Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic 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: NCT01174121
Recruitment Status : Recruiting
First Posted : August 3, 2010
Last Update Posted : September 26, 2018
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

July 31, 2010
August 3, 2010
September 26, 2018
August 26, 2018
December 29, 2023   (Final data collection date for primary outcome measure)
Response rate [ Time Frame: 6 and 12 weeks after cell infusion, then every 3 months x 3, then every 6 months x 2 years, then per PI discretion ]
Percentage of patients who have a clinical response to treatment (objective tumor regression)
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Complete list of historical versions of study NCT01174121 on Archive Site
  • Frequency and severity of treatment-related to adverse events [ Time Frame: 30 days after end of treatment ]
    Aggregate of all adverse events, as well as their frequency and severity
  • Safety and efficacy of pembrolizumab following TIL therapy [ Time Frame: Every 6 weeks (week 6, 12, 18, 24) within 24 hours prior to next scheduled pembrolizumab dose ]
    Response rate and evaluation of treatment-related adverseevents for patients who experience progressive disease and receivepembrolizumab
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Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic Cancer
A Phase II Study Using Short-Term Cultured, Autologous Tumor-Infiltrating Lymphocytes Following a Lymphocyte Depleting Regimen in Metastatic Cancers Plus the Administration of Pembrolizumabat Time of Progression


The NCI Surgery Branch has developed an experimental therapy that involves taking white blood cells from patients' tumors, growing them in the laboratory in large numbers, and then giving the cells back to the patient. These cells are called Tumor Infiltrating Lymphocytes, or TIL and we have given this type of treatment to over 200 patients with melanoma. Researchers want to know if TIL shrink s tumors in people with digestive tract, urothelial, breast, or ovarian/endometrial cancers. In this study, we are selecting a specific subset of white blood cells from the tumor that we think are the most effective in fighting tumors and will use only these cells in making the tumor fighting cells.


The purpose of this study is to see if these specifically selected tumor fighting cells can cause digestive tract, urothelial, breast, or ovarian/endometrial tumors to shrink and to see if this treatment is safe.


- Adults age 18-70 with metastatic digestive tract, urothelial, breast, or ovarian/endometrial cancer who have a tumor that can be safely removed.


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.

Surgery: If the patients meet all of the requirements for the study they will undergo surgery to remove a tumor that can be used to grow the TIL product.

Leukapheresis: Patients may undergo leukapheresis to obtain additional white blood 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 TIL 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 will take up to 2 days.


  • Metastatic digestive tract cancers, in particular esophageal, gastric, pancreatic and hepatobiliary carcinomas, are associated with poor survival beyond five years and poor response to existing therapies.
  • Data from the Surgery Branch and from the literature support that metastatic cancers are potentially immunogenic and that TIL can be grown and expanded from these tumors.
  • In metastatic melanoma, TIL can mediate the regression of bulky disease at any site when administered to an autologous patient with high dose aldesleukin (IL-2) following a nonmyeloablative but lymphodepleting chemotherapy preparative regimen.
  • The recent young-TIL approach, in which TIL are minimally cultured in vitro, not selected for tumor recognition, before rapid expansion and infusion to metastatic melanoma patients, has lead to objective response rates comparable to previous trials relying on TIL screened for tumor recognition, with no added toxicities.
  • In pre-clinical models, the administration of an anti-PD-1 antibody enhances the anti-tumor activity of transferred T-cells.
  • With the approval of amendment Z, we propose to investigate the feasibility, safety, and efficacy of TIL adoptive transfer therapy with the addition of pembrolizumab at the time of progressive disease as treatment in Arm 4, including a 7th cohort (glioblastoma).


-With Amendment Z, to determine the ability of autologous TIL infused after minimal in vitro culture in conjunction with high dose aldesleukin following a non-myeloablative lymphodepleting preparative regimen and then the addition of anti-PD-1 at time of progressive disease per RECIST criteria to mediate tumor regression in patients with metastatic cancers.


