NWRD09 for HPV-16 Related Intraepithelial Neoplasia and Cervical Cancer

Inclusion Criteria:

Inclusion criteria for cohort A:

Patients had to meet all of the following inclusion criteria:

1. Women aged between 18 and 60 years.

2. HPV16 is positive during the screening period.

3. Histologically confirmed HPV-16-associated cervical, vaginal, and vulvarintraepithelial neoplasia (LSIL and HSIL). In the case of LSIL, it is necessary tomeet persistent HPV16 infection for more than 6 months. In the case of HSIL, it isnecessary to meet the requirements of satisfactory colposcopy at screening, which isdefined as the squamous columnar epithelial junction (class I or class IItransformation zone) is fully visible, and the upper limit of the white epitheliumacetate or suspected CIN lesions are fully visible.

4. Eligible subjects of childbearing potential must agree to use a reliable method ofcontraception (hormonal or barrier method or abstinence, etc.) with their partnerfor the duration of the trial or for at least 6 months after the last dose. Forpremenopausal women with the possibility of childbearing, blood pregnancy tests mustbe negative within 7 days prior to the first use of the NWRD09.

5. Have fully understood the study and voluntarily signed the ICF, have goodcommunication with the investigator, and are able to complete all treatments,examinations, and visits stipulated in the study protocol.

Inclusion criteria for cohort B:

Patients had to meet all of the following inclusion criteria:

1. Women aged ≥ 18 years.

2. HPV16-related recurrent or metastatic advanced cervical cancer (Histologicallyconfirmed squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma)patients who have progressed after at least one lines of standard therapy or areintolerant to toxic side effects, or for which there is no standard treatment atpresent (Treatment failure refers to: disease progression during or after treatmentwith systemic antineoplastic regimens; Intolerance refers to: the patient has grade 3-4 adverse reactions after receiving standard therapy, and the patient refuses tocontinue the original treatment).

3. At least 1 measurable lesion (RECIST 1.1). Tumor lesions that have received priorradiotherapy or other local therapy are considered measurable only if diseaseprogression at the treatment site is clearly documented after completion oftreatment.

4. Eastern Cooperative Oncology Group (ECOG) Performance status of 0 or 1.

5. Had recovered from all toxicities related to prior anticancer therapies to grade≤1or baseline level as defined by CTCAE v5.0 (except for the asymptomatic laboratoryexamination abnormalities such as elevated ALP, hyperuricemia, elevated serumamylase/lipase, elevated blood glucose, etc., and toxicities judged by theinvestigator to have no safety risk, such as alopecia, grade 2 peripheralneurotoxicity, and hypothyroidism stabilized by hormone replacement therapy, etc.).

6. Major organ functions must meet the following criteria:

7. Blood routine: absolute neutrophil count (ANC) ≥ 1.5×10^9/L, platelet count ≥ 80×10^9/L, hemoglobin ≥ 90 g/L,

8. Liver function: total bilirubin (TBIL) ≤ 1.5 ULN (≤ 3 ULN for Gilbert'ssyndrome, liver cancer, or liver metastases), AST and ALT ≤ 2.5 ULN forsubjects without liver metastases, and ≤ 5.0 ULN for subjects with livermetastases,

9. Renal function: creatinine (Cr) ≤ 1.5 ULN, or creatinine clearance (Ccr) ≥ 50mL/min (using the Cockcroft and Gault formula),

10. Coagulation function: international normalized ratio (INR) ≤ 1.5, and activatedpartial thromboplastin time (APTT) ≤ 1.5 ULN.

11. Has life expectancy of at least 3 months in the best judgement of the investigator.

12. Eligible subjects of childbearing potential must agree to use a reliable method ofcontraception (hormonal or barrier method or abstinence, etc.) with their partnerfor the duration of the trial or for at least 6 months after the last dose. Forpremenopausal women with the possibility of childbearing, blood pregnancy tests mustbe negative within 7 days prior to the first use of the NWRD09.

13. Have fully understood the study and voluntarily signed the ICF, have goodcommunication with the investigator, and are able to complete all treatments,examinations, and visits stipulated in the study protocol.

Exclusion Criteria:

Exclusion criteria for cohort A:

Patients with any of the following were excluded from the study:

1. Any histopathologically confirmed adenocarcinoma or adenocarcinoma in situ (AIS) orinvasive cancer.

2. Pregnant, breastfeeding, or planning to conceive during the study period.

3. Received any non-live vaccine injection within 2 weeks prior to the first dose ofNWRD09.

4. Received any live vaccine injection within 4 weeks prior to the first dose ofNWRD09.

5. Received treatment for LSIL or HSIL within 4 weeks prior to the first dose ofNWRD09.

6. Participated in another clinical trial or is in the observation period of anotherclinical trial within 30 days prior to screening.

7. Continuous (more than 1 week) use of corticosteroids (equivalent to >10 mg/day ofprednisone) within 30 days prior to screening, except for hormone replacementtherapy and local administration such as inhaled or ocular treatments.

8. History of immunodeficiency or autoimmune diseases (e.g., rheumatoid arthritis,systemic lupus erythematosus, multiple sclerosis).

9. Current or anticipated use of disease-modifying antirheumatic drugs (e.g.,azathioprine, cyclophosphamide, cyclosporine, methotrexate) and biological agents (e.g., infliximab, adalimumab, etanercept).

10. Continuous (more than 1 week) use of immunosuppressants (e.g., cyclosporine,tacrolimus, azathioprine, 6-mercaptopurine, and anti-lymphocyte globulin) within 30days prior to screening.

