Phase 1b Study Of TRICK-NK In Combination With T-Dxd In Treatment-Refractory Breast Cancers

Inclusion Criteria: 1. Patients must have histologically confirmed breast cancer that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective. 2. Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for nonnodal lesions and short axis for nodal lesions) as ≥20 mm (≥2 cm) by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam. 3. Age ≥18 years. Because no dosing or adverse event data are currently available on the use of TRICK-NK cells in patients \<18 years of age, children are excluded from this study. 4. For patients with triple negative subtype (TNBC, ER\<1%, PR 1%, HER2 negative per ASCO/ CAP 2018 guideline), must have received at least one dose of Sacituzumab govitecan or anti-TROP2 antibody drug conjugate (ADC) 5. Patients must be at least 2 weeks from last cytotoxic chemotherapy, tyrosine kinase inhibitors or other targeted therapies at the time of administration of lymphodepleting chemotherapy. 6. Patients must be at least 3 months from any cell therapy for malignancy (this is not a criteria for repeated treatments). 7. Localized radiotherapy to 1 or more disease sites is allowed prior to the lymphodepleting chemotherapy, if there are additional measurable non-irradiated disease sites. 8. Eastern Cooperative Oncology Group performance status 0 or 1 (Performance level as measured by Karnofsky for patients \> 16 years of age, see Appendix A). 9. Adequate organ function at screening, as defined by the following: 10. Renal: Estimated glomerular filtration rate (Chronic Kidney Disease Epidemiology Collaboration equation) ≥50 ml/min/1.73 m2 11. Hepatic: alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 2.5 x upper limit of normal (ULN) or ≤ 5 x ULN if documented liver metastases, total bilirubin ≤ 1.5 mg/dL or ≤ 3.0 mg/dL for patients with Gilbert's Syndrome. No history of liver cirrhosis. Cardiac: Cardiac ejection fraction ≥ 50%, no clinically significant pericardial effusion as determined by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan, and no symptomatic cardiac disease or history of serious ventricular arrhythmia (ie, ventricular tachycardia or ventricular fibrillation), high-grade atrioventricular block, or other cardiac arrhythmias requiring anti-arrhythmic medications (except for atrial fibrillation that is well controlled with anti-arrhythmic medication) Pulmonary: No clinically significant pleural effusion (per principal investigator \[PI\] judgement), and baseline oxygen saturation ≥ 92% on room air. Subjects with active interstitial lung disease (ILD)/pneumonitis requiring treatment with systemic steroids will be excluded. Hematological: absolute neutrophil count (ANC) ≥ 1000/mm3, platelet count ≥ 75,000/mm3, and hemoglobin ≥ 8 g/dL. Coagulation: International normalized ratio (INR) ≤ 1.5 ULN and activated partial thromboplastin time (aPTT) ≤ 1.5 ULN. Patients on therapeutic doses of anticoagulation medication must have INR and/or aPTT ≤ the upper limit of the therapeutic range for intended use. 12. Able to provide written informed consent. 13. Weight ≥40 kg (due to safety of NK-cell). 14. A female patient is eligible to participate if at least one of the following conditions applies: a. Not a woman of childbearing potential (WOCBP) as defined in Appendix 5 OR 15. A WOCBP who agrees to follow the contraceptive guidelines in Appendix 5 during the study treatment period and for 6 months post-TROP2 CAR/IL-15 TGFBR2 KO NK cell infusion. WOCBP must have a negative urine pregnancy test within 72 hours prior to the start of lymphodepleting chemotherapy. If a WOCBP has a urine pregnancy test that cannot be confirmed as negative, a serum (beta-human chorionic gonadotropin \[β-hCG\]) pregnancy test will be required. The effects of TROP2 CAR/IL-15 TGFBR2 KO NK cells on the developing human fetus are unknown. Radiation therapy is absolutely contraindicated in pregnant women. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. (Refer to Pregnancy Assessment Policy MD Anderson Institutional Policy # CLN1114). This includes all female patients, between the onset of menses (as early as 8 years of age) and 55 years unless the patient presents with an applicable exclusionary factor which may be one of the following: * Postmenopausal (no menses in greater than or equal to 12 consecutive months). * History of hysterectomy or bilateral salpingo-oophorectomy. * Ovarian failure (Follicle Stimulating Hormone and Estradiol in menopausal range, who have received Whole Pelvic Radiation Therapy). * History of bilateral tubal ligation or another surgical sterilization procedure. 