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

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

Background:

The National Cancer Institute (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:

- Patients 15 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 National Institutes of Health (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.

Study Overview

• Status: Completed
• Conditions: Melanoma; Breast Cancer; Non-Small Cell Lung Cancer; Meningioma; Hepatocellular Cancer
• Intervention / Treatment: Biological: Anti-NY ESO-1 mTCR PBL; Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Aldesleukin

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 New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1) (ESO) tumor antigen, which can be used to mediate genetic transfer of this T-cell receptor (TCR) with high efficiency.
• In co-cultures with human leukocyte antigen serotype within the HLA-A serotype group (HLA-A2) and ESO double positive tumors, anti-ESO mTCR transduced T cells secreted significant amounts of Interferons (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.

Eligibility:

• Age greater than or equal to 15 years and less than or equal to 70 years. Patients aged 15-17 years must weigh at least 50 kg.
• HLA-A*0201 positive
• Metastatic cancer including melanoma whose tumors express the ESO antigen
• Previously received and have been a non-responder to or recurred after receiving standard care for metastatic disease
• No contraindications for high-dose aldesleukin administration

Design:

• Peripheral blood mononuclear cells (PBMC) obtained by leukapheresis will be cultured in the presence of anti-CD3 monoclonal antibody (OKT3) and aldesleukin 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 human T-cell receptor (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% Partial Response (PR) + Complete Response (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
• Enrollment (Actual): 11
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years to 70 years (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

• INCLUSION CRITERIA - PATIENTS WITH SOLID TUMOR CANCERS AND MELANOMA:
• Measurable (per Response Evaluation Criteria in Solid Tumors (RECIST) v1.0 criteria) metastatic cancer or locally advanced refractory/recurrent malignancy including melanoma that expresses ESO as assessed by one of the following methods: reverse transcription polymerase chain reaction (RT-PCR) on tumor tissue, immunohistochemistry of resected tissue, or serum antibody reactive with ESO.
• Confirmation of diagnosis of metastatic cancer including melanoma by the National Cancer Institute (NCI) Laboratory of Pathology.
• 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.
• 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.
• More than four weeks must have elapsed since any prior systemic therapy at the time the patient receives the preparative regimen, and patient's 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 three weeks, as long as all toxicities have recovered to grade 1 or less.

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

INCLUSION CRITERIA - PATIENTS WITH MALIGNANT MENINGIOMA:

- 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.

• 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.
• At least 4 weeks post-surgery, and must be at least 3 months post-radiation therapy, with resolution of related toxicities.
• Measurable disease on magnetic resonance imaging (MRI) scan.
• No history of intracranial hemorrhage.
• Patients with a history of neurofibromatosis (NF) may have other stable central nervous system (CNS) tumors, such as schwannoma, acoustic neuroma, or ependymoma only if those lesions have been stable for the past 6 months.
• Patients must be on stable dose of steroids for at least 5 days prior to baseline imaging.

INCLUSION CRITERIA - ALL PATIENTS:

• Age greater than or equal to 15 years and less than or equal to 70 years.
• Patient, or their parent(s)/legal guardian(s) (if the patient is < 18 years of age), is able to understand and willing to sign a written informed consent. Written assent will be obtained for participants under the age of 18 as appropriate.
• All participants greater than or equal to 18 years of age must be willing to sign a durable power of attorney.
• Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1.
• Patients aged 15-17 years weigh greater than or equal to 50 kg.
• Human leukocyte antigen serotype within the HLA-A serotype group (HLA-A*0201) positive.
• Patients of both genders must be willing to practice birth control from the time of enrollment on this study and for four months after treatment.
• Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus.

• Serology

  • Seronegative for human immunodeficiency virus (HIV) antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive may have decreased immune-competence and thus may 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 Hepatitis C Virus Ribonucleic acid(HCV RNA) negative.

• Hematology

  • Absolute neutrophil count (ANC) greater than 1000/mm(3) without the support of filgrastim
  • White blood cells (WBC) greater than or equal to 3000/mm(3)
  • Platelet count greater than or equal to 100,000/mm(3)
  • Hemoglobin greater than 8.0 g/dl. Subjects may be transfused to reach this cut-off.

• Chemistry:

  • Serum alanine aminotransferase (ALT)/aspartate aminotransferase (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.
• Subjects must be co-enrolled in protocol 03-C-0277.

EXCLUSION CRITERIA:

• Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant.
• Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
• Active systemic infections requiring anti-infective treatment, coagulation disorders, or any other active or uncompensated major medical illnesses.
• 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).
• Concurrent systemic steroid therapy.
• History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine, or aldesleukin.
• History of coronary revascularization or ischemic symptoms.

