GUCY2C Prime-Boost Vaccination for Advanced Colorectal and Small Bowel Adenocarcinomas

Inclusion Criteria: * Individuals must meet all of the following inclusion criteria in order to be eligible to participate in the study: 1. Males or females aged ≥ 18 years 2. Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 3. Histologically or cytologically diagnosed, locally advanced or metastatic adenocarcinomas of colorectum or small bowel that have progressed after standard of care therapy or for which no standard therapy exists. Patients for whom standard therapies are intolerable or considered clinically inappropriate by the Investigator are eligible. If a patient refused available standard therapy or Investigator determined standard therapy was inappropriate, the reason for refusal or Investigator determination should be documented. 4. Patients with MSS CRC or small bowel adenocarcinoma must have received at least 1) a fluoropyrimidine, 2) oxaliplatin or irinotecan, and 3) a VEGF/VEGF receptor inhibitor unless deemed clinically inappropriate, refused by the patient, or not considered standard practice per institutional standards. 5. Patients with MSI-H and/or dMMR CRC or small bowel adenocarcinoma must have received a programmed death-1 or programmed death-ligand 1 (PD-L1) inhibitor unless deemed clinically inappropriate, refused by the patient, or not considered standard practice. 6. Have an anticipated life expectancy of greater than 12 weeks 7. Have at least 1 extracranial measurable tumor lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Exceptions may be made to this inclusion if a patient has biochemical evidence (ctDNA) of disease upon discussion with principal investigator provided other eligilbity criteria are fulfilled. 8. Adequate venous access by peripheral vein evaluation 9. Have adequate hematologic function at screening, as evidenced by: 1. ANC ≥ 1500 cells/mL; no growth factor support within 14 days prior to Screening assessment 2. Platelets ≥ 75,000 /mL; no transfusion within 14 days prior to Screening assessment 3. Hemoglobin ≥ 9.0 g/dL; no transfusion or erythyropoietin support within 14 days prior to Screening assessment. 10. Patients must have adequate hepatic function, as evidenced by: 1. Albumin ≥ 3.0 mg/dL; no albumin support within 14 days prior to Screening assessment, 2. Total bilirubin ≤ 2.0 x upper limit of normal (ULN), except in patients with congenital bilirubinemia, such as Gilbert syndrome (in which case direct bilirubin ≤ 1.5 x ULN is required) 3. Aspartate aminotransferase (AST) AND alanine aminotransferase ≤ 2.5 x ULN or ≤ 5 x ULN in the presence of liver metastases. 4. Serum creatinine \< 2.0 mg/dL 5. For other blood and urine tests including blood chemistry, hepatic and renal functions, test results should not be worse than grade 1 levels of abnormalities defined by CTCAE, NCI version 5 (CTCAEv5) issued by the US Department of Health and Human Services. 11. For women and men of childbearing potential, a medically acceptable method of highly effective contraception (oral hormonal contraceptive, condom plus spermicide, or hormonal implants) or abstinence must be used throughout the study period and for 28 days after their final vaccine administration. (A barrier method of contraception must be employed by all subjects \[male and female\], regardless of other methods unless abstinent.) A negative serum or urine pregnancy test is required as part of screening. Subjects capable of becoming pregnant include any female who has experienced menarche and has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) and who are not postmenopausal. Also, subjects assigned female sex at birth who are physiologically still able to become pregnant by similar definitions detailed here. Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes. In addition, women under the age of 55 must have a documented serum follicle stimulating hormone (FSH) level less than 40 mIU/ml. 12. Be willing to comply with all the study procedures. All subjects must be able to comprehend and sign a written informed consent document Exclusion Criteria: * An individual who meets any of the following criteria will be excluded from participation in this study: 1. History of splenectomy 2. History of infection with listeriosis or has prior serious reaction to adenovirus 3. Infection requiring systemic antibiotics within 1 week prior to administration of study intervention 4. Concurrent use of systemic steroids or immunosuppressive drugs (including TNF pathway inhibitors) with exceptions including: * Topical, ocular, intra-articular, intranasal, and inhalation corticosteroids (with minimal systemic absorption) * Adrenal replacement steroid dose \< 10 mg daily prednisone * A brief (fewer than three days) course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction cause by a contrast allergen) 5. Subjects who have implanted medical devices that pose high risks for colonization and cannot be easily removed (e.g., artificial heart valves, pacemakers, prosthetic joints, orthopedic screw(s), metal plate(s)). Chest wall infus-a-port catheter may be used for treatment administration and will not be subject to this exclusion. 6. Has any immunodeficiency disease or immunocompromised state (e.g., use of immunosuppressive agents including TNF pathway inhibitors, chemotherapy, PI3 kinase inhibitors or radiation therapy within four weeks of study treatment) 7. Has active or history of autoimmune disease (including inflammatory bowel disease), or is a transplant recipient requiring immunosuppressive treatment 8. Has received a diagnosis of HIV, hepatitis B, or hepatitis C (subjects who are hepatitis C positive may be enrolled if they are confirmed with negative viral load at screening) 9. Other malignancy within last 2 years except curatively treated non-melanomatous skin cancer and curatively treated carcinoma in situ (eg, cervix, bladder, breast), or prostate cancer in remission 10. Known active central nervous system metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are: 1. Radiologically stable, ie, without evidence of progression for at least 12 weeks by repeat imaging 2. Clinically stable per investigator assessment 3. Without requirement of steroid treatment for at least 14 days prior to first dose of study vaccine 11. Has an intercurrent illness that is either life-threatening or of clinical importance such that it might limit study compliance (such illnesses include, but are not limited to, ongoing or active infection, metabolic or neurologic disease, peripheral vascular disease, or psychiatric illness) 12. Has insufficient peripheral venous access to permit completion of the study phlebotomy regimen or infusion of study vaccine 13. Concurrent use of illicit drugs (e.g., opioids, cocaine, amphetamines, hallucinogens, etc.) that could potentially interfere with adherence to study procedures or requirements. 14. Be pregnant or breastfeeding 15. Toxicities from previous anti-cancer therapies that have not resolved to baseline levels or to grade 1 or less or baseline except for the following Grade 2 AEs that are considered chronic or irreversible: alopecia, peripheral neuropathy, endocrinopathies stable on therapy, and thromboembolic events stable on anticoagulation with no recurrence for \> 6 months. Other Grade 2 AEs may be permitted upon discussion with the PI if not otherwise specified in the protocol. 16. Are currently enrolled in an ongoing clinical trial or trial that could interfere with the protocol-specified requirements 17. There are no restrictions on concurrent or prior use of preventative vaccines for infectious diseases including influenza or COVID-19, however it is required to include at least one week interval between vaccines and study agent administration.