Regional Liver Therapy Using Oncolytic Virus to Target Hepatic Colorectal Metastases

Carpenter, Stephen M.; Carson, Joshua; Fong, Yuman

doi:10.1053/j.seminoncol.2010.03.001

Cited by 15 publications

(13 citation statements)

References 75 publications

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“…MSLN-targeted CAR T cells will be delivered through intrapleural catheters, an approach we developed to be the standard of care in managing patients with malignant pleural effusions (62). The regional administration of biological agents such as cytokines (63) and oncolytic virus (64) has been previously translated to the clinic with success. Our studies strongly support that regional CAR T cell administration to subjects with MPM will result in greater T cell anti-tumor potency with reduced T cell doses, owing in part to early CD4+ T cell activation and the systemic benefits that ensue.…”

Section: Discussionmentioning

confidence: 99%

Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity

et al. 2014

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Translating the recent success of chimeric antigen receptor (CAR) T cell therapy for hematological malignancies to solid tumors will necessitate overcoming several obstacles, including inefficient T cell tumor infiltration and insufficient functional persistence. Taking advantage of an orthotopic model that faithfully mimics human pleural malignancy, we evaluated two routes of administration of mesothelin-targeted T cells using the M28z CAR. We found that intra-pleurally administered CAR T cells vastly out-performed systemically infused T cells, requiring 30-fold fewer M28z T cells to induce long-term complete remissions. Following intrapleural T cell administration, prompt in vivo antigen-induced T cell activation allowed robust CAR T cell expansion and effector differentiation, resulting in enhanced anti-tumor efficacy and functional T cell persistence for 200 days. Regional T cell administration also promoted efficient elimination of extrathoracic tumor sites. This therapeutic efficacy was dependent on early CD4+ T cell activation associated with a higher intra-tumoral CD4/CD8 cell ratios and CD28-dependent CD4+ T cell-mediated cytotoxicity. In contrast, intravenously delivered CAR T cells, even when accumulated at equivalent numbers in the pleural tumor, did not achieve comparable activation, tumor eradication or persistence. The remarkable ability of intrapleurally administered T cells to circulate and persist supports the concept of delivering optimal CAR T cell therapy through “regional distribution centers.” Based on these results, we are opening a phase I clinical trial to evaluate the safety of intrapleural administration of mesothelin-targeted CAR T cells in patients with primary or secondary pleural malignancies.

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Section: Discussionmentioning

confidence: 99%

Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity

et al. 2014

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“…However, the safety of HAI administration of OVs is of great concern, particularly after the tragic incident of a fatal systemic inflammatory response syndrome in a patient following adenoviral gene transfer. 11 There have been a few preclinical and clinical studies on the safety of HAI of OVs, such as adenovirus, herpes simplex virus-1, and vesicular stomatitis virus (VSV), 12 – 14 but there is no safety information for the HAI administration of oncolytic poxvirus. In addition, it should be noted that >70% HCC patients have liver cirrhosis and/or other liver disorders; in a previous study conducted by Altomonte et al, the HAI administration of VSV showed no acute (up to 3 days) toxicity in rats with liver fibrosis.…”

Section: Introductionmentioning

confidence: 99%

Preclinical safety evaluation of hepatic arterial infusion of oncolytic poxvirus

Cho

Ryu²,

Feng³

et al. 2018

DDDT

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PurposeOncolytic poxvirus has shown promise in treating various solid tumors, such as liver cancer, and administration of oncolytic poxvirus via the hepatic artery may provide more survival benefits than other routes of administration. However, there is a lack of safety information to guide the application of hepatic arterial infusion (HAI) of oncolytic poxvirus in human studies. To investigate the acute and chronic toxicity of HAI administration of oncolytic poxvirus in animals and provide safety information for future human studies.MethodsVVtk−, a vaccinia poxvirus with inactivated thymidine kinase gene, was administered via HAI to rabbits with normal liver function under angiography (1×108 or 1×109 pfu), and rats with N-nitrosomorpholine-induced precancerous liver cirrhosis under open surgery (1×108 pfu). Body weights and survival were monitored and blood samples were collected for hematological and biochemical tests. Distribution of A56 (a specific marker for poxvirus infection) in rabbit organs was evaluated using immunofluorescence assays.ResultsHAI of high doses of VVtk− did not cause any acute or chronic changes in body weight, survival or in biochemical, hematological tests in the 2 animal models, and none of the changes showed dose dependency (in rabbit study), or were influenced by liver cirrhosis (in rat study). A56 was not detected in any of the major rabbit organs.ConclusionHAI may provide a safe alternative route of oncolytic poxvirus administration for human studies.

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“…1 Despite the fact that recent progress in diagnosis and treatment has increased the number of patients who have been completely cured at an early stage of the disease, the prognosis for advanced forms of this cancer is still very poor, with treatment limited to palliation for the vast majority of patients. 2 The development of colorectal cancer (CRC) is a multistep process brought about by the accumulation of several genetic alterations, including chromosomal abnormality, gene mutations and epigenetic modifications involving several genes regulating proliferation, differentiation, apoptosis and angiogenesis. 3,4 Of the various genetic alterations, only a few are involved in cell growth and will lead to cancer development.…”

Section: Introductionmentioning

confidence: 99%

Prognostic vs predictive molecular biomarkers in colorectal cancer: is KRAS and BRAF wild type status required for anti-EGFR therapy?

Rizzo

Bronte

Fanale

et al. 2010

Cancer Treatment Reviews

103

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s u m m a r yAn important molecular target for metastatic CRC treatment is the epidermal growth factor receptor (EGFR). Many potential biomarkers predictive of response to anti-EGFR monoclonal antibodies (cetuximab and panitumumab) have been retrospectively evaluated, including EGFR activation markers and EGFR ligands activation markers. With regard to the "negative predictive factors" responsible for primary or intrinsic resistance to anti-EGFR antibodies a lot of data are now available. Among these, KRAS mutations have emerged as a major predictor of resistance to panitumumab or cetuximab in the clinical setting and several studies of patients receiving first and subsequent lines of treatment have shown that those with tumors carrying KRAS mutations do not respond to EGFR-targeted monoclonal antibodies or show any survival benefit from such treatments. The role of B-RAF mutations, mutually exclusive with KRAS mutations, in predicting resistance to anti-EGFR mAbs is not yet consolidated. It therefore appears that BRAF mutations may play a strong negative prognostic role and only a slight role in resistance to anti-EGFR Abs.

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Regional Liver Therapy Using Oncolytic Virus to Target Hepatic Colorectal Metastases

Cited by 15 publications

References 75 publications

Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity

Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity

Preclinical safety evaluation of hepatic arterial infusion of oncolytic poxvirus

Prognostic vs predictive molecular biomarkers in colorectal cancer: is KRAS and BRAF wild type status required for anti-EGFR therapy?

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