• Documented Left Ventricular Ejection Fraction (LVEF) less than or equal to 45% tested in patients:

  • Age greater than or equal to 65 years
  • With clinically significant atrial and/or ventricular arrhythmias, including but not limited to: atrial fibrillation, ventricular tachycardia, second- or third-degree heart block or have a history of ischemic heart disease and/or chest pain.

• Documented forced expiratory volume 1 (FEV1) less than or equal to 60% predicted tested in patients with:

  • A prolonged history of cigarette smoking (greater than or equal to 20 pack-year smoking history, with cessation within the past two years).
  • Symptoms of respiratory dysfunction.
• Patients who are receiving any other investigational agents.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: 1/Cyclophosphamide & Fludarabine + Anti-ESO murine TCR transduced PBL + HD Aldesleukin; Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + anti-ESO murine T-cell receptor (TCR) transduced PBL + high-dose (HD) aldesleukin

Biological: Anti-NY ESO-1 mTCR PBL; Day 0: Cells will be infused intravenously (IV) on the Patient Care Unit over 20-30 minutes.; Drug: Cyclophosphamide; Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days intravenously (IV) in 250 mL dextrose 5% in water (D5W) infused simultaneously with mesna 15 mg/kg/day over 1 hour x 2 days.; Other Names: Cytoxan; Drug: Fludarabine; Days -7 to -3: Fludarabine 25 mg /m^2/day intravenous piggy back (IVPB) daily over 30 minutes for 5 days.; Other Names: Fludara; Drug: Aldesleukin; Aldesleukin 720,000 IU/kg intravenously (IV) (based on total body weight) over 15 minutes every 8 hours beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum 15 doses).; Other Names: Proleukin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With a Response	Percentage of patients who have a clinical response (complete response or partial response) to treatment (objective tumor regression). Response was determined entirely by radiographic imaging using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.0 to compare target lesions in centimeters. Complete Response is defined as disappearance of all target lesions. Partial Response is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD.	6 and 12 weeks after cell infusion, then every 3 months x3, then every 6 months x 2, then per principal investigator (PI) discretion, up to five years or disease progression.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of T Cell Receptor (TCR) in Cluster of Differentiation 3 (CD3) + Cells	T Cell Receptor (TCR) and vector presence will be quantitated in peripheral blood mononuclear cells (PBMC) samples using established polymerase chain reaction (PCR) techniques.	3 and 6 months, and 1 year post cell administration

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Serious and Non-serious Treatment Related Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)	Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.	Date treatment consent signed to approximately 6 weeks following cell administration.

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)

Publications and helpful links

General Publications

• Dudley ME, Yang JC, Sherry R, Hughes MS, Royal R, Kammula U, Robbins PF, Huang J, Citrin DE, Leitman SF, Wunderlich J, Restifo NP, Thomasian A, Downey SG, Smith FO, Klapper J, Morton K, Laurencot C, White DE, Rosenberg SA. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol. 2008 Nov 10;26(32):5233-9. doi: 10.1200/JCO.2008.16.5449. Epub 2008 Sep 22.
• Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS, Phan GQ, Citrin DE, Restifo NP, Robbins PF, Wunderlich JR, Morton KE, Laurencot CM, Steinberg SM, White DE, Dudley ME. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res. 2011 Jul 1;17(13):4550-7. doi: 10.1158/1078-0432.CCR-11-0116. Epub 2011 Apr 15.
• Robbins PF, Morgan RA, Feldman SA, Yang JC, Sherry RM, Dudley ME, Wunderlich JR, Nahvi AV, Helman LJ, Mackall CL, Kammula US, Hughes MS, Restifo NP, Raffeld M, Lee CC, Levy CL, Li YF, El-Gamil M, Schwarz SL, Laurencot C, Rosenberg SA. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol. 2011 Mar 1;29(7):917-24. doi: 10.1200/JCO.2010.32.2537. Epub 2011 Jan 31.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 24, 2013
• Primary Completion (ACTUAL): April 6, 2020
• Study Completion (ACTUAL): April 6, 2020

Study Registration Dates

• First Submitted: October 18, 2013
• First Submitted That Met QC Criteria: October 18, 2013
• First Posted (ESTIMATE): October 23, 2013

Study Record Updates

• Last Update Posted (ACTUAL): March 24, 2021
• Last Update Submitted That Met QC Criteria: March 1, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: Gene Therapy; Immunotherapy; Melanoma; Metastatic Cancer; Tumor Regression
• Additional Relevant MeSH Terms: Digestive System Diseases; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Central Nervous System Neoplasms; Nervous System Neoplasms; Neuroendocrine Tumors; Nevi and Melanomas; Neoplasms, Vascular Tissue; Meningeal Neoplasms; Carcinoma, Hepatocellular; Melanoma; Liver Neoplasms; Meningioma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Anti-HIV Agents; Anti-Retroviral Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Aldesleukin; Cyclophosphamide; Fludarabine
• Other Study ID Numbers: 130214; 13-C-0214

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No