Pilot trial of genetically modified, attenuated Salmonella expressing the E. coli cytosine deaminase gene in refractory cancer patients

Nemunaitis, John; Cunningham, Casey; Senzer, Neil; Kuhn, Joseph A.; Cramm, Jennifer; Litz, Craig E.; Cavagnolo, Robert; Cahill, Ann; Clairmont, Caroline; Sznol, Mario

doi:10.1038/sj.cgt.7700634

Cited by 289 publications

(222 citation statements)

References 30 publications

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“…20,31 For gene therapy in general, a paucity of technologies to monitor events post vector administration to patients represents a block in clinical progression. 32 Indeed, in response to the first gene therapy death, the NIH Recombinant DNA Advisory Committee (RAC) called for better assays to monitor gene delivery.…”

Section: Bacterial-mediated Tumor Therapymentioning

confidence: 99%

Bacterial vectors for imaging and cancer gene therapy: a review

et al. 2012

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The significant burden of resistance to conventional anticancer treatments in patients with advanced disease has prompted the need to explore alternative therapeutic strategies. The challenge for oncology researchers is to identify a therapy which is selective for tumors with limited toxicity to normal tissue. Engineered bacteria have the unique potential to overcome traditional therapies' limitations by specifically targeting tumors. It has been shown that bacteria are naturally capable of homing to tumors when systemically administered resulting in high levels of replication locally, either external to (non-invasive species) or within tumor cells (pathogens). Pre-clinical and clinical investigations involving bacterial vectors require relevant means of monitoring vector trafficking and levels over time, and development of bacterial-specific real-time imaging modalities are key for successful development of clinical bacterial gene delivery. This review discusses the currently available imaging technologies and the progress to date exploiting these for monitoring of bacterial gene delivery in vivo.Cancer Gene Therapy ( INTRODUCTIONAlthough the potential anti-cancer effects of acquired bacterial infection have been evident for over 120 years and the presence of bacteria in excised tumors has been noted for over 60 years, 1 it is only in more recent times that the tumor-specific growth of bacteria has been considered for therapeutic purposes. While the precise mechanism(s) behind preferential bacterial tumor colonization remain poorly understood, this phenomenon must relate to unique tumor attributes that separate them from healthy tissues. Factors such as the irregular blood supply; local immune suppression; inflammation; and unique nutrient supply (e.g., purines) in tumors have been proposed to play a role. 2 Bacterial entry into the tumor environment is proposed to be facilitated by the leaky vasculature. Cancer cells are characterized by an aberrantly accelerated metabolism and proliferation leading to an imbalance of oxygen supply and consumption which is a major causative factor of tumor hypoxia. 3 The hypoxic nature of solid tumors enhances the growth of anaerobic and facultatively anaerobic bacteria. In addition, these areas with low oxygen and high interstitial pressure are considered to be an immunological sanctuary, where bacterial clearance mechanisms are greatly inhibited. 4 Necrotic regions are also rich in nutrients favoured by bacteria due to tumor cell turnover. However, tumor selective bacterial colonization now appears to be both bacterial species and tumor origin independent, since aerobic bacteria are also capable of colonising tumors, and even small tumors lacking an anaerobic center are colonised. See Figure 1 for proposed mechanisms.Invasive bacteria can internalize and replicate within tumor cells, while non-invasive bacteria grow externally to tumor cells, within the tumor micro-environment. 5 The tumor selective growth of bacteria has made them an attractive vehicle for the delivery of ...

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Section: Bacterial-mediated Tumor Therapymentioning

confidence: 99%

Bacterial vectors for imaging and cancer gene therapy: a review

et al. 2012

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“…In spite of great success in a preclinical setting, the application of bacteria for human tumor therapy has not been particularly efficacious, although this approach was well tolerated in most studies. [61][62][63] In light of above-mentioned findings, however, we would suggest that angiogenesis would be a meaningful target for further experimental and clinical studies of bacteria-mediated anti-cancer therapy, particularly if used in conjunction with oncolytic strains of bacteria.…”

Section: Alternative Gene Therapymentioning

confidence: 99%

Gene therapy for cancer: bacteria-mediated anti-angiogenesis therapy

et al. 2011

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Several bacterial species have inherent ability to colonize solid tumors in vivo. However, their natural anti-tumor activity can be enhanced by genetic engineering that enables these bacteria express or transfer therapeutic molecules into target cells. In this review, we summarize latest research on cancer therapy using genetically modified bacteria with particular emphasis on blocking tumor angiogenesis. Despite recent progress, only a few recent studies on bacterial tumor therapy have focused on anti-angiogenesis. Bacteria-mediated anti-angiogenesis therapy for cancer, however, is an attractive approach given that solid tumors are often characterized by increased vascularization. Here, we discuss four different approaches for using modified bacteria as anti-cancer therapeutics-bactofection, DNA vaccination, alternative gene therapy and transkingdom RNA interference-with a specific focus on angiogenesis suppression. Critical areas and future directions for this field are also outlined.

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“…Replicating bacteria have also been briefly tested in clinical trial. 313 Additional measures to modify viral activity by combining treatment with relevant immune modulation therapy (rituximab, enbrel) requires further exploration. Other studies have also shown that modification of the E3 region may minimize viral potency with respect to the durability of selective replication.…”

Section: Other Viral Approachesmentioning

confidence: 99%

Oncolytic viral therapies

2004

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Molecular research has vastly advanced our understanding of the mechanism of cancer growth and spread. Targeted approaches utilizing molecular science have yielded provocative results in the treatment of cancer. Oncolytic viruses genetically programmed to replicate within cancer cells and directly induce toxic effect via cell lysis or apoptosis are currently being explored in the clinic. Safety has been confirmed and despite variable efficacy results several dramatic responses have been observed with some oncolytic viruses. This review summarizes results of clinical trials with oncolytic viruses in cancer.

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Pilot trial of genetically modified, attenuated Salmonella expressing the E. coli cytosine deaminase gene in refractory cancer patients

Cited by 289 publications

References 30 publications

Bacterial vectors for imaging and cancer gene therapy: a review

Bacterial vectors for imaging and cancer gene therapy: a review

Gene therapy for cancer: bacteria-mediated anti-angiogenesis therapy

Oncolytic viral therapies

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