy on your cancer and general health.

Purpose of this study is to evaluate the safety and tolerability of autologous genetically modified T cells. Genetic material is transferred into the subject's previously harvested autologous T cells to redirect them to target melanoma cells rather than their usual target. Study subjects must have histologically or cytologically melanoma stage 3/4 and their tumor must express HLA Class 1 allele HLA-A*0201 for NY-ESO-1/LAGE. Subjects must also have measureable disease on study entry, as defined by at least one lesion that can be measured in at least one dimension >= 10mm with spiral CT scan.

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed melanoma stage III/IV, unresectable. Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >10 mm with spiral CT scan.
• One prior cytotoxic therapy for the treatment of metastatic disease is allowed. Unlimited regimens using biological agents (vaccines), immunotherapy, or targeted agents is permitted. For example, BRAF inhibitors and ipilimumab are permitted. Patients must have fully recovered from the acute toxicities related to any prior therapy. Prior therapy must be completed >28 days before the first dose of cyclophosphamide.
• Age ≥ 18 years.
• Life expectancy of greater than 3 months.
• ECOG performance status ≤ 1

• Patients must have normal organ and marrow function as defined below:

  • leukocytes ≥ 3,000/mcL
  • absolute neutrophil count ≥ 1,500/mcL
  • platelets ≥ 100,000/mcL
  • total bilirubin within normal institutional limits
  • AST(SGOT)/ALT(SGPT)≤ 2.5 X institutional upper limit of normal
  • creatinine ≤ 2.0 mg/dl OR creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal
• Tumor must express the cancer-testis antigen as determined by the study laboratory. The patient must express the appropriate HLA class I allele (HLA-A2 for NY-ESO-1).
• The effects of transduced T cells on the developing human fetus at the recommended therapeutic dose are unknown. For this reason and because cyclophosphamide is known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
• Ability of the patient (or legally authorized representative if applicable) to understand and the willingness to sign a written informed consent document.
• Both men and women and members of all races and ethnic groups are all eligible

Exclusion Criteria:

• Patients who have had 2 or more regimens containing cytotoxic chemotherapy for metastatic melanoma.
• Patients may not be receiving any other investigational agents.
• Patients with active brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to cyclophosphamide or other agents used in the study.
• Active infection.
• Prior malignancy (except non-melanoma skin cancer) within 3 years.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. All patients will undergo a cardiac stress test for evaluation of cardiac function. PI will use his or her discretion to choose the stress test best suited to evaluate the patient.
• Pregnant women are excluded from this study because cyclophosphamide has the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with cyclophosphamide, breastfeeding should be discontinued if the mother is treated with cyclophosphamide. These potential risks may also apply to other agents used in this study.
• Active infection with HIV, HPV or HCV as defined by positive serology for HIV, Hepatitis B, or Hepatitis C. Patients are excluded due to the immunosuppressive dose of cyclophosphamide used and the unknown risks associated with viral replication.