A Study of Metastatic Gastrointestinal Cancers Treated With Tumor Infiltrating Lymphocytes in Which the Gene Encoding the Intracellular Immune Checkpoint CISH Is Inhibited Using CRISPR Genetic Engineering

Inclusion Criteria:

* 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 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.
* Age ≥ 18 years and ≤ 70 years.
* Clinical performance status of ECOG 0 or 1.
* Serology testing within 3 months of study enrollment (tumor collection):

  * Seronegative for HIV antibody. (The investigational treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immunocompetence 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 RT-PCR and be HCV RNA negative.
  * Seronegative for anti-HBc, HBV/HCV/HIV-1 NAT, anti-HTLV-I/II, anti-T.cruzi, West Nile Virus NAT, anti-CMV, and RPR. (Note: Other blood viral testing may be required as updated on the FDA website: https://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/TissueSafety/ucm095440.htm#approved)
* Hematology within 14 days of study enrollment:

  * Absolute neutrophil count \> 1000/mm\^3 without the support of filgrastim
  * WBC ≥ 3000/mm\^3
  * Platelet count ≥ 75,000/mm\^3
  * Hemoglobin \> 8.0 g/dl. Subjects may be transfused to reach this cutoff.
* 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, who must have a total bilirubin ≤ 3.0 mg/dl.
* 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

Exclusion Criteria:

* 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 FSH ≤ 40 IU/L) must have a negative pregnancy test (serum or urine) within 7 days of enrollment. A repeat negative pregnancy test is required within 7 days of beginning the preparative chemotherapy.
* 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 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 PI would compromise the 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 the past 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 study treatment, the following eligibility criteria must be met:

* Clinical performance status of ECOG 0 or 1
* Hematology within 7 days of starting lymphodepleting chemotherapy:

  * Absolute neutrophil count \> 1000/mm\^3 without the support of filgrastim
  * WBC ≥ 3000/mm\^3
  * Platelet count ≥ 100,000/mm\^3
  * Hemoglobin \> 8.0 g/dl. Subjects may be transfused to reach this cutoff.
* 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, who must have a total bilirubin ≤ 3.0 mg/dl.
* Seronegative for HIV antibody, hepatitis B antigen, and hepatitis C antibody as tested within 3 months of beginning lymphodepleting chemotherapy. 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
* More than four weeks must have elapsed since the last dose of prior systemic therapy and the start of the lymphodepleting chemotherapy, and acute toxicities must have recovered 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 of child-bearing potential must agree to use effective contraception for the duration of study treatment starting with the 1st dose of fludarabine and for 4 months after the last dose of aldesleukin. Examples of effective contraception includes an IUD or implant plus a condom. Women of non-childbearing potential are defined as those who have no uterus, ligation of the fallopian tubes, or permanent cessation of ovarian function due to ovarian failure or surgical removal of the ovaries. A woman also is presumed to be infertile due to natural causes if she has been amenorrheic for \> 12 months and/or has an FSH \> 40 IU/L.
* Negative pregnancy test within 7 days of starting lymphodepleting chemotherapy in women of childbearing potential.
* No change in medical status or social situation that would make study participation not 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 drive of the University of Minnesota) after the CISH KO TILs infusion through the End of Treatment visit (Day 28)
* Voluntary signed the study treatment consent form within 28 days prior to the start of the lymphodepleting chemotherapy.