CISH Inactivated Tumor-Infiltrating Lymphocytes for the Treatment of Metastatic Gastrointestinal Epithelial Cancer
- Diagnosis of metastatic gastrointestinal epithelial cancer with progressive disease following at least one first line standard therapy. When available, archived tissue from original diagnosis will be obtained for research related testing
- Must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 with at least one lesion identified as resectable for TIL generation (minimum volume of tumor tissue required is 1 cm^2 as single mass or fragments) and at least one other lesion meeting the RECIST criteria for measurable to serve as an indicator of disease response. The location of the tumor for TIL generation and method used to obtain (i.e. laparoscopy, endoscopic ultra sound, etc.) will be determined based on an individual patient’s disease
- 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. Patients must not be receiving systemic steroids. Brain metastases are assessed using the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria
- Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1
- Serology testing within 3 months of study enrollment (tumor collection): * Seronegative for human immunodeficiency virus (HIV) antibody. (The investigational 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 study 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 real time polymerase chain reaction (RT-PCR) and be hepatitis C virus (HCV) ribonucleic acid (RNA) negative. * Seronegative for hepatitis B core antibody (anti-HBc), hepatitis B virus (HBV)/HCV/HIV-1 nucleic acid testing (NAT), human T-lymphotropic virus-I/II antibody (anti-HTLV-I/II), Trypanosoma cruzi antibody (anti-T. cruzi), West Nile virus NAT, Cytomegalovirus antibody (anti-CMV), and rapid plasma reagin (RPR). (Note: Other blood viral testing may be required as updated on the Food and Drug Administration [FDA] website: https://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/TissueSafety/ucm09 5440.htm#approved).
- Absolute neutrophil count > 1000/mm^3 without the support of filgrastim (within 14 days of study enrollment)
- White blood cell (WBC) >= 3000/mm^3 (within 14 days of study enrollment)
- Platelet count >= 75,000/mm^3 (within 14 days of study enrollment)
- Hemoglobin > 8.0 g/dl (within 14 days of study enrollment). Subjects may be transfused to reach this cut-off
- Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 5.0 x upper limit of normal (ULN) (within 14 days of study enrollment)
- Serum creatinine =< 1.6 mg/dl (within 14 days of study enrollment)
- Total bilirubin =< to 2.0 mg/dl, except in patients with Gilbert’s Syndrome, who must have a total bilirubin =< 3.0 mg/dl (within 14 days of study enrollment)
- More than four weeks must have elapsed since prior systemic therapy at the time the patient receives the preparative regimen, and acute toxicities must have recovered to grade 1 or less (except for toxicities such as alopecia or vitiligo). Disease appropriate standard therapy is permitted between tumor collection and start of the fludarabine and cyclophosphamide. Investigational therapy is prohibited * Note: Patients may have undergone minor surgical procedures within the 3 weeks of the start of preparative therapy as long as all toxicities have recovered to grade 1 or less
- Willing to undergo outpatient non-mobilized leukapheresis (3 hour collection) prior to the tumor collection
- Agrees to remain in the Twin Cities metropolitan area (within 1 hour drive of the University of Minnesota) after the CISH KO TILs infusion through the end of treatment visit (~ day 28)
- Voluntary written consent prior to the performance of any research related procedures
- Pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant. Women of childbearing potential (defined as menses within previous 12 month and/or follicle stimulating hormone [FSH] =< 40 IU/L) must have a negative pregnancy test (serum or urine) within 7 days of enrollment
- Any form of primary immunodeficiency (such as severe combined immunodeficiency disease)
- Concurrent opportunistic infection (The treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune-competence may be less responsive to the treatment and more susceptible to its toxicities)
- Active systemic infections requiring anti-infective treatment, coagulation disorders or any other active major medical illnesses
- 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) =< 45% tested in patients age >= 65 years and/or 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. Patients < 65 years of age who present with cardiac risk factors (e.g., diabetes, hypertension, obesity) may undergo cardiac evaluation as noted above
- Clinically significant patient history that in the judgment of the principal investigator (PI) would compromise the patient’s ability to tolerate high-dose aldesleukin
- Documented forced expiratory volume in 1 second (FEV1) =< 50% predicted tested in patients with: * A prolonged history of cigarette smoking (approximately 20 packs/year within the past 2 years) and/or * Symptoms of respiratory dysfunction
- Receiving any investigational agents
I. Determine the safety and maximum tolerated dose (MTD) of tumor reactive autologous lymphocytes with knockout of the CISH gene (CISH KO tumor infiltrating lymphocytes [TIL]) in patients with refractory metastatic gastrointestinal epithelial cancer. (Phase I)
II. Determine the efficacy of tumor-reactive autologous lymphocytes with knockout of CISH gene in patients with refractory metastatic gastrointestinal epithelial cancer. (Phase II)
I. Evaluate the progression-free survival (PFS) and overall survival (OS) of patients with metastatic gastrointestinal cancer treated using the autologous lymphocytes.
II. Evaluate toxicity profiles resulting from treatment using these engineered tumor-infiltrating lymphocytes.
I. Evaluate the persistence of CISH knockout mutation reactive lymphocytes in patients with metastatic gastrointestinal cancer.
II. Analyze extent of immune infiltration in pre- and post-treatment tumor specimens.
III. Evaluate immune evolution in these patients.
OUTLINE: This is a phase I, dose-escalation study of CISH inactivated TIL followed by a phase II study.
PREPARATIVE CHEMOTHERAPY: Patients receive fludarabine phosphate intravenously (IV) over 1 hour daily on days -7 to -3 and cyclophosphamide IV over 2 hours daily on days -6 to -5 in the absence of unacceptable toxicity.
CELL INFUSION: Patients receive CISH inactivated TIL IV on day 0 over 10-20 minutes or as clinically determined by an investigator.
ALDESLEUKIN (IL-2): Beginning day 1, patients receive high dose aldesleukin IV over 15 minutes every 8-12 hours for up to 6 doses in the absence of unacceptable toxicity.
After completion of study, patients are followed up at 6 and 12 weeks, 3, 6, 12, 18, and 24 months after TIL administration, and then annually for up to 15 years.
Trial Phase Phase I/II
Trial Type Treatment
University of Minnesota / Masonic Cancer Center
- Primary ID 2019LS002
- Secondary IDs NCI-2020-08589, NCT03538613
- Clinicaltrials.gov ID NCT04426669