Immunotherapy Targeting HPV16/18 Generates Potent Immune Responses in HPV-Associated Head and Neck Cancer

Abstract

Purpose: Clinical responses with programmed death (PD-1) receptor directed antibodies occur in about 20% of patients with advanced head and neck squamous cell cancer (HNSCCa). Viral neoantigens, such as the E6/E7 proteins of HPV16/18 are attractive targets for therapeutic immunization, and offer an immune activation strategy that may be complementary to PD-1 inhibition. Experimental Design: We report Phase Ib/II safety, tolerability and immunogenicity results of immunotherapy with MEDI0457 (DNA immunotherapy targeting HPV16/18 E6/E7 with IL-12 encoding plasmids) delivered by electroporation with CELLECTRA® constant current device. Twenty-two patients with locally advanced, p16+ HNSCCa received MEDI0457. Results: MEDI0457 was associated with mild injection site reactions but no treatment related grade 3–5 adverse events (AEs). Eighteen of 21 evaluable patients showed elevated antigen specific T cell activity by IFNγ ELISpot and persistent cellular responses surpassing 100 SFU/106 PBMC were noted out to one year. Induction of HPV-specific CD8+ T cells was observed. MEDI0457 shifted the CD8+/FoxP3+ ratio in 4/5 post-immunotherapy tumor samples and increased the number of perforin+ immune infiltrates in all five patients. One patient developed metastatic disease and was treated with anti-PD-1 therapy with a rapid and durable complete response. Flow cytometric analyses revealed induction of HPV16 specific PD-1+ CD8+ T cells that were not found prior to MEDI0547 (0% vs. 1.8%). Conclusions: These data demonstrate that MEDI0457 can generate durable HPV16/18 antigen-specific peripheral and tumor immune responses. This approach may be used as a complementary strategy to PD-1/PD-L1 inhibition in HPV-associated HNSCCa to improve therapeutic outcomes.

DNA vaccines: prime time is now

“…In the clinic McNeel et al reported that combination anti-PD-1 immunotherapy with a T-cell stimulating DNA vaccine was well-tolerated and promoted antitumor responses [25]. A more recent study by Agarwall et al tested the adaptive EP delivery of a synHPV vaccine for treatment of HPV positive head and neck cancers [26]. This phase Ib/II safety, tolerability, and immunogenicity study reported results of immunotherapy with MEDI0457 (DNA immunotherapy targeting HPV16/18 E6/E7 co-delivered with plasmid IL12) delivered by adaptive CELLECTRA-EP.…”

Novel immune‐modulating drugs for advanced head and neck cancer

“…The most common AE was grade I/II injection site pain. No grade III/IV AEs were reported . Finally, in a current phase Ib/II study, the combination of durvalumab and MEDI0457 is being evaluated as second‐line treatment in HPV‐16‐ or HPV‐18‐associated R/M HNSCC.…”

“…No grade III/IV AEs were reported. 61 Finally, in a current phase Ib/II study, the combination of durvalumab and MEDI0457 is being evaluated as second-line treatment in HPV-16-or HPV-18-associated R/M HNSCC. Safety, efficacy, and immunogenicity will be evaluated.…”

Immune Therapy Targeting E6/E7 Oncogenes of Human Papillomavirus Type 6 (HPV-6) Reduces or Eliminates the Need for Surgical Intervention in the Treatment of HPV-6 Associated Recurrent Respiratory Papillomatosis

“…HPV E6 and E7 oncoproteins represent ideal targets for this type of therapeutic intervention because of their constitutive expression in HPV associated tumors and their crucial role in the induction and maintenance of HPV associated diseases [11]. To that end, our previous clinical studies of HPV-specific immunotherapy engendering T cell responses have shown to translate in clinical benefit for woman exhibiting advanced dysplastic cervical lesions as well as patients with HPV associated squamous cell carcinoma of the head and neck [11,12].…”