ADXS11-001 LM-LLO as specific immunotherapy in cervical cancer

Figures & data

Figure 1. Antigen processing and presentation of Listeria monocytogenes. Lm is identified by a macrophage through pattern recognition receptors TLR2/TLR5, these initiate the MyD88 signaling pathway that leads to the activation of NF-κB, which promotes the transcription of pro-inflammatory genes and subsequent production of proinflammatory cytokines TNF-α, IL-6, and IL-12. Lm is endocytosed by the macrophage and contained in a phagosome. The phagosome fuses with a lysosome to form a phagolysosome where Lm is killed and digested, antigenic peptides derived from the digested bacteria are loaded into MHC class II molecules and presented to CD4+ Helper T cells. Alternatively, Lm has the ability to express the pore-forming listeriolysin O (LLO) toxin that perforates the phagosome and allows it to escape into the cytosol. Once in the cytosol, Lm secretes proteins that are degraded by the proteasome, these antigenic peptides are loaded into MHC class I molecules and presented to CD8+ Cytotoxic T cells. NK cells respond to IL-12 by producing IFN-γ, which enhances Cytotoxic T cell activation.²⁰

Figure 2. Antigen processing and presentation of ADXS11-001 Lm LLO-HPV E7 fusion protein

ADXS11-001 is Listeria monocytogenes genetically engineered to produce the LLO-(HPV) E7 fusion protein for immunotherapy. After injection in vivo, these Lm are recognized and endocytosed by dendritic cells. The bacterium stimulates both arms of the adaptive immune system because it is processed by both, the endogenous and exogenous pathways for antigen presentation. HPV E7 antigens from the bacteria processed by the phagolysosome are presented in MHC class II molecules to helper T cells. Fusion proteins LLO-HPV E7 from the bacteria that escaped to the cytosol are processed through the proteasome and HPV E7 antigens are presented in MHC class I molecules to cytotoxic T cells. This process generates and activates HPV specific cytotoxic T cell clones that will identify and destroy HPV+ infected cells. Lm also causes a strong innate immune response that leads to the generation of numerous mediators, including nitric oxide (NO), which participates in the destruction of bacteria, and the production of cytokines, such as TNF-α, IL-1, IL-12, IL-18 and IFN-γ, which enhance T cell activation. Adapted from Wallecha A ⁷

Table 1. Clinical trials with ADX11-001 in cervical cancer

Type of cancer	Trial Phase	Author	Indication	Vaccine alone or in combination	Treatment regimen	Estimated N	Completion	Efficacy	Safety
Cervix	I	Maciag PC (31)	Recurrent/metastatic	Monotherapy	Staggered dose 3 5-subject dose cohorts: 1 x 10^9, 3.3 × 10^9 or 1 × 10^10 CFU	15/20	2009	PR: 1 patient SD: 7 patients PD: 5 patients	Pyrexia (100%) Vomiting (60%) Myalgia (57%) Cold, headache and anemia (53%) Nausea and tachycardia (49%) DLT: 1 × 10^9 CFU
	I–II	Ghamande SA (32) NCT021 64461	Persistent/recurrent/metastatic	Monotherapy	Single group Staggered dose 5 x 10^9 CFU 5 x 10^10 CFU ADXS11-001 every 3 wk x 2 doses	25	Dec-18	-	Common TrAEs: Cold or vomiting Hypotension Tachycardia Fever Nausea
	II	Huh WK (33) GOG 0265 NCT012 66460	Persistent/recurrent metastatic	Monotherapy	Single group: 1 x 10^9 CFU ADXS11-001 every 4 wk x 3 doses	67	Oct-18	1-year OS: 38.5% PFS: 3.1 m OS: 7.7 m PR: 1 patient SD: 9 patients	TrAEs 38%: Vomiting Cold Fatigue Fever
	II	Basu P (34) CTRI/2010/091/001232	Persistent/recurrent	ADXS11-001 ± cisplatin	Two groups: Monotherapy: ADXS11-001 (1 x 10^9 CFU) x 1 cycle (3 applications on days 1, 29 and 57) Combination: ADXS11-001 (1 x 10^9 CFU) x 1 application on day 1, followed 4 wk later by 5 doses/wk of cisplatin (40 mg/m^2)	110	2017	12-m OS: 34.9% 18-m OS: 24.8% RR: 11% (6 CR, 6 PR) SD: 35 patients	TrAEs: 46% serious AEs G3: 7.3%
	III	Herzog T (36) AIM2CERV NCT028 53604	High-risk, locally advanced	Monotherapy	ADXS11-001 (1 x 10^9 CFU) every 4 wk x 3 doses (wk 1, 4 and 7), then every 8 wk x 5 doses (wk 15, 23, 31, 39 and 46)	450	Jun-21	Pending	Pending
Cervix or head and neck	I/II	Cohen EEW (37) NCT022 91055	Persistent/recurrent metastatic	ADXS11-001 ± Durvalumab	Phase I: ADXS11-001 at 1 × 10^9 doses + Durvalumab 3 mg/kg (3 + 3 design for the staggered dose) Phase II: ADXS11-001 at 1 × 10^9 CFU doses + Durvalumab 10 mg/kg	66	Dec-19	Pending	Pending