16. Approved methods of birth control are as follows: Hormonal contraception (i.e. birth control pills, injection, implant, transdermal patch, vaginal ring), Intrauterine device (IUD), Tubal Ligation or hysterectomy, Subject/Partner post vasectomy, Implantable or injectable contraceptives, and condoms plus spermicide. Not engaging in sexual activity for the total duration of the trial and the drug washout period is an acceptable practice; however periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. 17. Male patients treated or enrolled on this protocol must agree to follow the contraceptive guidelines in Appendix 5 prior to study entry and for the duration of study participation and for 6 months post-TROP2 CAR/IL-15 TGFBR2 KO NK cell infusion. Male patients who father a child or suspect that they have fathered a child must immediately notify their doctor. 18. Willing to undergo mandatory blood collections and biopsies as required by the study. 19. Willing to sign consent for long-term follow-up on protocol PA17-0483. 20. Willing to stay within a 2-hour drive (approximately 100-mile radius) of the study site during the first 4 weeks after the TROP2 CAR/IL-15 TGFBR2 KO NK cell infusion. Exclusion Criteria: Patients who meet any of the following criteria will be excluded from study entry: 1. Presence of clinically significant ongoing Grade ≥ 2 toxicity unequivocally associated with the previous anticancer treatment, as determined by the PI. Toxicities related to prior surgery, radiation, prior systemic immune checkpoint inhibitors and chemotherapy should be resolved to Grade 1 or below prior to lymphodepletion. 2. Presence of fungal, bacterial, viral, or other infection requiring IV antimicrobials for management or not responding to appropriate therapy. Note: Patients with simple urinary tract infection and uncomplicated bacterial pharyngitis are permitted if responding to active treatment. 3. Known active hepatitis B or C. 4. Known human immunodeficiency virus (HIV). 5. Presence of active neurological disorder(s). 6. Active autoimmune disease within 12 months of enrollment (excluding low-grade psoriasis or well-controlled autoimmune thyroid disease). 7. Amyloidosis or POEMS syndrome. 8. Symptomatic or uncontrolled central nervous system involvement or signs of cord compression. In the case radiation therapy is indicated, the washout must be at least 14 days. 9. Patients must not have any other malignancies within the past 2 years except for in situ carcinoma of any site, adequately treated (without recurrence post resection or post radiotherapy) carcinoma of the cervix or basal or squamous cell carcinomas of the skin, or active non-life-threatening second malignancy that would not, in the investigator's opinion, potentially interfere with the patient's ability to participate and/or complete this trial. Examples include but are not limited to urothelial cancer Grade Ta or T1 and adenocarcinoma of the prostate treated by active surveillance. 10. Presence of any other serious medical condition that may endanger the patient at investigator's discretion, including but not limited to: 11. New York Heart Association Class III or IV heart failure 12. Myocardial infarction or stroke ≤ 26 weeks prior to CAR NK cell infusion 13. Unstable angina within ≤ 13 weeks prior to CAR NK cell infusion unless the underlying disease has been corrected by procedural intervention (e.g., stent, bypass) 14. Severe aortic stenosis 15. Uncontrolled arrhythmia. PI approval is required for patients with arrhythmia who may be included as an exception. 16. Congenital long QT syndrome. PI approval is required. 17. Documentation, during the screening process, of a QTc \> 470 milliseconds by Fredericia criteria (QTcF) based on the average of 3 electrocardiograms (ECGs) taken approximately 1 minute apart and all within 10 minutes of each other. The patient should be reclining for 5 minutes prior to ECGs. Local readings may be used for this exclusion criterion. 18. Major surgery \< 4 weeks prior to first dose of lymphodepleting chemotherapy. 19. Concomitant use of other investigational agents. 20. Concomitant use of other anticancer agents. 21. Patients receiving systemic steroid therapy at time of enrollment, with an exception for topical, ocular, intranasal, and inhaled corticosteroids, or systemic corticosteroids at an equivalent dose ≤ 10 mg of prednisone daily (physiological substitutive doses are allowed). 22. Received anti-thymocyte globulin within 14 days or alemtuzumab within 28 days of enrollment. 23. Patients receiving immunosuppressive therapy. 24. Pregnant or breastfeeding. 25. Has received a live vaccine within 6 weeks prior to CAR NK cell infusion. 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, and typhoid vaccine. Seasonal influenza and COVID-19 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.