Mechanistic insights into ADXS11-001 human papillomavirus-associated cancer immunotherapy

Abstract

Immune responses to the facultative intracellular bacterium Listeria monocytogenes (Lm) are robust and well characterized. Utilized for decades as a model of host-disease immunology, Lm is well suited for use as an immunotherapeutic bacterial vector for the delivery of foreign antigen. Genetic modification of Lm has been undertaken to create an attenuated organism that is deficient in its master transcriptional regulator, protein-related factor A, and incorporates a truncated, nonhemolytic version of the listeriolysin O (LLO) molecule to ensure its adjuvant properties while also preventing escape of the live organism from the phagolysosome. Delivery of a vaccine construct (Lm-LLO-E7; axalimogene filolisbac [AXAL] or ADXS11-001) in which the modified LLO molecule is fused with the E7 oncoprotein of human papillomavirus type 16 (HPV-16) consistently stimulates strong innate and E7 antigen-specific adaptive immune responses, resulting in reduction of tumor burden in animal cancer models. In the clinical setting, AXAL has shown early promise in phase I/II trials of women with cervical cancer, and several more trials are currently underway to assess the efficacy and safety of this antitumor vaccine in patients with HPV-positive head and neck and anal cancers.

Keywords: ADXS11-001; AXAL; Axalimogene filolisbac; Cancer immunotherapy; Human papillomavirus; Mechanism of action; Vaccine therapy.

Fig. 1

Innate and adaptive immunity mediated by Lm. Adapted from Promises and challenges for the development of Listeria monocytogenes-based immunotherapies. Brockstedt DG, Dubensky TW, 2008 [10]. Expert Review of Vaccines. 2008. Taylor & Francis Ltd. Reprinted by permission of Taylor & Francis Ltd. CD, cluster of differentiation; CTL, cytotoxic T lymphocyte; DCs, dendritic cells; IFN, interferon; IL-12, interleukin-12; Lm, Listeria monocytogenes; MHC-I, major histocompatibility complex class I; NLRs, nucleotide-binding oligomerization domain-like receptors; PAMP, pathogen-associated molecular pattern; PRRs, pattern recognition receptors; TLR, Toll-like receptor

Fig. 2

Schematic depiction of processing and presentation of the LLO-Ag fusion protein in an antigen-presenting cell. Adapted from Wallecha A, French C, Petit R, Singh R, Amin A, Rothman J. Lm-LLO-based immunotherapies and HPV-associated disease. J Oncol. 2012;2012:542851 [27], under Creative Commons Attribution 3.0 Unported (CC BY 3.0) license (https://creativecommons.org/licenses/by/3.0/). Figure is a derivative of the original. Ag, antigen; CD, cluster of differentiation; CTL, cytotoxic T lymphocyte; LLO, listeriolysin O; Lm, Listeria monocytogenes; MHC-I, major histocompatibility complex class I; MHC-II, major histocompatibility complex class II; TAA, tumor-associated antigen

Fig. 3

Step-by-step Lm-LLO immunomodulation. APCs, antigen-presenting cells; CD, cluster of differentiation; CTL, cytotoxic T lymphocyte; MDSC, myeloid-derived suppressor cell; TAA, tumor-associated antigen; tLLO, truncated LLO; TME, tumor microenvironment; Treg, regulatory T cell

Fig. 4

Schematic of the planned AIM2CERV phase III study. FIGO, International Federation of Gynecologic Oncology; GOG, Gynecologic Oncology Group; IV, intravenous; Q, quarter