The goal of this clinical research study is to study the recommended dose of TROP2 CAR/IL-15 TGFBR2 KO NK cells that can be given intraperitoneally (infused directly into the stomach area) to participants with adenocarcinoma of the stomach that has spread to the peritoneum. The safety and effectiveness of this treatment will also be studied.

Primary Objectives:

To determine the safety, MTD, and RP2D of TROP2 CAR/IL-15 TGFBR2 KO NK cells delivered intraperitoneally and define the MTD/RP2D.

Endpoints

1. Dose-limiting toxicity
2. MTD and RP2D of TROP2 CAR/IL-15 TGFBR2 KO NK cells

Secondary Objectives:

1. To estimate median overall survival.
2. To quantify persistence of infused allogeneic donor CAR-transduced CB-derived NK cells in the peripheral blood and peritoneal cavity in the recipient.
3. To profile and assess the dynamic changes in the peritoneal tumor microenvironment before and after treatment using single-cell transcriptional and immune profiling on peritoneal cells before and after treatment.
4. To compare changes in circulating tumor DNA (ctDNA) with response as determined by the peritoneal carcinomatosis index

Endpoints

1. Median overall survival
2. TROP2 CAR/IL-15 TGFBR2 KO NK cells numbers in peripheral blood and peritoneal cavity vs time profile
3. Characterization of lymphocyte populations before and after treatment
4. Plasma ctDNA concentration and peritoneal carcinomatosis index at baseline and after treatment

Although the clinical benefit of this treatment has not yet been established, the intent of offering this treatment is to provide a possible therapeutic benefit, and thus the patient will be carefully monitored for tumor response in addition to safety and tolerability

Inclusion Criteria:

1. Subjects must be 18 years or older. Because no dosing or adverse event data are currently available on the use of CAR NK cells in combination with our standard of care approaches of cytoreductive surgery with intraperitoneal chemotherapy in patients <18 years of age, children are excluded from this study.

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

3. Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

4. A female participant is eligible to participate if at least one of the following conditions applies:

   1. Not a woman of childbearing potential (WOCBP) as defined in Appendix 1 OR
   2. A WOCBP who agrees to follow the contraceptive guidelines in Appendix 1 during the treatment period and for at least 3 months after the last dose of study treatment.

5. Subjects must have histology confirming diagnosis of adenocarcinoma of the stomach or gastroesophageal junction with pathology reviewed at MD Anderson Cancer Center.

6. Subjects must have histology confirming diagnosis of Stage IV adenocarcinoma of the stomach or gastroesophageal junction metastatic to the peritoneum based on either positive cytology (peritoneal washings/ascites) or peritoneal biopsy, with pathology reviewed at MD Anderson Cancer Center. Ovarian metastases are considered peritoneal metastases. Disease outside the peritoneal cavity is allowed as long as metastases are present within the peritoneal cavity.

7. Subjects must be at least 4 weeks from last cytotoxic chemotherapy at the time of starting lymphodepleting chemotherapy. Zolbetuximab may be continued during the peritoneal-directed treatment and NK cell therapy.

8. Subjects must be willing and able to undergo a minimally invasive staging cytoreductive surgery with intraperitoneal port placement and scheduled peritoneal fluid and peripheral blood draws.

9. Subjects must have adequate organ function as defined in the following table (Table 1).

Specimens must be collected within 10 days prior to the start of study treatment.

Exclusion Criteria:

1. Pregnant, breastfeeding, or expecting to conceive within the projected duration of the study, starting with the screening visit through 3 months after the last dose of trial treatment. WOCBP must have a negative serum pregnancy test within 72 hours of admission prior to lymphodepleting chemotherapy (see Appendix 1).
2. Has received systemic anti-cancer therapy including investigational agents within 4 weeks of starting lymphodepleting chemotherapy.
3. If a participant received previous systemic or targeted therapy, immunotherapy, or major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment. In patients receiving standard of care zolbetuximab, this therapy may be continued.
4. Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-central nervous system (CNS) disease.
5. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
6. Is currently receiving another investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention. Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
7. Diagnosis of immunodeficiency or receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
8. Known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention.
9. Active autoimmune disease that has required systemic treatment in the past 2 months (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is allowed.
10. History of interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
11. Serious active infection, as determined by Principal Investigator or treating physician, requiring intravenous systemic therapy.
12. Known history of uncontrolled Human Immunodeficiency Virus (HIV) infection. Patients with HIV infection and undetectable viral load may participate.
13. Known history of chronic Hepatitis B or Hepatitis C virus infection.
14. Known history of active TB (Bacillus Tuberculosis).
15. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
16. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
17. Has had an allogenic tissue/solid organ transplant.
18. Clinically significant cardiovascular disease within 12 months from first dose of study intervention, including New York Heart Association (NYHA) Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular event, or cardiac arrhythmia associated with hemodynamic instability. Note: medically controlled arrhythmia would be permitted.
19. Bleeding or thrombotic disorders or subjects at risk for severe hemorrhage. Subject with known deep vein thrombosis/pulmonary embolism that are under appropriate anti-coagulation treatment are eligible.
20. Radiographic distribution of disease that in the investigator's opinion would impart excessive risk to participation in this protocol.
21. Active peritonitis or diverticulitis.
22. Medical or surgical history that in the treating physician's opinion would make the subject not a suitable candidate for intraperitoneal therapy. Examples would include surgically documentedextensive intraperitoneal adhesions or large volume ascites.
23. History of severe hypersensitivity reaction with biologic therapy (e.g. monoclonal antibodies)