CFU: colony forming units; CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease; RR: response rates; DLT: dose limiting toxicity; AEs: adverse events; TrAEs: treatment-related adverse events; OS: overall survival; PFS: progression-free survival; wk: week; m: months.

Table 2. Clinical trials with ADX11-001 in HPV-associated cancers

Type of cancer	Trial Phase	Author	Indication	Vaccine alone or in combination	Treatment regimen	Estimated N	Completion	Efficacy	Safety
Head and neck	I	Sacco JJ (41) REALISTIC- NCT015 98792 NCT020 02182	Oropharyngeal cancer	Monotherapy	Staggered dose 3.3 x 10^8 CFU 1 x 10^9 CFU 3.3 x 10^9 CFU	36	Nov-14	No results	Interrupted
	II	Krupar R (38)	Resectable, treatment naïve, stage II–IV oropharyngeal cancer	ADXS11-001 + robotic trans-oral surgery	ADXS11-001 at 1 × 10^9 CFU doses every 3 wk for 6 wk (total of 2 doses) prior to surgery	25	Aug-19	Pending	Pending
Anal canal	I/II	Safran H (39) NCT016 71488	Locally advanced	ADXS11-001 + CT/RT (mitomycin, 5FU, IMRT)	ADXS11-001 at 1 × 10^9 CFU doses 4 doses: 1 to 14 d prior to CT/RT; 10 to 28 d after CT/RT; subsequent doses 3 and 4 at 28-d intervals Mitomycin 10 mg/m^2 d 1 and 29 5FU 1 mg/m^2 continuous infusion d 1–4 and 29–32	25	Feb-18	CR 9 patients 89% disease free at 42 m	G3 AEs in 2 patients: Cold (2) Back pain (1) Hyponatremia (1)
	II	Fakin M (40) NCT023 99813	Persistent/recurrent metastatic	Monotherapy	ADXS11-001 at 1 × 10^9 CFU doses every 3 wk in 9-wk cycles for ≤ 2 years or until discontinuation	55	Mar-22	Pending	Pending
Lung	II	NCT025 31854	HPV+ NSCLC on induction treatment	Maintenance pemetrexed ± ADXS11-001	Maintenance pemetrexed Maintenance pemetrexed + ADXS11-001	124	Mar-19	Pending	Pending

CFU: colony forming units; CR: complete response; AEs: adverse events; CT/RT: chemo-radiotherapy; IMRT: intensity-modulated radiotherapy; 5-FU: 5-fluoruracil; NSCLC: non-small cell lung cancer; HPV: human papillomavirus; d: day; wk: week; m: month.

Flickinger JC Jr, Rodeck U, Snook AE. Listeria monocytogenes as a vector for cancer immunotherapy : current understanding and progress. vaccines. 2018;6(3):48. doi:10.3390/vaccines6030048.

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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. doi:10.1155/2012/542851.

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