ArticlePDF Available

ADXS11-001 LM-LLO Immunotherapy Targeting HPV-E7: Preliminary Safety and Survival Data From a Phase 2 Study in Indian Women With Recurrent/Refractory Cervical Cancer

DOI:10.1186/2051-1426-1-S1-P231
Authors:
Robert Petit at RGP Biotech
Robert Petit
  • RGP Biotech
Partha Basu at International Agency for Research on Cancer
Partha Basu
Download full-text PDF
Read full-text
Download citation

Abstract

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.
Available via license: CC BY 2.0
Content may be subject to copyright.
P O STER P RESENTATION Open Access
ADXS11-001 immunotherapy targeting HPV-E7:
updated survival and safety data from a phase
2 study in Indian women with recurrent/refractory
cervical cancer
Robert G Petit
1*
, Partha Basu
2
From Society for Immunotherapy of Cancer 28th Annual Meeting
National Harbor, MD, USA. 8-10 November 2013
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, stimulat-
ing MHC class I and II pathways resulting in specific
T-cell immunity to tumors. Here we describe final
12 month ov era ll s urvi val data associated with ADXS11-
001 administ ration in Lm-L LO-E7- 015, a randomized P2
study conduct ed in India in 110 pat ients with recurrent
cervical cancer; previously treate d w ith c hemotherapy,
radiotherapy or both. Patients were randomized to either
1cycle(3doses)ofADXS11-001at1x10
9
cfu or 4
dosesofADXS11-001at1x10
9
cfuwithcisplatinche-
motherapy. 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 end-
point 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 adv erse events
consisted predominately of transient, non-cumulative flu-
like symptoms associated with infusion that eithe r s elf-
resolved or responded to symptomatic treatment.
ADXS11-001 can be safely admi nist ered to patien ts with
advanced cancer alone and in combination with che-
motherapy. 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 signifi-
cantly improve tumor responses or overall survival.
Objective t umor responses included CR’ s a nd apparent
prolonged survival with minimal adverse experiences.
Average duration of response in both treatment groups
was 10.5 mon ths. 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.
Authors’ details
1
Advaxis, Inc., Princeton, NJ, USA.
2
Chittaranjan National Cancer Institute,
Kolkata, India.
Published: 7 November 2013
doi:10.1186/2051-1426-1-S1-P231
Cite this article as: Petit and Basu: ADXS11-001 immunotherapy
targeting HPV-E7: updated survival and safety data from a phase
2 study in Indian women with recurrent/refractory cervical cancer.
Journal for ImmunoTherapy of Cancer 2013 1(Suppl 1):P231.
1
Advaxis, Inc., Princeton, NJ, USA
Full list of author information is available at the end of the article
Petit and Basu Journal for ImmunoTherapy of Cancer 2013, 1(Suppl 1):P231
http://www.immunotherapyofcancer.org/content/1/S1/P231
© 2 013 Petit and Basu; licensee BioMed Central Ltd. This is a n Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/lice nses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
... It is worth mentioning that Advaxis, a clinical-stage biotechnology company, has made a major breakthrough in Lm immunotherapy technology. Among them, the ADXS11-001 vaccine, a live attenuated Lm bacterium bioengineered to secrete the HPV-16 E7 protein fused with a truncated fragment of listeriolysin O (tLLO), has been used in the treatment of anal and cervical cancer and has conducted clinical trials [8,9]. In addition, the ADXS31-142 (secretion of LLO and human prostate specific antigen) and ADXS31-164 (secretion of chimeric tLLO fusion protein containing immunogenic regions of HER2 protein) vaccines were used to treat prostate and breast cancer, respectively [10,11]. ...
