A Randomized Phase 2 Study of ADXS11-001 Listeria monocytogenes–Listeriolysin O Immunotherapy With or Without Cisplatin in Treatment of Advanced Cervical Cancer

Basu, Partha; Mehta, Ajay; Jain, Minish; Gupta, Sudeep; Nagarkar, Rajnish; John, Subhashini; Petit, Robert G.

doi:10.1097/igc.0000000000001235

Cited by 132 publications

(89 citation statements)

References 22 publications

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“…Existing HPV prophylactic vaccines that elicit a humoral immune response cannot clear pre-established papillomavirus infections, which requires cellular immune responses that recognize and kill infected cells. There are ongoing efforts to develop therapeutic vaccines that can elicit effective cellular immune responses [43][44][45]; however, their effectiveness in eliciting a clinical response has been poor. Here, we identify K17 as a host factor induced in papillomaviruses-associated disease that mediates an immune-suppressive state within infected tissue in a natural infection model for HPVs.…”

Section: Discussionmentioning

confidence: 99%

Stress keratin 17 enhances papillomavirus infection-induced disease by downregulating T cell recruitment

et al. 2020

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High-risk human papillomaviruses (HPVs) cause 5% of human cancers. Despite the availability of HPV vaccines, there remains a strong urgency to find ways to treat persistent HPV infections, as current HPV vaccines are not therapeutic for individuals already infected. We used a mouse papillomavirus infection model to characterize virus-host interactions. We found that mouse papillomavirus (MmuPV1) suppresses host immune responses via overexpression of stress keratins. In mice deficient for stress keratin K17 (K17KO), we observed rapid regression of papillomas dependent on T cells. Cellular genes involved in immune response were differentially expressed in the papillomas arising on the K17KO mice correlating with increased numbers of infiltrating CD8 + T cells and upregulation of IFNγ-related genes, including CXCL9 and CXCL10, prior to complete regression. Blocking the receptor for CXCL9/CXCL10 prevented early regression. Our data provide a novel mechanism by which papillomavirus-infected cells evade host immunity and defines new therapeutic targets for treating persistent papillomavirus infections.

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Section: Discussionmentioning

confidence: 99%

Stress keratin 17 enhances papillomavirus infection-induced disease by downregulating T cell recruitment

et al. 2020

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“…62 Listeria infects APCs and replicates within the cytoplasm of the host through degradation of the phagosomal membrane. Basu et al 63 recently published the findings from their phase II trial of ADXS11-001 ± cisplatin in the treatment of 109 patients with CC who previously received chemotherapy, RT, or CRT. Patients were randomized to either 3 or 4 doses of ADXS11-001 with intravenous cisplatin chemotherapy (40 mg/m 2 ).…”

Section: Recombinant Listeria Monocytogenes Vaccinementioning

confidence: 99%

Role of Immunotherapy in the Management of Locally Advanced and Recurrent/Metastatic Cervical Cancer

Dyer¹,

Zamarin²,

Eskandar³

et al. 2019

J Natl Compr Canc Netw

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Despite combined therapeutic approaches, there is an unmet clinical need to identify effective strategies for improved patient outcomes in treating locally advanced and metastatic cervical cancer (CC). Immunotherapy is emerging as a novel therapeutic approach in this disease for which the causative agent, human papillomavirus (HPV), has dynamic, complex immunomodulatory effects. This review explores the biologic rational of immuno-oncology in the treatment of CC and discusses the initial clinical efficacy, ongoing clinical trials, and rationale for combined multimodal treatment approaches for locally advanced and recurrent/metastatic CC. The utility of immune checkpoint inhibitors is explored, including anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4), PD-1, and PD-L1. Preliminary data supporting the combination of radiotherapy and immunotherapy and areas of active drug development for CC are also reviewed.

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“…Two Phase II studies of ADXS11‐011 in women with persistent, recurrent and/or refractory cervical cancer have been undertaken, with an ORR of between 2 and 11% and a 12‐month survival rate of 34–38% . Whether early introduction of ADXS11‐011 can delay or prevent recurrences is currently under evaluation in the Phase III trial, AIM2CERVE (clinicaltrials.gov NCT02853604).…”

Section: Hpv Therapeutic Vaccinesmentioning

confidence: 99%

“…[75][76][77] Two Phase II studies of ADXS11-011 in women with persistent, recurrent and/or refractory cervical cancer have been undertaken, with an ORR of between 2 and 11% and a 12-month survival rate of 34-38%. 78,79 Whether early introduction of ADXS11-011 can delay or prevent recurrences is currently under evaluation in the Phase III trial, AIM2-CERVE (clinicaltrials.gov NCT02853604). Here, 450 patients with high-risk locally advanced cervical cancer will be randomised to receive ADXS11-011 vaccine or placebo following standard chemoradiation.…”

Section: Hpv Therapeutic Vaccinesmentioning

confidence: 99%

Targeted therapies in gynaecological cancers

Crusz

Miller

2019

Histopathology

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The treatment of cancer has changed dramatically over the last decade, driven by increased understanding of the cancer genome, immune landscape, molecular alterations and aberrant pathways that drive cancer progression. Advances in molecular biology have led to the development of targeted agents, including monoclonal antibodies, small molecules and check‐point inhibitors. Unlike chemotherapy, which inhibits DNA replication and mitosis, these agents target cancer signalling pathways, stroma, immune microenvironment and vasculature in tumour tissues. In gynaecological cancer, drugs targeting defective DNA repair, such as PARP inhibitors, have been approved for advanced ovarian cancer, and drugs targeting angiogenesis have been used in the treatment of advanced or recurrent ovarian and cervical cancers. Immune check‐point inhibitors such as anti‐PD‐1/PD‐L1 antibodies have proved successful for mismatch repair‐deficient endometrial cancers and HPV‐targeted therapies are under development for HPV‐related malignancies. In this era of precision medicine, improved understanding of cancer biology and genomics needs to be utilised to develop predictive biomarkers for these targeted therapies to maximise patient benefit.

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A Randomized Phase 2 Study of ADXS11-001 Listeria monocytogenes–Listeriolysin O Immunotherapy With or Without Cisplatin in Treatment of Advanced Cervical Cancer

Abstract: Supplemental digital content is available in the text.

Cited by 132 publications

References 22 publications

Stress keratin 17 enhances papillomavirus infection-induced disease by downregulating T cell recruitment

Stress keratin 17 enhances papillomavirus infection-induced disease by downregulating T cell recruitment

Role of Immunotherapy in the Management of Locally Advanced and Recurrent/Metastatic Cervical Cancer

Targeted therapies in gynaecological cancers

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