11. History of solid organ or bone marrow transplantation.

12. Past or current malignancies, except for adequately treated and completely curedductal carcinoma in situ of the breast, basal cell carcinoma of the skin,superficial bladder tumors, or any other malignancies cured more than 5 years beforeentering the study.

13. Uncontrolled severe infections (>Grade 2 NCI-CTCAE adverse events, version 5.0).

14. History of HIV infection or syphilis carrier.

15. Active infection (e.g., acute bacterial infection, tuberculosis, active syphilis,active phase of herpes zoster virus infection, active hepatitis B or C, etc.).

① Active hepatitis C is defined as: positive hepatitis C antibody and HCV-RNApositive.

② Active HIV infection is defined as: positive HIV antibody.

③ Active hepatitis B is defined as: HBV titer ≥ 2000 IU/mL (except for subjects whohave received anti-HBV treatment for at least 14 days before the first dose andagree to continue antiviral therapy during the study period).

16. Severe allergy history, or history of atopic diseases, or an allergic constitution,if any of these are met.

17. History of severe or multiple hypersensitivity to drugs or pharmaceuticalpreparations.

18. History of severe local or systemic reaction to vaccines, defined as:

19. Local reaction: extensive, indurated redness and swelling involving most of thearm, unresolved within 72 hours.

20. Systemic reaction: persistent fever ≥ 39.5°C within 48 hours. bronchospasm.laryngeal edema. syncope. convulsions or encephalopathy within 72 hours.

21. Severe dysfunction of other organs or heart and lung diseases.

22. History of definite neurological or psychiatric disorders, including epilepsy ordementia.

23. History of drug abuse or alcoholism.

24. Pregnant or breastfeeding women, or women of childbearing age with a positive bloodpregnancy test, or patients and their partners of childbearing potential unwillingto use effective contraception during the clinical study and for 6 months after theend of treatment.

25. Patients deemed unsuitable to participate in this clinical trial by theinvestigator.

Exclusion criteria for cohort B:

Patients with any of the following were excluded from the study:

1. Cervical carcinoma in situ that can be cured by local treatment or non-HPV relatedcervical cancer.

2. Has not recovered or be reasonably explained from all toxicities related to priortreatments such as surgery, radiotherapy, chemotherapy, immunotherapy, etc.

3. Participated in another clinical trial or is in the observation period of anotherclinical trial within 30 days prior to screening.

4. Received any non-live vaccine injection within 2 weeks prior to the first dose.

5. Received any live vaccine injection within 4 weeks prior to the first dose.

6. Continuous (more than 1 week) use of corticosteroids (equivalent to >10 mg/day ofprednisone) within 30 days prior to screening, except for hormone replacementtherapy and local administration such as inhaled or ocular treatments.

7. History of immunodeficiency or autoimmune diseases (e.g., rheumatoid arthritis,systemic lupus erythematosus, multiple sclerosis).

8. Current or anticipated use of disease-modifying antirheumatic drugs (e.g.,azathioprine, cyclophosphamide, cyclosporine, methotrexate) and biological agents (e.g., infliximab, adalimumab, etanercept).

9. Continuous (more than 1 week) use of immunosuppressants (e.g., cyclosporine,tacrolimus, azathioprine, 6-mercaptopurine, and anti-lymphocyte globulin) within 30days prior to screening.

10. History of solid organ or bone marrow transplantation.

11. Past or current malignancies, except for adequately treated and completely curedductal carcinoma in situ of the breast, basal cell carcinoma of the skin,superficial bladder tumors, or any other malignancies cured more than 5 years beforeentering the study.

12. Central nervous system (CNS) metastases and/or carcinomatous meningitis (meningealmetastasis).

13. Clinically significant or recurrent pleural, peritoneal, or pericardial effusionrequiring frequent drainage.

14. Uncontrolled severe infections (>Grade 2 NCI-CTCAE adverse events, version 5.0).

15. History of HIV infection or syphilis carrier.

16. Active infection (e.g., acute bacterial infection, tuberculosis, active syphilis,active phase of herpes zoster virus infection, active hepatitis B or C, etc.).

① Active hepatitis C is defined as: positive hepatitis C antibody and HCV-RNApositive.

② Active HIV infection is defined as: positive HIV antibody.

③ Active hepatitis B is defined as: HBV titer ≥ 2000 IU/mL (except for subjects whohave received anti-HBV treatment for at least 14 days before the first dose andagree to continue antiviral therapy during the study period).

17. Severe allergy history, or history of atopic diseases, or an allergic constitution,if any of these are met.

18. History of severe or multiple hypersensitivity to drugs or pharmaceuticalpreparations.

19. History of severe local or systemic reaction to vaccines, defined as:

20. Local reaction: extensive, indurated redness and swelling involving most of thearm, unresolved within 72 hours.

21. Systemic reaction: fever ≥ 39.5°C within 48 hours. bronchospasm. laryngealedema. syncope. convulsions or encephalopathy within 72 hours.

22. Severe dysfunction of other organs or heart and lung diseases.

23. History of definite neurological or psychiatric disorders, including epilepsy ordementia.

24. History of drug abuse or alcoholism.

25. Pregnant or breastfeeding women, or women of childbearing age with a positive bloodpregnancy test, or patients and their partners of childbearing potential unwillingto use effective contraception during the clinical study and for 6 months after theend of treatment.

26. Patients deemed unsuitable to participate in this clinical trial by theinvestigator.