Systematic identification of a panel of strong promoter regions from Listeria monocytogenes for fine-tuning gene expression
Article
Full-text available
Background Attenuated Listeria monocytogenes (Lm) has been widely used as a vaccine vector in the prevention and treatment of pathogen infection and tumor diseases. In addition, previous studies have proved that the attenuated Lm can protect zebrafish from Vibrio infections, indicating that the attenuated Lm has a good application prospect in the field of aquatic vaccines. However, the limitation mainly lies in the lack of a set of well-characterized natural promoters for the expression of target antigens in attenuated Lm. Results In our study, candidate strong promoters were identified through RNA-seq analysis, and characterized in Lm through enhanced green fluorescent protein (EGFP). Nine native promoters that showed stronger activities than that of the known strong promoter P 36 under two tested temperatures (28 and 37 °C) were selected from the set, and P 29 with the highest activity was 24-fold greater than P 36 . Furthermore, we demonstrated that P 29 could initiate EGFP expression in ZF4 cells and zebrafish embryos. Conclusions This well-characterized promoter library can be used to fine-tune the expression of different proteins in Lm. The availability of a well-characterized promoter toolbox of Lm is essential for the analysis of yield increase for biotechnology applications.
... ADXS11-001 showed a disease control rate (DCR) of 43%, a RR of 11%, and 18-month OS of 28%. Despite the combination was well tolerated, adding cisplatin to ADXS11-001 did not show any additional benefit [36]. ...
Targeted Agents in Cervical Cancer: Beyond Bevacizumab
Article
Full-text available
Cervical cancer constitutes a leading cause of morbidity and cancer deaths in women throughout the world. Approximately two thirds of the patients are diagnosed with locally advanced cervical cancer, showing disappointing survival rates despite correct multidisciplinary management. Metastatic disease implies a poor prognosis itself since diagnosis. Platinum-based chemotherapy has been the backbone treatment of metastatic cervical cancer for years with no major outstanding improvements on survival. The addition of new molecules, such as antiangiogenic agents, dramatically changed the treatment of this disease. Bevacizumab, an antiangiogenic agent that targets vascular endothelial growth factor 2 (VEGF-2), added to standard chemotherapy in cervical cancer showed significant improvement on survival; therefore, the combination of carboplatin, paclitaxel, and bevacizumab is currently the standard frontline treatment in cervical cancer. Other antiangiogenic agents have been tested in this disease with no further development nor approvals. New compounds are currently being under development with promising results in this disease as well as a number of new strategies that could potentially fulfill the unmet need of establishing effective therapeutic approaches in cervical cancer.
... The safety of LM vaccine has been well-demonstrated in human clinical trials: Angelakopoulos's clinical trial demonstrated the ability of an attenuated LM-based empty vaccine to safely and effectively induce antigen-specific T cell responses in humans (Angelakopoulos et al., 2002); Maciag's Phase I trial and Petit's Phase II clinical trial with LM-LLO-E7 verified that the safe and effective recombinant vaccines could be potentially a new therapeutic option (Maciag et al., 2009;Petit and Basu, 2013). LM has particular advantages to offer as a neonatal vaccine vehicle: attenuated strains of LM that are safe for neonates have now been identified, and interestingly, they are very efficient at inducing robust Th1-type immunity in neonates (Kollmann et al., 2007). ...
A Promising Listeria-Vectored Vaccine Induces Th1-Type Immune Responses and Confers Protection Against Tuberculosis
Article
Full-text available
  • Sep 2017
Deaths associated with tuberculosis (TB) is rising and accounted for 1.4 million deaths in 2015 many of which were due to drug-resistant bacteria. Vaccines represent an important medical intervention, but the current Bacilli Calmette-Guerin (BCG) vaccine is not ideal for the protection of teenagers and adults. Therefore, a safe and effective vaccine is urgently needed. In this study, we designed a novel vaccine using an attenuated Listeria monocytogenes strain carrying fusion antigen FbpB-ESAT-6 (rLM) and characterized its safety and protective efficacy against Mycobacterium tuberculosis (M.tb) infection in mice. Compared to the wild type strain yzuLM4 and parental strain LMΔactA/plcB (LM1-2), the virulence of rLM was significantly reduced as judged by its infectious kinetics and LD50 dose. Further characterization of intravenous immunization showed that prime-boost vaccination significantly increased the levels of Th1 cytokines (IFN-γ, IL-17, and IL-6), and enhanced cytotoxic T lymphocyte (CTL) CTLs activity, suggesting that rLM could elicit potent Th1/Th17 responses. More importantly, rLM significantly conferred the protection against M.tb H37Rv challenge. Collectively, our findings indicated that rLM is a novel and useful tool to prevent M.tb infection, and can be potentially be used to boost BCG-primed immunity.
