Phase I Trial of Intratumoral Injection of an Adenovirus Encoding Interleukin-12 for Advanced Digestive Tumors

Sangro, Bruno; Mazzolini, Guillermo; Ruiz, Juan; Herraiz, Maite; Quiroga, Jorge; Herrero, Ignacio; Benito, Alberto; Larrache, Javier; Pueyo, Jesús C.; Súbtil, José Carlos; Olagüe, Cristina; Sola, Josu; Sádaba, Belén; Lacasa, Carlos; Melero, Ignacio; Qian, Cheng; Prieto, Jesús

doi:10.1200/jco.2004.04.059

Cited by 292 publications

(211 citation statements)

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“…28–30 However, Ad/IL-12 alone failed in clinical trials of patients with hepatic malignancy. 31 One of the challenges in treating established hepatic tumor with immunotherapy is to induce anti-tumor immune responses within the tolerogenic microenvironment of the liver and in the hepatic tumor. There is growing evidence suggesting that RT may be a practical solution in overcoming his hurdle, and may enhance antitumor efficacy of immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

Combination of radiation and interleukin 12 eradicates large orthotopic hepatocellular carcinoma through immunomodulation of tumor microenvironment

Tsai

Lee

et al. 2018

OncoImmunology

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Immunotherapies have shown promising results in certain cancer patients. For hepatocellular carcinoma (HCC), the multiplicity of an immunotolerant microenvironment within both the tumor, and the liver per se may limit the efficacy of cancer immunotherapies. Since radiation induces immunogenic cell death and inflammatory reactions within the tumor microenvironment, we hypothesized that a combination therapy of radiation and lasting local immunostimulating agents, achieved by intratumoral injection of an adenoviral vector encoding interleukin 12, may reverse the immunotolerant microenvironment within a well-established orthotopic HCC toward a state favorable for inducing antitumor immunities. Our data showed that radiation and IL-12 combination therapy (RT/IL-12) led to dramatic tumor regression in animals bearing large subcutaneous or orthotopic HCC, induced systemic effect against distant tumor, and significantly prolonged survival. Radiation monotherapy induced tumor regression at early times but afterwards most tumors regained exponential growth, while IL-12 monotherapy only delayed tumor growth. Mechanistic studies revealed that RT/IL-12 increased expression of MHC class II and co-stimulatory molecules CD40 and CD86 on tumor-infiltrating dendritic cells, suggesting an improvement of their antigen presentation activity. RT/IL-12 also significantly reduced accumulation of tumor-infiltrating myeloid-derived suppressor cells (MDSCs) and impaired their suppressive functions by reducing production of reactive oxygen species. Accordingly, tumor-infiltrating CD8+ T cells and NK cells were significantly activated toward the antitumor phenotype, as revealed by increased expression of CD107a and TNF-α. Together, our data showed that RT/IL-12 treatment could reset the intratumoral immunotolerant state and stimulate activation of antitumor cellular immunity that is capable of eliminating large established HCC tumors.

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Section: Discussionmentioning

confidence: 99%

Combination of radiation and interleukin 12 eradicates large orthotopic hepatocellular carcinoma through immunomodulation of tumor microenvironment

Tsai

Lee

et al. 2018

OncoImmunology

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“…130 Viral delivery of IL-12 was also used in patients with advanced digestive cancer, but only led to mild antitumor effects. 131 Even though the treatment was well tolerated, adverse reactions were associated to vector injection. 131 Hence, a conscious manipulation of the balance between antivirus and antitumor responses is of special importance when using oncolytic viruses for IL-12-based immunotherapy.…”

Section: Il-12 To Treat Human Cancermentioning

confidence: 99%

New insights into IL-12-mediated tumor suppression

et al. 2014

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During the past two decades, interleukin-12 (IL-12) has emerged as one of the most potent cytokines in mediating antitumor activity in a variety of preclinical models. Through pleiotropic effects on different immune cells that form the tumor microenvironment, IL-12 establishes a link between innate and adaptive immunity that involves different immune effector cells and cytokines depending on the type of tumor or the affected tissue. The robust antitumor response exerted by IL-12, however, has not yet been successfully translated into the clinics. The majority of clinical trials involving treatment with IL-12 failed to show sustained antitumor responses and were associated to toxic side effects. Here we discuss the therapeutic effects of IL-12 from preclinical to clinical studies, and will highlight promising strategies to take advantage of the antitumor activity of IL-12 while limiting adverse effects.

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“…[27][28][29] However, although in our phase I/II study, the intratumor administration of firstgeneration adenovirus encoding human IL-12 (hIL-12) has been well tolerated, the antitumor effects were quite weak. 30 This lack of efficacy likely depends on short duration of transgene expression and on the fact that the tumor tissue is not easily infected with adenoviral vectors. Thus, to be effective, it would be necessary to infect peritumoral tissue with long-term expression vectors encoding cytokines endowed with potent immunostimulant and antiangiogenic properties such as IL-12.…”

mentioning

confidence: 99%

Prolonged and inducible transgene expression in the liver using gutless adenovirus: A potential therapy for liver cancer

et al. 2004

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Phase I Trial of Intratumoral Injection of an Adenovirus Encoding Interleukin-12 for Advanced Digestive Tumors

Abstract: Intratumoral injection of up to 3 x 10(12) viral particles of Ad.IL-12 to patients with advanced digestive malignancies is a feasible and well-tolerated procedure that exerts only mild antitumor effects.

Cited by 292 publications

References 19 publications

Combination of radiation and interleukin 12 eradicates large orthotopic hepatocellular carcinoma through immunomodulation of tumor microenvironment

Combination of radiation and interleukin 12 eradicates large orthotopic hepatocellular carcinoma through immunomodulation of tumor microenvironment

New insights into IL-12-mediated tumor suppression

Prolonged and inducible transgene expression in the liver using gutless adenovirus: A potential therapy for liver cancer

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