Phase 1 Study Of TROP2 CAR/IL-15 TGFBR2 KO NK Cell In Patients With Oral Premalignant Lesions

Phase 1 Dose Escalation And Expansion Study Of Intralesional TROP2-CAR/ IL15 TGFBR2 KO Engineered Cord Blood-Derived NK Cells In Patients With Diffused Or Multifocal Oral Premalignant Lesions

This is a phase 1, single-arm, open-label, dose-escalation and dose-expansion study designed to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of TGFBR2 TROP2 CAR/IL15 NK cells in patients with high-risk oral premalignant lesions.

Primary Objective:

• To characterize the safety and tolerability of TROP2 CAR/IL15 TGFBR KO NK cells in patients with high-risk oral premalignant lesions.

Secondary Objectives:

• To determine the antitumor activity of TROP2 CAR/IL15 TGFBR KO NK cells.
• To quantify the persistence of infused allogeneic donor CAR-transduced CB-derived NK cells in recipient.
• To conduct comprehensive immune correlative studies by evaluating tissue and bloodbased biomarkers associated with response and resistance to TROP2 CAR/IL-15 TGFBR2 KO NK cell injection in part using longitudinal paired biopsies obtained at preinjection, Week 2, and Week 8 post-injection.
• To obtain preliminary data on quality of life and patient experience.

Inclusion Criteria:

1. Subjects with diffuse or multifocal oral premalignant lesions are eligible for this study and must have a confirmed histologic diagnosis of oral epithelial dysplasia or oral intraepithelial neoplasia. Diffuse disease is defined as a single lesion measuring 2 cm in greatest dimension, and multifocal disease is defined as the presence of two or more spatially distinct premalignant lesions within the oral cavity. Patients with a history of histologically confirmed head and neck squamous cell carcinoma, including oral cavity squamous cell carcinoma, are eligible provided there is no evidence of active invasive malignancy at the time of enrollment. For patients without a prior history of oral cavity squamous cell carcinoma, eligible lesions must demonstrate high-risk histology, including moderate dysplasia, severe dysplasia, or carcinoma in situ; in patients with a prior history of oral cavity squamous cell carcinoma, dysplasia of any grade identified on prior resection specimens or surveillance biopsies is acceptable. Histologic evidence of oral epithelial dysplasia identified on prior oral cancer resection specimens or surveillance biopsies is acceptable. A visible, clinically measurable oral lesion, such as leukoplakia, erythroplakia, or other clinically apparent premalignant mucosal abnormality, must be present and accessible for intralesional injection and clinical assessment.

2. Age ≥18 years

3. Patient tumors must demonstrate TROP2 expression of 1+ as determined by IHC at the MDACC CAP and CLIA accredited Clinical Laboratories

4. ≥2 weeks from the last cytotoxic chemotherapy, ≥3 days from last TKI or other targeted therapies, and ≥3 months from any cell therapy for any malignancy at the time of consent.

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

6. Life expectancy ≥3 months per PI or treating physician's discretion.

7. Women of childbearing potential (WOCBP) must have a negative urine pregnancy test within 72 hours prior to initiation of lymphodepleting chemotherapy. If the urine pregnancy test cannot be confirmed as negative, a serum β-hCG test must be performed and must be negative prior to treatment initiation.

   1. A WOCBP is defined (in Appendix 1) as a female who has experienced menarche (as early as 8 years of age) and has not undergone successful surgical sterilization or is not postmenopausal (defined as ≥12 consecutive months of amenorrhea without an alternative medical cause). Women will be considered not of childbearing potential if they have undergone hysterectomy, bilateral salpingo-oophorectomy, bilateral tubal ligation, or other permanent sterilization procedures, or have ovarian failure with follicle-stimulating hormone (FSH) and estradiol levels in the menopausal range, including those who have received whole pelvic radiation therapy. Due to the unknown effects of TROP2 CAR/IL-15 TGFBR2 KO NK cell therapy on a developing fetus, and because radiation therapy is contraindicated during pregnancy, women of childbearing potential and male participants with partners of childbearing potential must agree to use effective contraception prior to study entry, for the duration of study participation, and for 6 months following TROP2 CAR/IL-15 TGFBR2 KO NK cell injection. Acceptable methods of contraception include hormonal contraceptives (oral, injectable, implantable, transdermal, or vaginal ring), intrauterine devices (IUDs), surgical sterilization (tubal ligation or hysterectomy), partner vasectomy, or barrier methods (e.g., condoms) used with spermicide. Complete abstinence is acceptable if consistent with the participant's lifestyle; however, periodic abstinence, the rhythm method, and withdrawal are not acceptable.
   2. Participants must agree to notify the treating physician immediately if pregnancy is suspected or confirmed during the study. Male participants must also notify the investigator if they father a child during the study period.

