Coexpression of IL-18 Strongly Attenuates IL-12-Induced Systemic Toxicity through a Rapid Induction of IL-10 without Affecting its Antitumor Capacity

Rodríguez-Galán, María Cecilia; Reynolds, Della; Correa, Silvia G.; Iribarren, Pablo; Watanabe, Morihiro; Young, Howard A.

doi:10.4049/jimmunol.0804166

Cited by 26 publications

(53 citation statements)

References 46 publications

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“…ALT levels, which are often elevated following systemic IL-12 administration, 49 were substantially increased in mice receiving daily i. p. IL-12 but not a single i.t. chitosan/IL-12 injection.…”

Section: Discussionmentioning

confidence: 97%

Neoadjuvant immunotherapy with chitosan and interleukin-12 to control breast cancer metastasis

Yang

Kurtz

et al. 2014

OncoImmunology

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Metastasis accounts for approximately 90% of breast cancer-related deaths. Therefore, novel approaches which prevent or control breast cancer metastases are of significant clinical interest. Interleukin-12 (IL-12)-based immunotherapies have shown promise in controlling metastatic disease, yet modest responses and severe toxicities due to systemic administration of IL-12 in early trials have hindered clinical application. We hypothesized that localized delivery of IL-12 co-formulated with chitosan (chitosan/IL-12) could elicit tumor-specific immunity and provide systemic protection against metastatic breast cancer while minimizing systemic toxicity. Chitosan is a biocompatible polysaccharide derived primarily from the exoskeletons of crustaceans. In a clinically relevant resection model, mice bearing spontaneously metastatic 4T1 mammary adenocarcinomas received intratumoral injections of chitosan/IL-12, or appropriate controls, prior to tumor resection. Neoadjuvant chitosan/IL-12 immunotherapy resulted in long-term tumor-free survival in 67% of mice compared to only 24% or 0% of mice treated with IL-12 alone or chitosan alone, respectively. Antitumor responses following chitosan/IL-12 treatment were durable and provided complete protection against rechallenge with 4T1, but not RENCA renal adenocarcinoma, cells. Lymphocytes from chitosan/IL-12-treated mice demonstrated robust tumor-specific lytic activity and interferon-g production. Cell-mediated immune memory was confirmed in vivo via clinically relevant delayed-type hypersensitivity (DTH) assays. Comprehensive hematology and toxicology analyses revealed that chitosan/IL-12 induced transient, reversible leukopenia with no changes in critical organ function. Results of this study suggest that neoadjuvant chitosan/IL-12 immunotherapy prior to breast tumor resection is a promising translatable strategy capable of safely inducing to tumor-specific immunity and, in the long term, reducing breast cancer mortality due to progressive recurrences.

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Section: Discussionmentioning

confidence: 97%

Neoadjuvant immunotherapy with chitosan and interleukin-12 to control breast cancer metastasis

Yang

Kurtz

et al. 2014

OncoImmunology

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“…Our previous work also demonstrated that IFNγ was partially responsible for the IL-12-side effects. Moreover, our data demonstrated that increased survival of IL-12+IL-18-treated mice is associated with early IL-10 production and a reduction of IFNγ and TNFα serum levels [10]. In this context, the present work demonstrates that by using hydrodynamic injection to induce systemic co-expression of IL-12+IL-18 cDNAs or by pre-injecting a low dose of IL-12 cDNA prior to a large dose of IL-12 cDNA, we observed significantly increased survival and diminished hepatotoxicity.…”

Section: Introductionmentioning

confidence: 51%

“…Moreover, co-expression of IL-12+IL-18 was able to improve survival by diminishing IL-12-side effects [10]. Our previous work also demonstrated that IFNγ was partially responsible for the IL-12-side effects.…”