Patients who are 18 years of age or older must have:

  • Metastatic digestive tract, urothelial, breast, ovarian/endometrial cancer, or glioblastoma refractory to standard chemotherapy, originating from the a) gastric, gastroesophageal junction, b) pancreas, liver or biliary tree, c) colon or rectum, d) bladder, e) breast, or f) ovarian/endometrial;
  • Normal basic laboratory values.

Patients may not have:

  • Concurrent major medical illnesses
  • Severe hepatic function impairment due to liver metastatic burden
  • Unpalliated biliary or bowel occlusion, cholangitis, or digestive tract bleeding
  • Any form of immunodeficiency
  • Severe hypersensitivity to any of the agents used in this study


  • Patients will undergo resection or biopsy to obtain tumor for generation of autologous TIL cultures and autologous cancer cell lines, and for frozen tissue archive. Lymph nodes, ascites,peritoneal implants, and normal tissue adjacent to metastatic deposit will also be obtained when possible for ongoing and future research as described in 03-C-0277.
  • With the approval of amendment X, all patients on Arm 4 will receive a non-myeloablative lymphocyte depleting preparative regimen of cyclophosphamide and fludarabine followed by the infusion of autologous TIL and then begin high-dose aldesleukin (720,000 IU/kg IV every 8 hours for up to 12 doses).
  • Once patients meet progressive disease by RECIST criteria, Pembrolizumab will be administered within 4 weeks after PD for up to 8 doses..
  • Clinical and immunologic response will be evaluated at the first follow-up evaluation following the last dose of study drug.
  • Twenty-one patients will be initially enrolled in each group to assess toxicity and tumor responses. If two or more of the first 21 patients per groups shows a clinical response (PR or CR), accrual will continue to 41 patients, targeting a 20% goal for objective response.
  • Up to 332 patients may be enrolled over 3-8 years.
Phase 2
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
  • Metastatic Colorectal Cancer
  • Metastatic Gastric Cancer
  • Metastatic Pancreatic Cancer
  • Metastatic Hepatocellular Carcinoma
  • Progressive Glioblastoma
  • Metastatic Ovarian Cancer
  • Metastatic Breast Cancer
  • Biological: Young TIL
    On day 0, cells will be infused intravenously on the Patient Care Unit over 20 to 30 minutes (one to four days after the last dose of fludarabine).
  • Drug: Aldesleukin
    Aldesleukin 720,000 IU/kg IV (based on total body weight) over 15 minutes every eight hours (+/- 1hr) beginning within 24 hours of cell infusion and continuing for up to 4 days (maximum of 12 doses.)
  • Drug: Cyclophosphamide
    Days -7 and day -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml D5W Mesna 15mg/kg/day x2 days over 1 hr.
  • Drug: Fludarabine
    Days -7 to -3: Fludarabine 25 mg /m2/day IVPB daily over 30 minutes for 5 days.
  • Drug: Pembrolizumab
    Pembrolizumab 2mg /kg IV over approximately 30 minutes (for patients who meet progressive disease per RECIST criteria and have resolved major toxicities after cell infusion or anytime during the post-treatment evaluation period; may receive up to 8 doses every 3 weeks).
  • Experimental: 2/Unselected TIL (CLOSED)
    Young unselected TIL (CLOSED)
    • Biological: Young TIL
    • Drug: Aldesleukin
    • Drug: Cyclophosphamide
    • Drug: Fludarabine
  • Experimental: 4/Unselected TIL + Pembro at POD
    Young unselected TIL + pembrolizumab at time of progression for a total of 4 doses.
    • Biological: Young TIL
    • Drug: Aldesleukin
    • Drug: Cyclophosphamide
    • Drug: Fludarabine
    • Drug: Pembrolizumab
  • Experimental: 3/Unselected TIL + Pembro Prior to Cells (CLOSED)
    Young unselectedTIL + pembrolizumab prior to cell administration and continuing for a total of 4 doses (CLOSED)
    • Biological: Young TIL
    • Drug: Cyclophosphamide
    • Drug: Fludarabine
    • Drug: Pembrolizumab
  • Experimental: 1/CDS+ Enriched TIL (CLOSED)
    Young CD8+ enriched TIL (CLOSED)
    • Biological: Young TIL
    • Drug: Aldesleukin
    • Drug: Cyclophosphamide
    • Drug: Fludarabine

