Dose Escalation and Expansion Study of TROP2 CAR Engineered IL-15- Transduced Cord Blood-derived NK Cells in Combination With Cetuximab in Patient With Colorectal Cancer (CRC) With Minimal Residual Disease (MRD)

Inclusion Criteria:

1. Participants must be 18 years or older.

2. Participants must be willing and able to provide informed consent.

3. Willing and able to comply with clinical trial instructions and requirements.Individuals lacking the ability, based on reasonable medical judgment, to understandand appreciate the nature and consequences of participation in this study will notbe eligible for participation.

4. In both the dose escalation and dose expansion cohorts, participants must havedocumented colorectal cancer (CRC) with MRD following complete disease resectionfollowed by standard-of-care adjuvant treatment. MRD is defined as NO evidence ofradiological disease (including patients with undefinable lesion with max diameter <1 cm or with a short axis < 1cm for lymph nodes) and presence of circulating ctDNAin the bloodstream.

5. Participants must have an Eastern Cooperative Oncology Group (ECOG) performancestatus of 0 or 1 (Appendix 3).

6. Life expectancy > 3 months.

7. A female patient is eligible to participate if at least one of the followingconditions applies:

• Not a woman of childbearing potential (WOCBP) as defined in Appendix 4 OR

• A WOCBP who agrees to follow the contraceptive guidelines in Appendix 4 duringthe study treatment period and for 6 months post TROP2-CAR-NK cell infusion.

8. Female participants who become pregnant or suspect pregnancy must immediately notifytheir doctor. Females' participants who become pregnant will be taken off study.

9. Male participants must agree to follow the contraceptive guidelines in Appendix 4during the study treatment period and for 6 months post TROP2-CAR-NK cell infusion.Male participants who father a child or suspect that they have fathered a child mustimmediately notify their doctor.

10. WOCBP must have a negative urine pregnancy test within 72 hours prior to the startof lymphodepleting chemotherapy. If a WOCBP has a urine pregnancy test that cannotbe confirmed as negative, a serum (beta-human chorionic gonadotropin [â-hCG])pregnancy test will be required.

11. Participants must have adequate organ function as defined below (Table 1) within 10days prior to the start of lymphodepleting chemotherapy: Table 1. Adequate Organ Function Laboratory Values Systemic Function Test LaboratoryValue Hematologic ANC = ≥1500/ƒÊL Platelets = ≥100,000/ƒÊL Hemoglobin = ≥9.0 g/dLaRenal CrCl by Cockcroft-Gault formula = ≥45 mL/min for patients with creatinine >1.5x ULNb Hepatic Total bilirubin = ≤1.5 x ULN OR direct bilirubin ≤ULN for patientswith total bilirubin levels >1.5 x ULN AST and ALT = ≤2.5 x ULN (≤5 x ULN forpatients with history of resected liver metastases) Coagulation PT/INR aPT = ≤1.5 xULN unless patient is receiving anticoagulant therapy as long as PT or aPTT iswithin therapeutic range

12. Left ventricular ejection fraction >50%. Of note, those patients with risk factorsand/or with LVEF <55% additional testing may need to be performed as perinstitutional guidelines and/or PI guidance.

13. Adequate respiratory reserve defined as dyspnea Grade 0 or 1 and saturated oxygen >92% in room air.

14. Willing to undergo mandatory blood collections and biopsies as required by thestudy.

15. Willing to stay within a 2-hour drive (approximately 100-mile radius) of the studysite during the first 4 weeks after the TROP2-NK cell infusion.

Exclusion Criteria:

1. Participants with known active disease by RECIST v1.1.

2. Pregnant, breastfeeding, or expecting to conceive within the projected duration ofthe study, starting with the screening visit through 6 months post TROP2-CAR-NK cellinfusion.

3. Has received systemic anticancer therapy within 2 weeks or 3 half-lives, whicheveris shorter, prior to the start of lymphodepleting chemotherapy. For patients treatedwith monoclonal antibodies, at least 3 weeks must have elapsed prior to the start oflymphodepleting chemotherapy. Participants who have entered the follow-up phase ofan investigational study may participate as long as it has been 3 weeks after thelast dose of the previous investigational agent.

4. Participants must have recovered from all AEs due to previous therapies to . Grade 1or baseline. Participants with ≤ Grade 2 neuropathy, alopecia, or other non-relevantAEs may be deemed eligible at the discretion of the principal investigator (PI). Ifa participants received major surgery, they must have recovered adequately from thetoxicity and/or complications from the intervention prior to the start oflymphodepleting chemotherapy.

5. Has received prior radiotherapy within 2 weeks of the start of lymphodepletingchemotherapy. Participants must have recovered from all radiation-relatedtoxicities, not require corticosteroids, and not have had radiation pneumonitis orcolitis.

6. Has received a live vaccine within 6 weeks prior to TROP2-CAR-NK infusion and for atleast 24 months post infusion. Examples of live vaccines include, but are notlimited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox),yellow fever, rabies, Bacillus Calmette. Guerin, and typhoid vaccine. Seasonalinfluenza and COVID-19 vaccines for injection are generally killed virus vaccinesand are allowed; however, intranasal influenza vaccines (e.g., FluMistR) are liveattenuated vaccines and are not allowed.

7. Prior genetically modified T or NK cell therapy.

8. Has diagnosis of immunodeficiency or receiving chronic systemic steroid therapy (indoses exceeding 10 mg daily of prednisone equivalent).

9. History of a second malignancy, unless potentially curative treatment has beencompleted with no evidence of malignancy for 2 years. The time requirement does notapply to patients who underwent successful definitive resection of basal cellcarcinoma of the skin, squamous cell carcinoma of the skin, superficial bladdercancer, in situ cervical cancer, or other in situ cancers.

10. Active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressivedrugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroidreplacement therapy for adrenal or pituitary insufficiency, etc.) is allowed.

11. History of interstitial lung disease (ILD) that required steroids or has currentpneumonitis/ILD.

12. Active infection requiring systemic therapy.

13. Known human immunodeficiency virus (HIV) infection.

14. Known active or chronic hepatitis B or hepatitis C virus infection.

15. Known history of active tuberculosis (Mycobacterium Tuberculosis).

16. History or current evidence of any condition, therapy, or laboratory abnormalitythat might confound the results of the study, interfere with the participant'sparticipation for the full duration of the study, or is not in the best interest ofthe participants to participate, in the opinion of the treating investigator.

17. Known psychiatric or substance abuse disorders that would interfere with cooperationwith the requirements of the study.

18. Has had an allogenic tissue/solid organ transplant.

19. Clinically significant cardiovascular disease within 12 months prior to the start oflymphodepleting chemotherapy, including New York Heart Association Class III or IVcongestive heart failure, unstable angina, myocardial infarction, cerebrovascularevent, or cardiac arrhythmia associated with hemodynamic instability. NOTE:medically controlled arrhythmia would be permitted if meet criteria per Appendix X.

20. Prolongation of corrected QT interval using Fridericia's formula to >480milliseconds, unless cleared after cardiology evaluation.

21. Participant with bleeding or thrombotic disorders or at risk for severe hemorrhage.Participants with known deep vein thrombosis/pulmonary embolism who are onappropriate anti-coagulation treatment are eligible.