Abstract 1193: Peripheral immune analyses from phase I trial of HPV vaccine PRGN-2009 in combination with bintrafusp alfa in patients with HPV-associated cancers
Authors: Goswami Meghali , Floudas Charalampos S. , Strauss Julius , Brough Douglas E. , Lankford Amy R. , Jochems Caroline , Gulley James L. , Schlom Jeffrey , Donahue Renee N. 
Published: March 2024

Abstract
Background: PRGN-2009 is a novel gorilla adenovirus vaccine targeting HPV16/18, and bintrafusp alfa (BA) is a bifunctional anti-PD-L1/TGFβ fusion protein. Patients with pretreated advanced HPV-associated malignancies received PRGN-2009 vaccine (5 × 1011 particle units, subcutaneous administration) q2 weeks for 3 administrations and biweekly 1200mg BA followed by q4 weeks vaccine and biweekly BA (NCT04432597), with an overall response rate of 30%. We report here correlative analyses from this first-in-human Phase I study using peripheral blood from 10 patients with HPV16+ (n=8), HPV18+ (n=1), or HPV45+ (n=1) disease to identify immune correlates associated with clinical response.
Methods: Peripheral HPV-specific T cell responses, HPV circulating tumor DNA (ctDNA) from plasma, serum cytokines and soluble factors, and peripheral immune cell subsets were assessed to evaluate changes induced with treatment and peripheral correlates associated with clinical activity. Patients with complete response (CR, n=1), partial response (PR, n=2; 1 confirmed) or stable disease (SD, n=1) (n=4 total) were compared to patients with progressive disease (PD, n=6).
Results: Eighty percent (8/10) of patients developed either HPV16 or HPV18-specific T-cell responses after repeat administration of PRGN-2009 with BA. Eight of 10 patients had detectable HPV16 or 18 ctDNA at baseline and changes in ctDNA load with treatment generally correlated with outcomes. Early transient increases in IL-8, TNFα, and IFNγ occurred, with greater increases in IL-8 at 2 weeks and TNFα at 4 weeks in patients with PD compared to CR/PR/SD. The patient who achieved a durable CR had HPV45+ disease, and had a) a 50% increase in CD8+ T cell frequency at 2 weeks, b) increases in frequencies of CD8+ naïve T cells expressing Ki67+ and central and effector memory T cells expressing 4-1BB, PD-1, or TIM-3, and c) considerable increases in HPV18-specific T cell responses through 484 days after treatment start, indicating durable antigen-specific T cell activity.
Conclusions: The majority of patients developed HPV16/18 specific T-cell responses after repeat administration of PRGN-2009 in combination with BA. Transient increases in IL-8 and TNFα 2-4 weeks after start of treatment were associated with worse outcomes, suggesting that early changes in cytokines may reflect disease course. Furthermore, the early expansion of CD8+ T cell subsets in the patient developing a CR with HPV45+ disease after receiving a vaccine targeting HPV16 and HPV18 epitopes suggest a broadening and boosting of T cell responses that enabled potent anti-tumor activity. A high degree of homology between HPV18 and HPV45 may have contributed to the expansion of HPV18 specific T cells in the patient with CR. These data highlight the importance of assessing peripheral blood in immunotherapy trials to reveal important immunological phenomena.
Citation Format: Meghali Goswami, Charalampos S. Floudas, Julius Strauss, Douglas E. Brough, Amy R. Lankford, Caroline Jochems, James L. Gulley, Jeffrey Schlom, Renee N. Donahue. Peripheral immune analyses from phase I trial of HPV vaccine PRGN-2009 in combination with bintrafusp alfa in patients with HPV-associated cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1193.