8. Male patients treated or enrolled on this protocol must agree to follow the contraceptive guidelines in Appendix 1 prior to study entry and for the duration of study participation and for 6 months post-TROP2 CAR/IL-15 TGFBR2 KO NK cell injection.

9. Patients must have measurable disease as defined above in 4.1.1. Patients must have adequate organ function as defined below Table 1. Adequate Organ Function Laboratory Values Systemic Function Test Laboratory Value Hematologic ANC ≥1500/µL Platelets ≥100,000/µL Hemoglobin ≥9.0 g/dLa Renal Creatinine ≤1.5 × ULNb OR CrCl by Cockcroft-Gault ≥45 mL/min for patients with creatinine formula >1.5 × ULNb Hepatic Total bilirubin ≤1.5 × ULN OR direct bilirubin ≤ ULN for patients with total bilirubin levels >1.5 × ULN AST and ALT ≤2.5 × ULN (≤5 × ULN for patients with liver metastases) Coagulation PT/INR ≤1.5 × ULN unless patient is receiving aPTT anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants ALT=alanine aminotransferase; ANC=absolute neutrophil count; aPTT=activated partial thromboplastin time; AST=aspartate aminotransferase; CrCl=creatinine clearance; INR=international normalized ratio; PT=prothrombin time; ULN=upper limit of normal.

   1. Criteria must be met without erythropoietin dependency (and without packed red blood cell transfusion within last 2 weeks of the screening test) defined as an initiation or dose increase within 12 weeks prior to screening.Patients on a stable dose for >/= 12 weeks are permitted...
   2. Serum creatinine and CrCl should be interpreted and calculated per institutional standard.

10. Left ventricular ejection fraction >50%.

11. Adequate respiratory reserve defined as dyspnea Grade 0 or 1 and saturated oxygen >92% in room air. See Table 2 for a grading scale of dyspnea per the CTCAE v6.0.

    Table 2. Dyspnea grading scale. Grade 0 - No shortness of breath Grade 1 - Shortness of breath with moderate exertion Grade 2 - Shorness of breath with minimal exertion; limiting instrumental ADL Grade 3 - Shortness of breath at rest; liniting self-care ADL Grade 4 - Life-threatening consequences; urgent intervention indicated Grade 5 - Death

12. Prior treatment with TROP2-targeted therapy will be allowed.

13. Willing to undergo mandatory blood collections and biopsies as required by the study.

14. Willing to sign consent for long-term follow-up on protocol PA17-0483.

15. 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 injection.

16. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.

17. Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better.

18. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1. Pregnant, breastfeeding, or expecting to conceive within the projected duration of the study, starting with the screening visit through 6 months post TROP2 CAR/IL-15 TGFBR2 KO NK cell injection.
2. Patients must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline.
3. Patients with ≤Grade 2 neuropathy, alopecia, or other non-relevant AEs may be deemed eligible at the discretion of the principal investigator (PI)/co-PIs. If a patient received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to the start of lymphodepleting chemotherapy.
4. If patients receive RT within 2 weeks of the start of treatment, they must not require corticosteroids and must not have had radiation pneumonitis. Of note, patients with prior RT to the esophagus or with RT plans predicted to expose the esophagus to RT are excluded.
5. Has received a live vaccine within 6 weeks prior to TROP2 CAR/IL-15 TGFBR2 KO NK injection and agrees to not receive live vaccine for at least 24 months post-injection. 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.
6. Prior CAR T or NK cell or other genetically modified T or NK cell therapy.
7. Receiving chronic systemic steroid therapy (in doses exceeding 10 mg daily of prednisone equivalent).
8. Known active CNS metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate if they completed radiation therapy, are clinically stable, and without requirement of steroid treatment for at least 2 weeks prior to study enrollment.
9. History of interstitial lung disease (ILD) that required steroids or has current pneumonitis/ILD.
10. Active infection requiring systemic therapy.
11. Known human immunodeficiency virus (HIV) infection.
12. Known active or chronic hepatitis B or hepatitis C virus infection.
13. Known history of active tuberculosis (Mycobacterium tuberculosis).
14. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating investigator.
15. Clinically significant cardiovascular disease within 12 months prior to the start of lymphodepleting chemotherapy, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebrovascular event, or cardiac arrhythmia associated with hemodynamic instability. NOTE: medically controlled arrhythmia would be permitted.
16. Patients with bleeding or thrombotic disorders or at risk for severe hemorrhage. Patients with known deep vein thrombosis/pulmonary embolism who are on appropriate anticoagulation treatment are eligible.
17. Patients with a history of ≥Grade 3 stomatitis or mucositis with prior therapy.