A Study in Patients With Metastatic Gastrointestinal Epithelial Cancer Administering Tumor-Infiltrating Lymphocytes in Which the Gene Encoding CISH Was Inactivated Using the CRISPR/Cas9 System

Inclusion Criteria:

• Diagnosis of metastatic gastrointestinal epithelial cancer with progressive diseasefollowing at least one first line standard therapy. When available, archived tissuefrom original diagnosis will be obtained for research related testing.

• Must have measurable disease per RECIST 1.1 with at least one lesion identified asresectable for TIL generation (minimum volume of tumor tissue required is 1 cm2 assingle mass or fragments) and at least one other lesion meeting the RECIST criteriafor measurable to serve as an indicator of disease response. The location of the tumorfor TIL generation and method used to obtain (i.e. laparoscopy, endoscopic ultrasound, 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 andasymptomatic are eligible. Lesions that have been treated with stereotacticradiosurgery must be clinically stable for 1 month after treatment for the patient tobe eligible. Patients with surgically resected brain metastases are eligible. Patientsmust not be receiving systemic steroids. Brain metastases are assessed using theResponse Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria.

• Age ≥ 18 years and ≤ 70 years.

• Clinical performance status of ECOG 0 or 1 (refer to Appendix III).

• Serology testing within 3 months of study enrollment (tumor collection):

• Seronegative for HIV antibody. (The investigational treatment being evaluated inthis protocol depends on an intact immune system. Patients who are HIVseropositive can have decreased immune-competence and thus may be less responsiveto 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 thepresence of antigen by RT-PCR and be HCV RNA negative.

• Seronegative for anti-HBc, HBV/HCV/HIV-1 NAT, anti-HTLV-I/II, anti-T. cruzi, WestNile Virus NAT, anti-CMV, and RPR. (Note: Other blood viral testing may berequired as updated on the FDA website: https://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/TissueSafety/ucm09 5440.htm#approved).

• Hematology within 14 days of study enrollment:

• Absolute neutrophil count > 1000/mm3 without the support of filgrastim

• WBC ≥ 3000/mm3

• Platelet count ≥ 75,000/mm3

• Hemoglobin > 8.0 g/dl. Subjects may be transfused to reach this cut-off.

• Adequate organ function within 14 days of study enrollment defined as:

• Serum ALT and AST ≤ 5.0 x ULN

• Serum creatinine ≤ 1.6 mg/dl

• Total bilirubin ≤ to 2.0 mg/dl, except in patients with Gilbert's Syndrome, whomust have a total bilirubin ≤ 3.0 mg/dl.

• More than four weeks must have elapsed since prior systemic therapy at the time thepatient receives the preparative regimen, and acute toxicities must have recovered toGrade 1 or less (except for toxicities such as alopecia or vitiligo). Diseaseappropriate standard therapy is permitted between tumor collection and start of thefludarabine and cyclophosphamide. Investigational therapy is prohibited. Note: Patients may have undergone minor surgical procedures within the 3 weeks of the startof preparative therapy as long as all toxicities have recovered to Grade 1 or less.

• Agrees to remain in the Twin Cities metropolitan area (within 1 hour drive of theUniversity of Minnesota) after the CISH KO TILs infusion through the End of Treatmentvisit (Day 28)

• Voluntary written consent prior to the performance of any research related procedures

Exclusion Criteria:

• Pregnant or breastfeeding because of the potentially dangerous effects of thetreatment on the fetus or infant. Women of childbearing potential (defined as menseswithin previous 12 month and/or FSH ≤ 40 IU/L) must have a negative pregnancy test (serum or urine) within 7 days of enrollment. A repeat negative pregnancy test isrequired within 7 days of beginning the preparative chemotherapy.

• Any form of primary immunodeficiency (such as Severe Combined ImmunodeficiencyDisease).

• Concurrent opportunistic infection (The treatment being evaluated in this protocoldepends on an intact immune system. Patients who have decreased immune-competence maybe less responsive to the treatment and more susceptible to its toxicities).

• Active systemic infections requiring anti-infective treatment, coagulation disordersor 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 LVEF ≤ 45% tested in patients:

• Age ≥ 65 years and/or

• With clinically significant atrial and/or ventricular arrhythmias, including butnot limited to: atrial fibrillation, ventricular tachycardia, second- orthird-degree heart block, or have a history of ischemic heart disease and/orchest pain. Patients < 65 years of age who present with cardiac risk factors (e.g., diabetes, hypertension, obesity) may undergo cardiac evaluation as notedabove.

• Clinically significant patient history that in the judgment of the PI would compromisethe patient's ability to tolerate high-dose aldesleukin.

• Documented FEV1 ≤ 50% predicted tested in patients with:

• A prolonged history of cigarette smoking (approximately 20 packs/year within thepast 2 years) and/or

• Symptoms of respiratory dysfunction

• Receiving any investigational agents. Confirmation of Eligibility Prior to CY/FU Start Due to a 10-12 week or more delay between study enrollment and the start of studytreatment, the following eligibility criteria must be met:

• Clinical performance status of ECOG 0 or 1 (refer to Appendix III)

• Hematology within 7 days of starting lymphodepleting chemotherapy:

• Absolute neutrophil count > 1000/mm3 without the support of filgrastim

• WBC ≥ 3000/mm3

• Platelet count ≥ 100,000/mm3

• Hemoglobin > 8.0 g/dl. Subjects may be transfused to reach this cut-off.

• Adequate organ function within 7 days of starting lymphodepleting chemotherapy:

• Serum ALT and AST ≤ 5.0 x ULN

• Serum creatinine ≤ 1.6 mg/dl

• Total bilirubin ≤ to 2.0 mg/dl, except in patients with Gilbert's Syndrome, whomust have a total bilirubin ≤ 3.0 mg/dl.

• Seronegative for HIV antibody, hepatitis B antigen, and hepatitis C antibody as testedwithin 3 months of beginning lymphodepleting chemotherapy. If hepatitis C antibodytest is positive, then patient must be tested for the presence of antigen by RT-PCRand be HCV RNA negative

• More than four weeks must have elapsed since the last dose of prior systemic therapyand the start of the lymphodepleting chemotherapy, and acute toxicities must haverecovered to Grade 1 or less (except for toxicities such as alopecia or vitiligo).

• Sexually active females of child-bearing potential and males with female partners ofchild-bearing potential must agree to use effective contraception for the duration ofstudy treatment starting with the 1st dose of fludarabine and for 4 months after thelast dose of aldesleukin. Examples of effective contraception includes an IUD orimplant plus a condom. Women of non-childbearing potential are defined as those whohave no uterus, ligation of the fallopian tubes, or permanent cessation of ovarianfunction due to ovarian failure or surgical removal of the ovaries. A woman also ispresumed to be infertile due to natural causes if she has been amenorrheic for > 12months and/or has an FSH > 40 IU/L.

• Negative pregnancy test within 7 days of starting lymphodepleting chemotherapy inwomen of childbearing potential.

• No change in medical status or social situation that would make study participationnot in the best interest of the patient in the opinion of the enrolling investigator.

• Continues to agree to remain in the Twin Cities metropolitan area (within 1 hour driveof the University of Minnesota) after the CISH KO TILs infusion through the End ofTreatment visit (Day 28)

• Voluntary signed the study treatment consent form within 28 days prior to the start ofthe lymphodepleting chemotherapy.