This is a phase I clinical trial to determine the maximum tolerated dose (MTD) of KK-LC-1 TCR-T cells for the treatment of metastatic cancers that express KK-LC-1. Participants will receive a conditioning regimen, KK-LC-1 TCR-T cells, and aldesleukin. The safety profile and clinical response to treatment will be determined.

This study will determine the MTD of KK-LC-1 TCR-T cells for the treatment of metastatic cancers that express KK-LC-1 and will assess clinical tumor response to treatment. KK-LC-1 is an abnormal protein that is expressed by certain types of cancer. The cancers that most commonly express KK-LC-1 include gastric, lung, breast, and cervix cancer. KK-LC-1 TCR-T cells are autologous T cells that are genetically engineered to target the KK-LC-1 antigen. Tumor targeting by the KK-LC-1 TCR requires that subjects have the the HLA-A*01:01 allele. Participants will receive a conditioning regimen consisting of cyclophosphamide and fludarabine. They will then receive a single infusion of KK-LC-1 TCR-T cells, which will be followed by administration of aldesleukin. Adverse events, dose limiting toxicity, tumor response, and tumor response duration will be determined.

Inclusion Criteria: Subjects must meet all the following criteria to participate in this study.

1. Signed, written informed consent obtained prior to any study procedures.

2. Age ≥ 18 years at the time of informed consent.

3. Metastatic solid tumor with ≥ 10% of tumor cells positive for KK-LC-1 by IHC assay. Due to the low frequency of KK-LC-1 expression in most cancers, screening will focus on gastric, NSCLC, TNBC, and cervix cancers. The IHC test will be performed by the Rutgers Cancer Institute, Department of Biorepository Services.

4. HLA-A*01:01 allele by HLA haplotype test.

5. Measurable disease per RECIST Criteria Version 1.1 at time of enrollment.

6. Prior treatment with cancer type-specific standard of care systemic cancer therapy is required. Standard treatment options must be considered and declined. Documentation of rationale is required if a subject is deemed unsuitable for standard therapy.

7. Subjects with ≤ 3 brain metastases that have been treated with surgery or stereotactic radiosurgery are eligible. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for one month before protocol treatment. Patients with surgically resected brain metastases are eligible.

8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at screening.

9. Negative pregnancy test for women under 55 and all women who have had a menstrual period in the last 12 months. A pregnancy test is not required for women who have had a bilateral oophorectomy or hysterectomy.

10. Men and women of child-bearing potential must agree to use adequate contraception (i.e., intrauterine device, hormonal/barrier method of birth control, abstinence, tubal ligation, or vasectomy) prior to study entry and for 12 months after treatment. Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately.

11. Participants must have organ and marrow function as defined below:

    1. Leukocytes > 3,000/mcL
    2. Absolute neutrophil count > 1,500/mcL
    3. Platelets > 100,000/mcL
    4. Hemoglobin > 9.0 g/dL
    5. Total bilirubin within normal institutional limits except in participants with Gilbert's Syndrome who must have a total bilirubin < 3.0 mg/dL.
    6. Serum AST (SGOT)/ALT (SGPT) < 2.5 x ULN
    7. Calculated creatinine clearance (CrCl) > 50 mL/min/1.73 m² for participants with creatinine levels above institutional normal (by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation).
    8. INR or aPTT ≤ 1.5 X ULN unless the subject is receiving anticoagulant therapy. Subjects on anticoagulant therapy must have a PT or PTT within therapeutic range and no history of severe hemorrhage.

12. Serology:

    • HIV antibody negative
    • Hepatitis B antigen negative
    • Hepatitis C antibody negative or HCV RNA negative (i.e., no current HCV infection)

13. More than four weeks must have elapsed since any prior systemic therapy at the time the patient receives the KK-LC-1 TCR-T cells. Adverse events from prior therapy must have resolved to ≤ grade 1 according to CTCAE Version 5.0 or have demonstrated clinical stability and meet the eligibility criteria for the protocol.

14. Participants must agree to participate in Rutgers protocol 192103 (Pro2021002307) for gene therapy long term follow up and in Rutgers protocol 192002 (Pro2021000281) or NIH protocol 16C0061 (Rutgers 192202) for biospecimen collection study.

Note: Patients may have undergone minor surgical procedures within the past three weeks, as long as all toxicities have recovered to Grade 1 or less.

Exclusion Criteria: Subjects who meet any of the following criteria will be excluded from participation in this study:

1. Current treatment with another investigational agent.

2. History of severe allergic reactions to compounds of similar chemical or biologic composition to agents used in study.

3. History of coronary revascularization or ischemic symptoms unless patient has a normal cardiac stress test.

4. Documented LVEF of less than or equal to 45% tested. The following participants will undergo cardiac evaluations:

   1. Clinically significant atrial and/or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart block or
   2. Age greater than or equal to 50 years old

5. Participants with baseline screening pulse oxygen level of less than or equal to 92% on room air will not be eligible. If the underlying cause of hypoxia improves, then they may be reevaluated.

6. Uncontrolled intercurrent illness such as active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations at the time of treatment that would limit compliance with study requirements.

7. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with KK-LC-1 TCR-T cells, breastfeeding should be discontinued if the mother is treated with KK-LC-1 TCR cells. The potential risks may also apply to other agents used in this study.

8. Participants with a systemic immunodeficiency including acquired deficiency such as HIV or primary immunodeficiency such as Severe Combined Immunodeficiency Disease are ineligible. The experimental treatment being evaluated in this protocol depends on an intact immune system. Participants who have decreased immune competence may be less responsive to the treatment.

9. Participants on immunosuppressive drugs including corticosteroids unless meeting criteria outlined in Section 6.1 (Prohibited Medications).

10. Subjects with HLA-A*01:01 damaging mutation or allele loss or other molecular resistance detected by clinical or research genomic profiling will not be eligible.

11. Participants with potentially severe autoimmune diseases such as Crohn's disease, ulcerative colitis, rheumatoid arthritis, autoimmune hepatitis, autoimmune pancreatitis, or systemic lupus erythematosus are not eligible. Prior history of potentially severe autoimmune diseases without a current, active diagnosis is not exclusionary. Patients with less severe autoimmune diseases such as hypothyroidism, vitiligo, and other minor autoimmune disorders are eligible.

12. Participants with prior or concurrent malignancy whose natural history or treatment is unlikely to interfere with the safety or efficacy assessments of the investigational regimen are eligible for this trial. Examples include, but are not limited to:

    1. Carcinoma in situ
    2. Cutaneous skin cancers requiring only local excision
    3. Low grade non-muscle invasive bladder cancer
    4. Low grade prostate cancer Participants with prior or concurrent malignancy that do not meet the above criteria are excluded.

13. Subjects who received a live vaccine within 30 days prior to enrollment are not eligible.

14. Determination by the Principal Investigator that participation is not in the best interest of the research subject or may jeopardize the safety of the subject or integrity of the clinical trial data.

Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices).

Data will be made available through the publisher at the time of publication.

Data will be accessible through the publisher.