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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT01967823
Recruitment Status : Recruiting
First Posted : October 23, 2013
Last Update Posted : May 30, 2018
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:


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.


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.


- Adults 18 years old and older with cancer that has the ESO-1 molecule on their tumors.


  • 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.

Condition or disease Intervention/treatment Phase
Melanoma Synovial Sarcoma Breast Cancer Non-Small Cell Lung Cancer Hepatocellular Cancer Biological: Anti-NY ESO-1 mTCR PBL Drug: Cyclophosphamide Drug: Fludarabine Drug: Aldesleukin Phase 2

Detailed Description:



  • 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.

Primary objective:

- 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 including melanoma expressing the ESO antigen.


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.


  • 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).

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 43 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Study of Metastatic Cancer That Expresses NY-ESO-1 Using Lymphodepleting Conditioning Followed by Infusion of Anti-NY ESO-1 Murine TCR-Gene Engineered Lymphocytes
Study Start Date : October 18, 2013
Estimated Primary Completion Date : July 5, 2027
Estimated Study Completion Date : July 28, 2028

Arm Intervention/treatment
Experimental: Single Arm
Non-myeloablative lymphodepleting preparative regimen of cyclophosphamide and fludarabine + anti-NY ESO-1 mTCR PBL + highdose aldesleukin
Biological: Anti-NY ESO-1 mTCR PBL
Patients will receive non-myeloablative lymphodepleting preparative regimen consisting of cyclophosphamide and fludarabine followed by the administration of anti-NY ESO-1 mTCR PBL and high dose aldesleukin. On day 0,cells (1x10e9 to 2x10e11) will be infused intravenously on the Patient Care Unit over 20-30 minutes.

Drug: Cyclophosphamide
Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml D5W with Mesna 15 mg/kg/day X 2 days over 1 hr.

Drug: Fludarabine
Fludarabine 25 mg/m2/day IVPB daily over 30 minutes for 5 days.

Drug: Aldesleukin
Aldeskeukin 720,000 IU/kg IV (based on total body weight) over 15 minutes every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses)

Primary Outcome Measures :
  1. Response Rate [ Time Frame: 6 and 12 weeks after cell infusion, then every 3 months x3, then every 6 months x2, then PI discretion ]
    Percentage of patients who have a clinical response to treatment (objective tumor regression)

Secondary Outcome Measures :
  1. In vivo survival of TCR gene-engineered cells [ Time Frame: 3 and 6 months, and 1 year post cell administration ]
    TCR and vector presence will be quantitated in PBMC samples using established PCR techniques

  2. Frequency severity of treatment related adverse events [ Time Frame: 5 years following cell infusion ]
    Aggregate of all adverse events and their frequency and severity

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

    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.

Note: Patients who have previously received ipilimumab and have documented GI toxicity must have a normal colonoscopy with normal colonic biopsies.


  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


  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. Patients must be HLA-A*0201 positive
  6. 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
  7. 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.
  8. Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus.
  9. 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
  10. 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.
  11. Subjects must be co-enrolled in protocol 03-C-0277.


  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 (e.g.: requiring anti-infective treatment), coagulation disorders or any other major medical illnesses.
  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 chest pain, or ischemic heart disease.
    • Age greater than or equal to 65 years old
  9. Documented FEV1 less than or equal to 60% predicted tested in patients with:

    • A prolonged history of cigarette smoking (20 pk/year of smoking within the past 2 years).
    • Symptoms of respiratory dysfunction
  10. Patients who are receiving any other investigational agents.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01967823

Contact: Margaret Shovlin, R.N. (866) 820-4505

United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact NCI/Surgery Branch Recruitment Center    866-820-4505   
Sponsors and Collaborators
National Cancer Institute (NCI)
Principal Investigator: Steven A Rosenberg, M.D. National Cancer Institute (NCI)

Additional Information:
Responsible Party: National Cancer Institute (NCI) Identifier: NCT01967823     History of Changes
Other Study ID Numbers: 130214
First Posted: October 23, 2013    Key Record Dates
Last Update Posted: May 30, 2018
Last Verified: May 21, 2018

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Metastatic Cancer
Gene Therapy
Tumor Regression

Additional relevant MeSH terms:
Carcinoma, Non-Small-Cell Lung
Liver Neoplasms
Sarcoma, Synovial
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Nevi and Melanomas
Digestive System Neoplasms
Digestive System Diseases
Liver Diseases
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Fludarabine phosphate