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
December 27, 2024
December 29, 2023   (Final data collection date for primary outcome measure)


  1. Measurable metastatic (stage IV) gastric, gastroesophageal, pancreatic, hepatocellular carcinoma, cholangiocarcinoma, gallbladder, colorectal, urothelial, breast, ovarian/endometrial carcinoma, or glioblastoma with at least one lesion that is resectable for TIL generation with minimal morbidity preferentially using minimal invasive laparoscopic or thoracoscopic surgery for removal of superficial tumor deposit, plus one other lesion that can be measured.
  2. All patients must be refractory to approved standard systemic therapy.

    Specifically :

    • Metastatic colorectal patients must have received oxaliplatin or irinotecan.
    • Hepatocellular carcinoma patients must have received sorafenib (Nexavar ), since level 1 data support a survival benefit with this agent.
    • Breast and Ovarian cancer patients must be refractory to both 1st line and 2nd line treatments and must have received at least one second line chemotherapy regimen.
    • Patients with recurrent glioblastoma that have received standard surgery, radiation therapy, and chemotherapy for their primary tumors and require resection of their tumors for palliative or other clinical indications. These patients will not undergo surgery solely for treatment on this protocol.
  3. 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.
  4. Clinical performance status of ECOG 0 or 1.
  5. Greater than or equal to 18 years of age and less than or equal to 70 years of age.
  6. Willing to practice birth control during treatment and for four months after receiving the treatment.
  7. Willing to sign a durable power of attorney.
  8. Able to understand and sign the Informed Consent Document.
  9. Hematology:

    • Absolute neutrophil count greater than 1000/mm(3) without support of filgrastim.
    • Normal WBC (> 3000/mm(3)).
    • Hemoglobin greater than 8.0 g/dl. Subjects may be transfused to reach this cut-off.
    • Platelet count greater than 100,000/mm(3).
    • Normal prothrombin time (less than or equal to 15.2 seconds).
  10. 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 may be less responsive to the experimental treatment and more susceptible to its toxicities.)
    • Seronegative for active hepatitis B, 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.
  11. Chemistry:

    • Serum ALT/AST less than five times the upper limit of normal.
    • Serum creatinine less than or equal to 1.6 mg/dl.
    • Total bilirubin less than or equal to 2 mg/dl, except in patients with Gilbert's Syndrome, who must have a total bilirubin less than or equal to 3 mg/dl.
  12. 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. Patients may have undergone minor surgical procedures with the past 3 weeks, as long as all toxicities have recovered to grade 1 or less.
  13. Four weeks must have elapsed since any prior antibody therapies to allow antibody levels to decline.
  14. 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. Concurrent systemic steroid therapy. (Note: Patients with recurrent glioblastoma who require steroids for clinical indications are eligible.)
  3. Active systemic infections (e.g.: requiring anti-infective treatment), coagulation disorders or any other active major medical illnesses
  4. Advanced primary with impeding occlusion, perforation or bleeding, dependant on transfusion.
  5. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease and AIDS).
  6. History of major organ autoimmune disease.
  7. Grade 3 or 4 major organ Immune-Related Adverse Events (IRAEs) following treatment with anti-PD-1/PD-L1
  8. 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.)
  9. History of severe immediate hypersensitivity reaction to any of the agents used in this study.
  10. History of coronary revascularization or ischemic symptoms.
  11. Any patient known to have an LVEF less than or equal to 45%.
  12. Documented LVEF of less than or equal to 45% tested 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
  13. Documented Child-Pugh score of B or C for hepatocellular carcinoma patients with known underlying liver dysfunction.
  14. 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
  15. Patients who are receiving any other investigational agents.
Sexes Eligible for Study: All
18 Years to 70 Years   (Adult, Older Adult)
Contact: Margaret Shovlin, R.N. (866) 820-4505
United States
Not Provided
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Not Provided
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Steven A Rosenberg, M.D. National Cancer Institute (NCI)
National Institutes of Health Clinical Center (CC)
September 20, 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP