Therapeutic Vaccination for Patients With HPV16+ Cervical Intraepithelial Neoplasia (CIN2/3)

This study will test the efficacy and safety of different routes of administration of a DNA vaccine in patients with HPV16+ CIN2/3. Subjects will be enrolled in one of six treatment groups. Subjects enrolled in the first two groups will receive vaccination intradermally with a needle-free delivery device. Subjects enrolled in groups 3 and 4 will receive vaccination intramuscularly. Subjects enrolled in groups 5 and 6 will receive vaccine intralesionally.

Primary Objectives

• To evaluate the feasibility and toxicity of vaccination in women with CIN2/3 caused by HPV16
• To evaluate the effect of vaccination on histology
• To compare immunogenicity of three different routes of administration: intradermal (ID), intramuscular (IM), intralesional (IL).

Secondary Objectives:

• To evaluate changes in HPV viral load
• To evaluate the cellular immune response to vaccination
• To evaluate the humoral immune response to vaccination
• To evaluate local tissue immune response
• To correlate measures of immune response with clinical response
• To correlate measures of immune response with those observed in the preclinical model

• HPV16+
• Cervical Intraepithelial Neoplasia (CIN 2/3)

• Biological: DNA vaccination
  vaccination with pNGVL4a-CRT/E7(detox)
  Other Name: Therapeutic vaccine
• Device: Gene gun vaccine
  8 micrograms (group 1) or 16 micrograms (group 2)
  Other Names:

  • PMED administration
  • ND10 device
• Biological: intramuscular vaccination
  1mg (group 3) or 3mg (group 4) of pNGVLra-CRT/E7(detox) administered intramuscularly
  Other Name: DNA vaccine
• Biological: intra-lesional vaccine administration
  1mg (group 5) or 3mg (group 6) of pNGVL4a-CRT/E7(detox)administered intra-lesionally
  Other Name: Intra-lesional DNA vaccination
• Procedure: therapeutic resection of the lesion
  at week 15, all residual lesions will be resected
  Other Name: LEEP or cold knife conization

• Experimental: PMED Delivery - groups 1 and 2
  Subjects will receive pNGVL4a-CRT/E7(detox) via gene gun at weeks 0, 4, 8 prior to therapeutic resection of their lesion at week 15.
  Interventions:

  • Biological: DNA vaccination
  • Device: Gene gun vaccine
  • Procedure: therapeutic resection of the lesion
• Experimental: IM injections - groups 5 and 6
  Subjects will receive pNGVL4a-CRT/E7(detox) intramuscularly at weeks 0, 4, 8 prior to therapeutic resection of their lesion at week 15.
  Interventions:

  • Biological: DNA vaccination
  • Biological: intramuscular vaccination
  • Procedure: therapeutic resection of the lesion
• Experimental: Intralesional delivery - group 3 and 4
  Subjects will receive pNGVL4a-CRT/E7(detox) intra-mucosally at weeks 0, 4, 8 prior to therapeutic resection of their lesion at week 15.
  Interventions:

  • Biological: DNA vaccination
  • Biological: intra-lesional vaccine administration
  • Procedure: therapeutic resection of the lesion

Inclusion Criteria:

• patients with high grade cervical intraepithelial lesions (CIN2/3)
• patients whose lesions are HPV16+
• patients who are age 18 or older
• patients who are able to give informed consent
• patients who are immunocompetent
• patients who are not pregnant, committed to using adequate contraception if of childbearing age
• patients who have a minimum hemoglobin level of 9

Exclusion Criteria:

• Patients with cytologic evidence of glandular dysplasia
• Patients with cytologic evidence of adenocarcinoma in situ
• Patients who are pregnant
• Patients with an active autoimmune disease
• Patients who are taking immunosuppressive medication
• Patients with concurrent malignancy except for nonmelanoma skin lesions
• Patients who have an allergy to gold.
• Patients with any evidence of damaged skin, or moles, scars, tattoos or marks at the proposed site(s) of administration that might interfere with the interpretation of local skin reactions.
• History or evidence of a physician-diagnosed chronic or recurrent inflammatory skin disease (e.g. psoriasis, eczema, atopic dermatitis, hypersensitivity) at the proposed site of administration in the past 5 years.
• Patients who have an active autoimmune disease or history of autoimmune disease requiring medical treatment with systemic immunosuppressants, including: inflammatory bowel disease, systemic vasculitis, scleroderma, psoriasis, multiple sclerosis, hemolytic anemic, or immune thrombocytopenia, rheumatoid arthritis, SLE, and Sjogren's syndrome, sarcoidosis. Asthma or COPD that does not require systemic corticosteroids or routine use of inhaled steroids is acceptable
• Patients who have received prior chrysotherapy (administration of gold salts to treat rheumatoid arthritis).
• Patients with a history of arterial or venous thrombosis
• Patients with non-healed wounds.
• Patients with a history of keloid formation ( ID delivery group only)
• Patients with a history of hepatitis B with persistent infection.

• National Institutes of Health (NIH)
• National Cancer Institute (NCI)