Neoadjuvant therapy with interleukin-12–loaded polylactic acid microspheres reduces local recurrence and distant metastases

Sabel, Michael S.; Hill, Hank C.; Jong, Yong S.; Mathiowitz, Edith; Bankert, Richard B.; Egilmez, Nejat K.

doi:10.1067/msy.2001.115839

Cited by 26 publications

(23 citation statements)

References 25 publications

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“…33 Another related study investigated the effect of neoadjuvant immunotherapy with IL-12-loaded microspheres in the Line-1 lung cancer model. 34 Administration of IL-12-loaded microspheres prior to resection resulted in decreased local recurrence and pulmonary metastases. The percentage of mice with pulmonary nodules was reduced from 60% following resection alone to 20% with neoadjuvant IL-12-loaded microspheres and resection.…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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

Yang

Kurtz

et al. 2014

OncoImmunology

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“…In this way, the tumor itself serves as the vaccine, precluding the cost and difficulty in establishing a cell line and transfecting it with the gene for a cytokine. We have previously described an alternate strategy for in situ cytokine delivery: the use of slowrelease polymer microspheres [1,12,13]. Using the poorly immunogenic B16 (murine melanoma) model, we sought to identify the optimum cytokines (or combination) for in situ vaccination, and to compare this neoadjuvant approach to the adjuvant use of autologous cellular vaccines.…”

Section: Discussionmentioning

confidence: 99%

Neoadjuvant intratumoral cytokine‐loaded microspheres are superior to postoperative autologous cellular vaccines in generating systemic anti‐tumor immunity

Arora

Mathiowitz

et al. 2006

Journal of Surgical Oncology

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“…In this study, by treatment of a single dose of microcapsules containing NIH3T3-mIL-12 cells, the growth of tumor xenografts was significantly inhibited and the mice survival time was significantly prolonged. This result also showed that the approach for local and sustained release of interleukin 12 could induces both innate and adaptive antitumor immune responses resulting in significant growth suppression and metastases of tumor [29][30][31] . It should also be emphasized that controlling the amount of encapsulated cells makes an appropriate concentration of IL-12 obtainable.…”

Section: Discussionmentioning

confidence: 99%

Continuous release of interleukin 12 from microencapsulated engineered cells for colon cancer therapy

Zheng

Xiao²,

Pan³

et al. 2003

WJG

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AIM:To explore the anti-tumor immunity against CT26 colon tumor of the microencapsulated cells modified with murine interleukine-12 (mIL-12) gene. METHODS:Mouse fibroblasts (NIH3T3) were stably transfected to express mIL-12 using expression plasmids carrying mIL-12 gene (p35 and p40), and NIH3T3-mIL-12 cells were encapsulated in alginate microcapsules for longterm delivery of mIL-12. mIL-12 released from the microencapsulated NIH3T3-mIL-12 cells was confirmed using ELISA assay. Transplantation of the microencapsulated NIH3T3-mIL-12 cells was performed in the tumor-bearing mice with CT26 cells. The anti-tumor responses and the anti-tumor activities of the microencapsulated NIH3T3-mIL-12 cells were evaluated. RESULTS:Microencapsulated NIH3T3-mIL-12 cells could release mIL-12 continuously and stably for a long time. After the microencapsulated NIH3T3-mIL-12 cells were transplanted subcutaneously into the tumor-bearing mice for 21 d, the serum concentrations of mIL-12, mIL-2 and mIFN-γ, the cytotoxicity of the CTL from the splenocytes and the NK activity in the treatment group were significantly higher than those in the controls. Moreover, mIL-12 released from the microencapsulated NIH3T3-mIL-12 cells resulted in a significant inhibition of tumor proliferation and a prolonged survival of tumor-bearing mice.

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Neoadjuvant therapy with interleukin-12–loaded polylactic acid microspheres reduces local recurrence and distant metastases

Cited by 26 publications

References 25 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

Neoadjuvant intratumoral cytokine‐loaded microspheres are superior to postoperative autologous cellular vaccines in generating systemic anti‐tumor immunity

Continuous release of interleukin 12 from microencapsulated engineered cells for colon cancer therapy

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