Project 3

A Phase I Open Label, Dose Escalation Clinical Trial Assessing the Safety, Tolerability, and Feasibility of pNGVL4aCRTE6E7L2 HPV DNA Vaccine Administration Via Intramuscular TriGridTM Electroporation

Surgical or ablative treatment of cervical cancer precursors, i.e., high-grade squamous intraepithelial lesion (HSIL)/cervical intraepithelial neoplasia (CIN2/3), has reduced disease incidence but is associated with increased rates of infectious complications, cervical incompetence with premature deliveries, failure to clear HPV, and disease recurrence. Additionally, persistent HPV infection can cause pre-invasive and invasive disease at other sites (vagina/vulva/anus) that are harder to treat.

Our goalis to test the safety and toxicity of a therapeutic HPV vaccine, the CRTE6E7L2 DNA vaccine, delivered intramuscularly (IM) via the TriGrid Electroporation Device, in HIV- and HIV+ patients (including HIV- patients on the kidney transplant waitlist) who have HPV16-associated HSIL lesions of the cervix (CIN), vagina (VaIN), and/or vulva (VIN). We will also examine virologic and disease outcomes. HPV16 is the most common genotype in cervical cancer, and it dominates (> 85%) in other anogenital and head and neck malignancies. HPV-related cancer incidence is significantly elevated in patients living with HIV and in organ transplant recipients, both in the cervix and at other sites. These patients acquire more frequent multi-genotype infections, including many of genotypes that are less common in healthy individuals and that are not targeted by the current HPV preventive vaccines. Our candidate therapeutic and preventive HPV vaccine, CRTE6E7L2, comprises the pNGVL4a DNA vector encoding the heat shock protein calreticulin (CRT) fused genetically with HPV16 E6 and E7 (each obligately expressed in HPV malignancies) as well as the L2 capsid protein (a broadly protective antigen). Fusion with CRT profoundly enhances the potency of DNA vaccines in generating HPV antigen-specific CD8+ T cell-mediated immune responses, even in CD4-depleted animals. CRTE6E7L2 DNA vaccination also induces L2-specific neutralizing antibodies and protects from experimental vaginal challenge. These features make the CRTE6E7L2 DNA vaccine particularly promising for use in patients living with HIV and transplant patients, which are both challenging groups to treat. Although DNA vaccines are relatively safe and well suited for multiple administrations, in the past, they have shown limited immunogenicity when administered alone by conventional intramuscular needle injection, likely reflecting inefficient host cell transduction. In vivo electroporation is a much more effective DNA vaccine administration method to generate HPV-specific CD8+ T cell immune responses. Clinical responses to date have been highly encouraging in both HIV+ and HIV- patients.

Aim 1: Evaluate the safety and toxicity of CRTE6E7L2 administered via electroporation in HIV- and HIV+ patients with HPV16+ high-grade CIN/VaIN/VIN, including HIV- patients on the kidney transplant waitlist

Aim 2: Characterize the HPV16 E6/E7/L2-specific cell-mediated responses to vaccination of each cohort.

Aim 3: Characterize the HPV16 E6/E7/L2-specific humoral immune responses to vaccination of each cohort

Aim 4: Determine the HPV and histopathological responses in the lesion and its microenvironment to vaccination in each cohort.

Investigators