A Phase I Study of a Tropism-Modified Conditionally Replicative Adenovirus for Recurrent Malignant Gynecologic Diseases

Kimball, Kristopher J.; Preuss, Meredith A.; Barnes, Mack N.; Wang, Minghui; Siegal, Gene P.; Wan, Wen; Kuo, Hui-Chien; Saddekni, Souheil; Stockard, Cecil R.; Grizzle, William E.; Harris, Raymond D.; Aurigemma, Rosemarie; Curiel, David T.; Alvarez, Ronald D.

doi:10.1158/1078-0432.ccr-10-0791

Cited by 90 publications

(74 citation statements)

References 25 publications

(26 reference statements)

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“…This increases the antitumor potential and efficacy of nanocarriers, since they decrease the nutrients and oxygen delivery to the tumors, and release the low molecular anticancer drugs in the vicinity of the tumor vasculature [49,85]. This promising strategy is under preclinical development, with a few clinical examples in phase I [87][88][89]. An additional drawback, that contributes to the current clinical failure of active targeting nanocarriers, comprises the increased immunogenicity and plasma protein adsorption when targeting moieties are included in the nanocarriers, decreasing their bloodstream circulation time and their ability to passively target the tumors [85].…”

Section: Reprinted By Permission From Macmillan Publishers Ltd: [Natumentioning

confidence: 99%

Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy

Pérez-Herrero

Fernández‐Medarde

2015

European Journal of Pharmaceutics and Biopharmaceutics

1,403

754

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Cancer is the second worldwide cause of death, exceeded only by cardiovascular diseases. It is characterized by uncontrolled cell proliferation and an absence of cell death that, except for hematological cancers, generates an abnormal cell mass or tumor. This primary tumor grows thanks to new vasculatization and, in time, adquires metastatic potential and spreads to other body sites, which causes metastasis and finally death. Cancer is caused by damage or mutations in the genetic material of the cells due to environmental or inherited factors. While surgery and radiotherapy are the primary treatment used for local and non-metastatic cancers, anti-cancer drugs (chemotherapy, hormone and biological therapies) are the choice currently used in metastasic cancers. Chemotherapy is based on the inhibition of the division of rapidly growing cells, which is a characteristic of the cancerous cells, but unfortunately, it also affects normal cells with fast proliferation rates, like the hair follicles, bone marrow and gastrointestinal tract cells, generating the characteristic side effects of chemotherapy. The indiscriminate destruction of normal cells, the toxicity of conventional chemotherapeutic Código de campo cambiado

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Section: Reprinted By Permission From Macmillan Publishers Ltd: [Natumentioning

confidence: 99%

Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy

Pérez-Herrero

Fernández‐Medarde

2015

European Journal of Pharmaceutics and Biopharmaceutics

1,403

754

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“…ONYX-015, H101 (Oncorine) and other first-generation oncolytic crHAdVs have gone through several phase I/II trials without relevant signs of high grade toxicity but also without significant therapeutic effects, resulting in discontinuation of further trails. 48 More recent clinical trials employing new generations of crHAdVs like RGD retargeted oncolytic crHAdVs, 20,49,50 crHAdV-5/3 chimeric vectors, 32,[51][52][53][54] ColoAd1, 55 hTERT-promoter driven crHAdV-5 vector Telomelysin, 56 E2F-1-promoter driven CG0070 33 , Rbtargeted crHAdV expressing hyaluronidase (VCN-01) 57 and crHAdV vectors expressing immunomodulating genes have shown safety (low toxicity) with some promising preliminary results.…”

Section: Family Herpesviridae: Herpes Simplex Virus 1 (Hsv)mentioning

confidence: 99%

“…Shedding of crHAdVs from injection sites and patient excretions, although not always reported, has been observed in several (pre) clinical trials, and increases with higher doses and systemic administration. 49,[58][59][60][61][62][63][64] Shedding of HAdV vectors could result in homologous recombination between AdVs of the same subgroup, which occurs with high efficiency during growth in co-infected cultured cells, and there is evidence of recombination events in humans as well. [65][66][67] Theoretically, homologous recombination between wildtype AdVs and recombinant crHAdVs could lead to new wildtype AdVs that e.g.…”

Section: Family Herpesviridae: Herpes Simplex Virus 1 (Hsv)mentioning

confidence: 99%

Oncolytic viruses: From bench to bedside with a focus on safety

Buijs

Verhagen

Eijck

et al. 2015

Human Vaccines & Immunotherapeutics

108

105

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“…Further studies showed that ORCA-010 kills cancer cells more effectively than primary nonmalignant cells. Despite the enhanced potency, ORCA-010 was as selective as Ad5-D24RGD, which was shown to be safe for use in humans up to 3 · 10 ORCA-010 ANTITUMOR ACTIVITY IN PRECLINICAL MODELSviral particles (Kimball et al, 2010;Pesonen et al, 2012;Clemens Dirven, personal communication). Moreover, intratumoral injection of ORCA-010 in human prostate, ovarian, and lung cancer tumors xenografted in immunedeficient mice resulted in significant inhibition of tumor growth and prolonged survival.…”

Section: Orca-010 Replicates In Pc-3 Tumor Xenograftsmentioning

confidence: 99%

ORCA-010, a Novel Potency-Enhanced Oncolytic Adenovirus, Exerts Strong Antitumor Activity in Preclinical Models

DongWenliang

GinkelJan-Willem²,

AuKam³

et al. 2014

Human Gene Therapy

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Improving the antitumor potency of current oncolytic adenoviruses represents one of the major challenges in development of these viruses for clinical use. We have generated an oncolytic adenovirus carrying the safetyenhancing E1AD24 deletion, the potency-enhancing T1 mutation, and the infectivity-enhancing fiber RGD modification. The results of in vitro cytotoxicity assays on 15 human cancer cell lines derived from different tumor types demonstrated that ORCA-010 is more potent than Ad5-D24RGD or ONYX-015. As ORCA-010 will initially be developed for the treatment of prostate cancer, selectivity experiments were performed using primary human prostate cells. ORCA-010 killed cancer cells more effectively than these primary human cells. In both primary prostate fibroblasts and epithelial cells, ORCA-010 was as safe as Ad5-D24RGD. Evaluation of ORCA-010 in in vivo xenograft tumor models in nude mice showed that ORCA-010 significantly inhibited growth of prostate, lung, and ovarian tumors and conferred prolonged survival of tumor-bearing animals. Furthermore, we observed a substantial increase in infectious viral particles in tumors injected with ORCA-010. The number of infectious viral particles increased after treatment and infectious particles remained present up to at least 4 weeks posttreatment. Intratumoral virus replication was associated with substantial necrosis and fibrosis. In conclusion, ORCA-010 is more potent than earlier generation oncolytic adenoviruses, without demonstrating increased toxicity. ORCA-010 exerted strong in vivo antitumor activity and is therefore a suitable candidate for clinical evaluation.

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A Phase I Study of a Tropism-Modified Conditionally Replicative Adenovirus for Recurrent Malignant Gynecologic Diseases

Abstract: Purpose: To determine the maximum tolerated dose (MTD), toxicity spectrum, clinical activity, and biological effects of the tropism-modified, infectivity-enhanced conditionally replicative adenovirus (CRAd), Ad5-

Cited by 90 publications

References 25 publications

Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy

Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy

Oncolytic viruses: From bench to bedside with a focus on safety

ORCA-010, a Novel Potency-Enhanced Oncolytic Adenovirus, Exerts Strong Antitumor Activity in Preclinical Models

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