Robert Petit

Lm-LLO-Based Immunotherapies and HPV-Associated Disease

HPV infection is a direct cause of neoplasia and malignancy. Cellular immunologic activity against cells expressing HPV E6 and E7 is sufficient to eliminate the presence of dysplastic or neoplastic tissue driven by HPV infection. Live attenuated Listeria monocytogenes- (Lm-) based immunotherapy (ADXS11-001) has been developed for the treatment of HPV-associated diseases. ADXS11-001 secretes an antigen-adjuvant fusion (Lm-LLO) protein consisting of a truncated fragment of the Lm protein listeriolysin O (LLO) fused to HPV-16 E7. In preclinical models, this construct has been found to stimulate immune responses and affect therapeutic outcome. ADXS11-001 is currently being evaluated in Phase 2 clinical trials for cervical intraepithelial neoplasia, cervical cancer, and HPV-positive head and neck cancer. The use of a live attenuated bacterium is a more complex and complete method of cancer immunotherapy, as over millennia Lm has evolved to infect humans and humans have evolved to prevent and reject this infection over millennia. This evolution has resulted in profound pathogen-associated immune mechanisms which are genetically conserved, highly efficacious, resistant to tolerance, and can be uniquely invoked using this novel platform technology.

ADXS11-001 immunotherapy targeting HPV-E7: updated survival and safety data from a phase 2 study in Indian women with recurrent/refractory cervical cancer

ADXS11-001 immunotherapy is a live attenuated Listeria monocytogenes (Lm) bioengineered to secrete a HPV-16-E7 fusion protein targeting HPV transformed cells. The Lm vector serves as its own adjuvant and infects antigen presenting cells (APC) where it cross presents, stimulating MHC class I and II pathways resulting in specific T-cell immunity to tumors. Here we describe final 12 month overall survival data associated with ADXS11-001 administration in Lm-LLO-E7-015, a randomized P2 study conducted in India in 110 patients with recurrent cervical cancer; previously treated with chemotherapy, radiotherapy or both. Patients were randomized to either 1 cycle (3 doses) of ADXS11-001 at 1 x 109 cfu or 4 doses of ADXS11-001 at 1 x 109 cfu with cisplatin chemotherapy. Naprosyn and oral promethazine were given as premedications and a course of ampicillin was given 72 hours after infusion. Patients received CT scans at baseline and 3, 6, 9, 12 and 18 months. The primary endpoint is overall survival. As of May 17, 2013, the trial has completed enrollment and 110 patients received 264 doses of ADXS11-001. The percentage of patients at 12 months is 36% (39/110) and currently the 18 month survival is 22% (16/73). The response rate was 11% (6 CRs and 6 PR/110) with tumor responses observed in both treatment arms. 33 additional patients had stable disease > 3 months, for a disease control rate of 41% (45/110). Activity was observed against all high risk HPV strains detected. Two Grade 3 serious adverse events and 104 mild-moderate adverse events possibly related/related to ADXS11-001 treatment have been reported in 41% (45/110) of patients. The non-serious adverse events consisted predominately of transient, non-cumulative flu-like symptoms associated with infusion that either self-resolved or responded to symptomatic treatment. ADXS11-001 can be safely administered to patients with advanced cancer alone and in combination with chemotherapy. ADXS11-001 is well tolerated and presents a predictable and manageable safety profile. The addition of cisplatin to ADXS11-001 in this study did not significantly improve tumor responses or overall survival. Objective tumor responses included CR’s and apparent prolonged survival with minimal adverse experiences. Average duration of response in both treatment groups was 10.5 months. The 36% 12 month survival and 11% response rate observed in this recurrent disease setting is encouraging and suggests that ADXS11-001 is an active agent in recurrent cervical cancer. Final 18 month overall survival will be presented at the meeting.

ADXS11-001 immunotherapy targeting HPV-E7: final results from a Phase II study in Indian women with recurrent cervical cancer

Meeting abstracts ADXS11-001 immunotherapy is a live attenuated Listeria monocytogenes ( Lm ) bioengineered to secrete a tLLO-HPV-16-E7 fusion protein targeting HPV-transformed cells. The Lm vector serves as its own adjuvant and infects APC where it cross presents HPV-E7-tLLO fusion peptide,

Abstract LB-229: Agonistic antibodies to costimulatory molecules, OX40 and GITR, significantly enhance the antitumor efficacy of Listeria monocytogenes (Lm-LLO)-based immunotherapy

Combinational anti-cancer immune therapies that target multiple tumor-mediated suppressive mechanisms or enhance effector immunity are emerging as promising strategies for cancer treatment. Recently, we demonstrated that the combination of Listeria monocytogenes (Lm-LLO)-based immunotherapy (ADXS11-001) and anti-PD-1 antibody results in improved anti-tumor therapeutic and immune efficacy. Interestingly, regardless of the presence of an antigen or treatment with anti-PD-1 antibody, treatment with the Lm-LLO alone significantly inhibited the suppressive arm of the immune system, including regulatory T cells and myeloid-derived suppressor cells. We therefore hypothesized that combination of ADXS11-001 with agonistic antibodies against co-stimulatory molecules will lead to further improvement of immune and therapeutic efficacy as a result of the combined down-regulation of the suppressive arm and the enhancement of the effector arm. Here we demonstrate that combining Lm-LLO-based immunotherapy with anti-OX40 or anti-GITR antibodies lead to significant inhibition of tumor growth and prolonged survival of animals. The complete regression of established TC-1 tumors occurs in 40% and 60% of animals treated with ADXS11-001 in combination with anti-OX40 and anti-GITR antibodies, respectively. We show that this therapeutic potency enhancement is due to a significant increase in antigen-specific immune responses along with ADXS11-001-mediated inhibition of suppressor cells. Thus, we believe that simultaneous stimulation of T cells while inhibiting the suppressor cells, specifically using Lm-LLO-based immunotherapy combination with agonistic anti-co-stimulatory molecule antibody is a feasible and translatable approach that can lead to overall enhancement of the efficacy of an anti-tumor immunotherapy. Citation Format: Mikayel Mkrtichyan, Rajeev Shrimali, Shamim Ahmad, Rasha Abu Eid, Zuzana Berrong, Anu Wallecha, Robert Petit, Samir N. Khleif. Agonistic antibodies to costimulatory molecules, OX40 and GITR, significantly enhance the antitumor efficacy of Listeria monocytogenes (Lm-LLO)-based immunotherapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-229. doi:10.1158/1538-7445.AM2015-LB-229