Nanoparticle‐based applications for cervical cancer treatment in drug delivery, gene editing, and therapeutic cancer vaccines
Article
Full-text available
  • May 2021
Cervical cancer is a leading cause of gynecological tumor related deaths worldwide. The applications of conventional approaches such as chemoradiotherapy and surgery are restricted due to their side effects and drug resistances. Although immune checkpoint inhibitors (ICIs) have emerged as novel choices, their clinical response rates are rather limited. To date there is a lack of effective treatment regimens for patients with metastatic or recurrent cervical cancer. Recently nanomaterials like liposomes, dendrimers, and polymers are considered as promising delivery carriers with advantages of tumor‐specific administration, reduced toxicity, and improved biocompatibility. Here, we review the applications of nanoparticles in the fields of drug delivery, CRISPR based genome‐editing and therapeutic vaccines in cervical cancer treatment. This article is categorized under: • Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Abstract Recent progresses in nanoparticle‐based delivery systems show potential foreground for enhancing clinical benefits while minimizing systemic toxicities in cervical cancer.
Anti-Cancer Vaccine for HPV-Associated Neoplasms: Focus on a Therapeutic HPV Vaccine Based on a Novel Tumor Antigen Delivery Method Using Endogenously Engineered Exosomes
Article
Full-text available
  • Jan 2019
Some human papillomavirus (HPV) genotypes are universally recognized as major etiological agents not only of ano-genital tumors but also of head and neck cancers, which show increasing incidence. The evaluation of current and future therapeutic approaches against HPV-induced tumors is a global health priority, despite an effective prophylactic vaccine against 7 of the 12 genotypes involved in the etiology of tumors being currently available. In this review, we present the main anti-HPV therapeutic approaches in clinical experimentation, with a focus on a novel tumor antigen delivery method using engineered exosomes, that we recently developed. Our system allows the induction of an efficient unrestricted cytotoxic T lymphocyte (CTL) immune response against the HPV16-E7 tumor-associated antigen, with the formation of endogenously engineered exosomes, i.e., nanovesicles spontaneously released by all cell types. Immunogenic exosomes are uploaded with HPV16-E7 due to the fusion with a unique exosome-anchoring protein referred to as Nefmut. Intramuscular injection of a DNA vector expressing the fusion protein generates exosomes sufficiently immunogenic to elicit a potent anti-16E7 CTL immune response. The approach is described here and the advantages over other existing methodologies are reported.
Prospects and progress of Listeria-based cancer vaccines
Article
Introduction: The development of an effective therapeutic vaccine to induce cancer-specific immunity remains problematic. Recently, a species of intracellular pathogen known as Listeria monocytogenes (Lm) has been used to transfer DNA, RNA and proteins into tumour cells as well as elicit an immune response against tumour-specific antigens. Areas covered: Herein, the authors provide the mechanisms of different Listeria monocytogenes strains, which are potential therapeutic cancer vaccine vectors, in addition to their preclinical and clinical development. They also speculate on the future of Lm-based tumour immunotherapies. The article is based on literature published on PubMed and data reported in clinical trials. Expert opinion: Attenuated strains of Listeria monocytogenes have safely been applied as therapeutic bacterial vectors for the delivery of cancer vaccines. These vectors stimulate MHCI and MHCII pathways as well as the proliferation of antigen-specific T lymphocytes. Several preclinical studies have demonstrated the potency of Lm in intracellular gene and protein delivery in vitro and in vivo. They have also indicated safety and efficiacy in clinical trials. Readers should be aware that the ability of attenuated Lm strains to induce potent immune responses depends on the type of deleted or inactivated Lm virulent gene or genes.