Section: Introductionmentioning

confidence: 57%

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Abrogation of TNFα Production during Cancer Immunotherapy Is Crucial for Suppressing Side Effects Due to the Systemic Expression of IL-12

et al. 2014

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For more than a decade, the cytokine interleukin-12 (IL-12) has been utilized, either alone or in combination with other drugs, as a treatment for cancer. The numerous anti-tumor properties of IL-12 still generate interest in the clinical use of this cytokine, even though it has demonstrated toxicity when administrated systemically. As an approach to overcome this toxicity, numerous laboratories have attempted to induce IL-12 expression at the site of the tumor. However for tumors that are difficult to remove surgically or for the treatment of disseminated metastases, systemic expression of this cytokine still remains as the most efficient method of administration. Nevertheless, finding alternative approaches for the use of IL-12 in the treatment of cancer and unraveling the basis of IL-12-side effects remain a challenge. In the present work we demonstrate that systemic expression of IL-12 through hydrodynamic injection of IL-12 cDNA is able to induce different types of liver lesions associated with a toxic pathology. However we report here that hepatic toxicity is diminished and survival of mice enhanced in the absence of tumor necrosis factor alpha (TNFα). This observation is in contrast to several murine models and clinical trials that postulate interferon gamma (IFNγ) as the main cytokine responsible for IL-12 toxicity. Moreover, our work demonstrates that when IL-12 cDNA is co-injected with IL-18 cDNA or when mice are pre-treated with a low dose of IL-12 cDNA prior to receiving a high dose of IL-12 cDNA, systemic levels of TNFα are almost completely abrogated, resulting in improved survival and less hepatic damage. Importantly, abrogation of TNFα signaling does not affect the strong anti-tumor activity of IL-12. Thus, neutralizing TNFα with antagonists already approved for human use offers a promising approach to abrogate IL-12 side effects during the use of this cytokine for the treatment of cancer.

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“…In later studies, the possibility to improve IL-12 as a therapeutic agent was explored by co-injecting mice with IL-12 and IL-18 cDNA. Surprisingly, this resulted in the rapid induction of IL-10, neutralization of tumour recrosis factor α (TNFα) and reduction in toxicity while anti-tumour activity of IL-12 was still retained [47]. Synergism was also shown in the clinic when patients with colorectal cancer were treated with pre-operative IL-2 immunotherapy resulting in increased IL-12 activity and decreased levels of VEGF in patient sera [48].…”

Section: Angiogenesis Inhibition In Combination With Immunotherapymentioning

confidence: 98%

The emerging quest for the optimal angiostatic combination therapy

Weiss

Berndsen

Abdul

et al. 2014

Biochemical Society Transactions

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Angiostatic therapies are now routinely embedded in the daily clinical management of cancer. Although these agents clearly benefit patient survival rates, the effect is only moderate with sometimes considerable side effects. A major cause of failure in this respect is the induction of resistance and tolerability against these drugs. Most angiostatic drugs are tyrosine kinase inhibitors that aim to inhibit or neutralize the activity of tumour-produced growth factors. Frustrating the tumour cells in this way results in genetic adaptations in the cells, turning them into mutants that are dependent on other growth mechanisms. It may therefore be necessary to shift to another class of drugs that directly target the tumour vasculature. It is evident that improvement of future angiogenesis inhibitors can only arise from two efforts. First, through the identification of better targets, preferably specifically expressed in the tumour vasculature. Secondly, through the development of combination therapies. The present review highlights the current efforts and challenges in trying to develop effective angiostatic combination therapies.

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Coexpression of IL-18 Strongly Attenuates IL-12-Induced Systemic Toxicity through a Rapid Induction of IL-10 without Affecting its Antitumor Capacity

Cited by 26 publications

References 46 publications

Neoadjuvant immunotherapy with chitosan and interleukin-12 to control breast cancer metastasis

Neoadjuvant immunotherapy with chitosan and interleukin-12 to control breast cancer metastasis

Abrogation of TNFα Production during Cancer Immunotherapy Is Crucial for Suppressing Side Effects Due to the Systemic Expression of IL-12

The emerging quest for the optimal angiostatic combination therapy

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