Patient case: 70-year-old male with melanoma; genetic feature: NF1 truncation

Clinical trial: T Cell Receptor Immunotherapy Targeting NY-ESO-1 for Patients With NY-ESO-1 Expressing Cancer

Summary: Background:
  The NCI Surgery Branch has developed an experimental therapy for treating patients with cancer that involves taking white blood cells from the patient, growing them in the laboratory in large numbers, genetically modifying them, and then giving the cells back to the patient. In a previous study the NCI Surgery Branch used the anti-ESO-1 gene and a type of virus (retrovirus) to make these tumor fighting cells (anti-ESO-1 cells). About half of the patients who received this treatment experienced shrinking of their tumors. In this study, we are using a slightly different method of producing the anti-ESO-1 cells which we hope will be better in making the tumors shrink.
  Objectives:
  The purpose of this study is to see if these tumor fighting cells (genetically modified cells) that express the receptor for the ESO-1 molecule on their surface can cause tumors to shrink and to see if this treatment is safe.
  Eligibility:
  - Adults 18 years old and older with cancer that has the ESO-1 molecule on their tumors.
  Design:
  -  Work up stage: Patients will be seen as an outpatient at the NIH clinical Center and undergo a history and physical examination, scans, x-rays, lab tests, and other tests as needed
  -  Leukapheresis: If the patients meet all of the requirements for the study they will undergo leukapheresis to obtain white blood cells to make the anti ESO-1 cells. {Leukapheresis is a common procedure which removes only the white blood cells from the patient.}
  -  Treatment: Once their cells have grown the patients will be admitted to the hospital for the conditioning chemotherapy, the anti-ESO-1 cells and aldesleukin. They will stay in the hospital for about 4 weeks for the treatment.
  -  Follow up: Patients will return to the clinic for a physical exam, review of side effects, lab tests, and scans about every 1-3 months for the first year, and then every 6 months to 1 year as long as their tumors are shrinking. Follow up visits take up to 2 days.

Detailed description: PRECIS
  Background:
  -  We have constructed a single retroviral vector that contains both and <= chains of a murine T cell receptor (mTCR) that recognizes the NY-ESO-1 (ESO) tumor antigen, which can be used to mediate genetic transfer of this TCR with high efficiency.
  -  In co-cultures with HLA-A2 and ESO double positive tumors, anti-ESO mTCR transduced T cells secreted significant amounts of IFN- >= with high specificity.
  Objectives:
  Primary objectives:
  - To determine whether the administration of anti-ESO mTCR-engineered peripheral blood lymphocytes (PBL) plus high-dose aldesleukin following a non-myeloablative lymphoid depleting preparative regimen may result in objective tumor regression in patients with metastatic cancers that express the ESO antigen.
  Secondary objectives:
  -  Determine the in vivo survival of mTCR gene-engineered cells.
  -  Determine the toxicity profile of this treatment regimen.
  Eligibility:
  Patients who are HLA-A*0201 positive and 18 years of age or older must have
  -  Metastatic cancer including melanoma whose tumors express the ESO antigen;
  -  Patients must have previously received and have been a non-responder to or recurred after receiving standard care for metastatic disease;
  Patients may not have:
  - Contraindications for high dose aldesleukin administration.
  Design:
  -  PBMC obtained by leukapheresis 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 cells to retroviral vector supernatant containing the anti- ESO mTCR genes. This mTCR targets the exact same epitope as the hTCR.
  -  All patients will receive a non-myeloablative lymphocyte depleting preparative regimen of cyclophosphamide and fludarabine.
  -  On day 0 patients will receive anti-ESO mTCR gene-transduced PBMC and then begin high dose aldesleukin.
  -  A complete evaluation of evaluable lesions will be conducted 6 weeks (+/- 2 weeks) following the administration of the cell product.
  -  The study will be conducted using a phase II optimal design (Simon R, Controlled Clinical Trials 10:1-10, 1989). The objective will be to determine if the combination of high dose aldesleukin, lymphocyte depleting chemotherapy, and anti-ESO TCR-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).
  -  A total of up to 43 patients may be enrolled (41, plus allowing for up to 2 non-evaluable patients).

Eligibility: -  INCLUSION CRITERIA
  PATIENTS WITH SOLID TUMOR CANCERS AND MELANOMA
  1. Measurable metastatic cancer or locally advanced refractory/recurrent malignancy including melanoma that expresses ESO as assessed by one of the following methods: RT-PCR on tumor tissue, or by immunohistochemistry of resected tissue, or serum antibody reactive with ESO.
  2. Confirmation of diagnosis of metastatic cancer including melanoma by the Laboratory of Pathology of the NCI.
  3. Patients must have previously received first line standard therapy (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.
  4. Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible. Patients with surgically resected brain metastases are eligible.
  5. 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).
  Note: Patients may have undergone minor surgical procedures within the past 3 weeks, as long as all toxicities have recovered to grade 1 or less or as specified in the eligibility criteria.
  6. Six weeks must have elapsed from the time of any antibody therapy that could affect an anti cancer immune response, including anti-CTLA 4 therapy, at the time the patient receives the preparative regimen to allow antibody levels to decline.
  Note: Patients who have previously received ipilimumab and have documented GI toxicity must have a normal colonoscopy with normal colonic biopsies.
  INCLUSION CRITERIA
  PATIENTS WITH MALIGNANT MENINGIOMA
  1. Histologically proven recurrent meningioma or aggressive meningioma
  Note: Confirmation of ESO expression and pathology is not required in patients with definitive radiologic evidence of meningioma who are unresectable, and in whom radiation therapy without biopsy is the standard treatment
  2. Recurrent disease/progression after receiving all standard treatments, which must include the following:
  -  surgical resection, if possible;
  -  definitive radiation therapy for unresectable meningioma, or for recurrent meningioma after resection
  3. At least 4 weeks post-surgery, and must be at least 3 months post-radiation therapy, with resolution of related toxicities
  4. Measurable disease on MRI scan
  5. No history of intracranial hemorrhage
  6. Patients with a history of NF may have other stable CNS tumors, such as schwannoma, acoustic neuroma, or ependymoma only if those lesions have been stable for the past 6 months
  7. Patients must be on stable dose of steroids for at least 5 days prior to baseline imaging
  INCLUSION CRITERIA ALL PATIENTS
  1. Greater than or equal to 18 years of age and less than or equal to 70 years of age.
  2. Willing to sign a durable power of attorney
  3. Able to understand and sign the Informed Consent Document
  4. Clinical performance status of ECOG 0 or 1
  5. Life expectancy of greater than three months
  6. Patients must be HLA-A*0201 positive
  7. 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 treatment
  8. 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 immune-competence 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.
  9. Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus.
  10. Hematology
  -  Absolute neutrophil count greater than 1000/mm(3) without the support of filgrastim
  -  WBC greater than or equal to 3000/mm(3)
  -  Platelet count greater than or equal to 100,000/mm(3)
  -  Hemoglobin > 8.0 g/dl
  11. Chemistry:
  -  Serum ALT/AST less than 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.
  EXCLUSION CRITERIA
  1. Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant.
  2. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
  3. 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.
  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 LVEF of less than or equal to 45%. Testing is required in patients with:
  -  Clinically significant atrial and/or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart block
  -  Age greater than or equal to 60 years old

Relevance to patient case: not relevant