Immunotherapy in ovarian, endometrial and cervical cancer: State of the art and future perspectives
Article
  • Jul 2017
The tumors of the female genital tract represent a leading cause of morbidity and mortality among women worldwide. Substantial progresses have been made in ovarian cancer, with the increasing knowledge about BRCA mutated tumors and the recent development of PARP inhibitors, and in cervical cancer, thanks to extensive screening and widespread of vaccination against Human Papilloma Virus. Nevertheless many needs remain unmet, advanced stage diseases are still incurable and cervical and endometrial carcinoma, as well as platinum-resistant ovarian carcinoma, can certainly be classifiable among the cancers with poor sensitivity to conventional chemotherapy. Immunotherapy, including a number of approaches, checkpoint inhibitors, adoptive cellular transfer, vaccines, has experienced a remarkable growth in the last few years and it is already an available option in melanoma, lung and renal malignancies. We reviewed the main findings about the immune microenvironment in ovarian, endometrial and cervical cancer with a special focus on the clinical data, the therapeutic implications and the most promising novel agents.
Investigational drugs for the treatment of cervical cancer
Article
  • Mar 2017
Introduction: Cervical cancer (CC) is currently the fourth most common malignant disease of women worldwide. Although the incidence and the mortality rates have been decreasing with screening detection and new treatment strategies, a significant number of metastatic or recurrent disease is still diagnosed. For those patients not amenable to curative treatments, such as surgery and radiation, palliative chemotherapy remains the standard of care. As chemotherapy regimens have limited activity, research is focalized on investigating novel pharmacologic strategies. Areas covered: This paper aims to give a complete and updated overview on investigated therapies for the treatment of CC. The authors review the results of clinical studies and highlight the ongoing trials. Expert opinion: Agents targeting various molecular pathways including epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), mammalian target of rapamycin (mTOR), poly ADP-ribose polymerase (PARP), epigenetics and other biological mechanisms represent interesting investigational opportunities. Amongst such drugs, bevacizumab, an anti-VEGF monoclonal antibody, was the first targeted drug recently approved by the FDA for the treatment of patients with metastatic, recurrent, or persistent CC. Another interesting experimental approach is represented by immunotherapy, which is leading to promising results with to the development of therapeutic vaccines and immune checkpoints inhibitors.
New Strategies for Multimodality Therapy in Treating Locally Advanced Cervix Cancer
Article
  • May 2016
Cervical cancer is the fourth most common cause of cancer of women worldwide. In the developing world, it comprises 12% of all cancers of women. Since 1999, the mainstay of treatment for locally advanced cervical cancer (LACC) has been concurrent cisplatin-based chemoradiation (CCR). However, outcomes in this disease remain suboptimal, with long-term PFS and OS rates of approximately 60%. There are several new strategies of combined modality treatment under evaluation in LACC, including chemotherapy before and after treatment as well as novel agents such as PARP inhibitors, anti-angiogenic blockage, and immunotherapy. We provide a brief overview of these strategies and their potential in the treatment of women with LACC.
Cervical cancer: Whats new?
Article
Full-text available
Cervical cancer is the most common gynecological cancer in Brazil. Among women, it is the second most frequent, second only to breast cancer. It is the fourth leading cause of cancer death in the country, with estimated 15,590 new cases (2014) and 5,430 deaths (2013). In order to update information to improve outcomes, reduce morbidity and optimize the treatment of this cancer, this article will address the advancement of knowledge on cervical cancer. The topics covered include the role of surgery in different stages, treatment of locally advanced carcinomas, fertility preservation, the role of the sentinel lymph node technique, indications and techniques of radiotherapy and chemotherapy, and some special situations.
ResearchGate has not been able to resolve any references for this publication.