A Phase II Study of Adjuvant Immunotherapy Targeting KRAS G12D, KRAS G12V, or TP53 R175H for Participants With Advanced Gastrointestinal Malignancies

* INCLUSION CRITERIA:
* Resected pancreas ductal adenocarcinoma (PDAC):

  * Resected pancreas ductal adenocarcinoma
  * If stage I-III has a history of detectable circulating tumor DNA (ctDNA) after resection/local treatment of all known disease.

OR

--If stage I-III, have a history of abnormally elevated cancer antigen (CA)19-9 at diagnosis (before surgery) AND a history of abnormally elevated post-operative CA19-9 measured at least 30 days after surgery AND a history of the relative increase of postoperative CA19-9 of 2.6-fold or more compared to the participant s post-operative baseline, as confirmed by two separate tests at least 3 weeks apart.

OR

* Had metastatic disease (stage IV) at diagnosis and were down staged with chemotherapy and underwent resection.

  -Colorectal liver, lung, and/or lymph node metastases (CRLM):
* Participants with stage IV colorectal cancer with metastases to the liver, lung, and/or lymph nodes that were completely treated with local therapy (resection, ablation, and/or radiotherapy).
* Must have a history of detectable ctDNA after resection/local treatment of all known disease.

  -Gastrointestinal carcinoma (GIC):
* Participants with resected gastroesophageal cancer, hepatocellular cancer, cholangiocarcinoma, duodenal, small bowel, or primary colorectal cancer (i.e., pathologic stage I-III as distinguished from CRLM).
* Must have a history of detectable ctDNA after resection/local treatment of all known disease.

  * Confirmation of diagnosis of cancer by the NCI Laboratory of Pathology (LP).
  * Must have a history of:
* KRAS G12D mutation plus HLA-A\*11:01

OR

--KRAS G12D mutation plus HLA-C\*08:02

OR

--KRAS G12V mutation plus HLA-C\*01:02

OR

* TP53 R175H mutation plus HLA-A\*02:01.

  -Treated with standard systemic and/or radiotherapy if indicated unless participant refusal or non-tolerance of the standard regimen. For example:
* Participants with PDAC should receive neoadjuvant or adjuvant chemotherapy (5-FU or gemcitabine-based).
* Participants with CRLM should have received at least one line of 5FU-based chemotherapy (i.e., FOLFOX or FOLFIRI).
* Participants with resected stage III colon cancer should have received 5FU-based adjuvant therapy (i.e., FOLFOX or FOLFIRI).

  * CRLM only: Participants with a history of brain metastases that have been treated with stereotactic radiosurgery or resection must be clinically stable for 3 months after treatment to be eligible.
  * Age \>= 18 years and \<= 72 years.
  * Clinical performance status of ECOG 0 or 1
  * Individuals of child-bearing potential (IOCBP) must agree to use highly effective contraception (hormonal, intrauterine device \[IUD\], abstinence, surgical sterilization) at the study entry and up to and 12 months after the last dose of combined chemotherapy. Individuals that can father children must agree to use an effective method of contraception (barrier, surgical sterilization, abstinence) at the study entry and up to 4 months after the last dose of study drugs. We also will recommend individuals that can father children with partners that can bear children ask their partners to be on highly effective birth control (hormonal, IUD, surgical sterilization). Individuals that can father

children must not freeze or donate sperm within the same period.

NOTE: IOCBP is defined as any female who has experienced menarche and who has not undergone successful surgical sterilization or who is not postmenopausal.

* Breastfeeding participants must be willing to discontinue breastfeeding from study treatment initiation through 4 months after the last dose of the study drug(s).
* Viral testing

  * Seronegative for human immunodeficiency virus (HIV) antibody.
  * Negative for hepatitis B (HBV) surface antigen (HbsAg), and seronegative for hepatitis C (HCV) antibody. If the HCV antibody test is positive, then the participant must be tested for the presence of antigen by RT-PCR and be HCV RNA negative to be eligible.
* Hematology

  * Absolute neutrophil count (ANC) \> 1000/mm\^3 without the support of filgrastim
  * White blood cells (WBC) \>= 2500/mm\^3
  * Platelet count \>= 80,000/mm\^3
  * Hemoglobin \> 8.0 g/dL.
* Chemistry

  * Alanine aminotransferase (ALT) \<= 5.0 x upper limit of normal (ULN)
  * Aspartate aminotransferase (AST) \<= 5.0 x ULN
  * Creatinine \<= 1.6 mg/dL
  * Total bilirubin \<= 2.0 mg/dL, except in participants with Gilbert s Syndrome, who must have a total bilirubin \< 3.0 mg/dL.
* Four weeks must have passed after any prior systemic therapy for cancer, any investigational agents, surgical procedures, or limited field radiotherapy prior to randomization, as long as related major organ toxicities have recovered to grade 1 or less per Common Terminology Criteria for Adverse Events (CTCAE) v.5.0.

NOTE: Participants with adverse events Grade 2 that are deemed irreversible and stable and will not prevent administration of the study drug(s)/intervention or prevent compliance with the study requirements (e.g., alopecia, peripheral neuropathy, laboratory parameters not

otherwise specified per the eligibility criteria) are an exception to this criterion and are eligible.

* Ability of the participant to understand and the willingness to sign a written informed consent document.
* Willing to sign a durable power of attorney.
* Participants must be co-enrolled on protocols 03-C-0277 (Cell Harvest and Preparation for Surgery Branch Adoptive Cell Therapy Protocols), and 09-C-0161 (Follow-up Protocol for Subjects Previously Enrolled on NCI Surgery Branch Studies).

EXCLUSION CRITERIA:

* Unequivocal radiographic evidence of residual tumor.
* Participants with measurable disease per RECIST v1.1 criteria.
* Any form of secondary immunosuppression.
* Active or chronic infections requiring anti-microbial, anti-fungal, or anti-viral treatment.
* Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease and Acquired immunodeficiency syndrome \[AIDS\]).
* History of major organ autoimmune disease.
* History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine, or aldesleukin.
* History of coronary revascularization or ischemic symptoms.
* Left ventricular ejection fraction (LVEF) \<= 45% for participants with a clinical history prompting cardiac evaluation (e.g., participants who are \>= 65 years of age, or who have a history of ischemic heart disease, chest pain, or clinically significant atrial and/or ventricular arrhythmias, including but not limited to atrial fibrillation, ventricular tachycardia, heart block OR Participants \< 65 years of age with cardiac risk factors \[e.g., diabetes, hypertension, obesity\]).
* Forced expiratory volume in the first second (FEV1) \<= 50% predicted for participants with a clinical history prompting pulmonary evaluation (e.g., a prolonged history of cigarette smoking \[\>= 20 pack-year smoking history within the past two years\], symptoms

of respiratory dysfunction, thoracic surgeries, or other clinical indications).

* Positive beta-human chorionic gonadotropin (beta-HCG) serum or urine pregnancy test performed in IOCBP at screening.
* Uncontrolled intercurrent illness evaluated by medical history and physical exam that are not stable and would potentially increase the risk to the participant.