Case Report: Intra-Tumoral Vaccinations of Quadrivalent HPV-L1 Peptide Vaccine With Topical TLR-7 Agonist Following Recurrence: Complete Resolution of HPV-HR-Associated Gynecologic Squamous Cell Carcinomas in Two Patients

Abstract

The human papilloma virus (HPV) high-risk variants (HPV-HR) such as HPV16 and HPV18 are responsible for most HPV related cancers, including anogenital and head and neck cancers. Here, we present two patients with HPV-HR-associated gynecological malignancies who, after failing radiation therapy, were treated with experimental salvage immunotherapy regimen resulting in complete, durable responses in both patients. Each patient was diagnosed with recurrent, radiation-refractory, HPV-HR positive, squamous cell carcinoma of the lower genital tract. Patient A was a 90-year-old, African American, with metastatic vulvar cancer to the right inguinal-femoral triangle and pulmonary metastases. Patient B was a 41-year-old, Caucasian, with a central-recurrence of cervix cancer. Each patient received at least two intratumoral quadrivalent HPV-L1 vaccine (Gardasil™) injections and daily topical TLR-7 agonist (imiquimod) to the tumor surface 2 weeks apart. This combination of intratumoral vaccinations and topical TLR-7 agonist produced unexpected complete resolution of disease in both patients. The importance of radiation therapy, despite being considered a treatment failure by current definitions, cannot be understated. Radiation therapy appears to have offered a therapeutic immune advantage by modifying the tumor microenvironment. This immune protocol has potential to help patients with advanced HPV-HR-related malignancies previously considered incurable.

Combined systemic and intralesional 9‐valent human papillomavirus vaccine for recurrent squamous cell carcinoma in situ of the penis

“…5 Although designed to be prophylactic, 2 the 9-valent HPV vaccine may also have therapeutic properties, consistent with this and other reports. 1,3,4 This treatment approach was well tolerated, effective, and improved our patient's quality of life dramatically; for patients with SCCIS of the penis who are poor surgical candidates, this may be an effective alternative treatment. Since the durability of the therapeutic response is unknown, close monitoring for recurrence is required.…”

“…Four doses of the 0.5 ml 9-valent HPV were administered undiluted intralesionally on 09/27/2019, 12/05/2019, 01/16/2020, and 03/10/2021. The patient experienced resolution without side effects and has not had a clinical recurrence in 20 months (Figure 2c,d).HPV is responsible for approximately 30% of viral-induced cancers 1. In the development of SCCIS of the penis, b-HPV subtypes 16 and 18 are the most common 2.…”

“…A 48-year-old male with non-Hodgkin lymphoma in remission, type 2 diabetes mellitus, HIV with an undetectable viral load on HAART, a history of circumcision, anogenital HSV infection, and recurrent SCCIS of the penis treated over 13 years with more than 10 surgeries presented with a painful, ulcerated plaque on his penis (Figure 1a 1,3,4 For example, two previous case reports described using systemic and intratumoral 9valent HPV vaccine to treat multiple basaloid SCCs on the leg 4 and multiple, treatment-refractory keratoacanthoma-type SCCs. 3 Genital HPV infection may cause the development of penile SCCIS through the viral oncogenes E6 and E7.…”

The HPV viral regulatory mechanism of TLRs and the related treatments for HPV-associated cancers

“…Patients with central recurrence of cervical cancer receive at least two intratumoral Gardasil injections and local injection of imiquimod on the tumor surface. The addition of a combination of local TLR7 agonist therapy on the basis of intratumoral vaccination can unexpectedly lead to complete regression of the disease in two patients ( 113 ). Due to the potential lack of immunogenicity of peptides themselves, it is widely believed that standard/conventional vaccine adjuvants may not provide the intense inflammatory signals required to provoke specific responses against peptide pointed at treatment tumor vaccines.…”

Radiotherapy combined with nano-biomaterials for cancer radio-immunotherapy

“…It has been known that radiation therapy induces immunogenic cell death to generate tumor antigens and improves antigen presentation efficiency. Clinical studies [ 70 ] have demonstrated that proton-beam radiotherapy combined with in situ vaccine is safe and feasible for patients with hepatocellular carcinoma. The first clinical trial conducted by Abei et al .…”