Review: Cardiopulmonary Toxicity of Adoptive Immunotherapy

Glauser, Frederick L.; DeBlois, Georgean G.; Bechard, Daniel E.; Fowler, Alpha A.; Merchant, Randall E.; Fairman, R. Paul

doi:10.1097/00000441-198812000-00007

Cited by 22 publications

(11 citation statements)

References 41 publications

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“…Because cytokines are the "master regulators of immunity," many therapeutic approaches attempted to use cytokines as adjuvant or single therapies. However, systemic administration of cytokines often resulted in significant toxicities, for example by IL-2, which caused vascular leak syndrome, or IFN-g, a neurotoxin when administered at higher doses (25,26). These findings emphasize the yet unmet need to refine the strategy of immunomodulation to induce an effective immunologic response while minimizing systemic toxicities.…”

Section: Discussionmentioning

confidence: 99%

Targeted Therapeutic Remodeling of the Tumor Microenvironment Improves an HER-2 DNA Vaccine and Prevents Recurrence in a Murine Breast Cancer Model

et al. 2011

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The tumor microenvironment (TME) mediates immunosuppression resulting in tumor cell escape from immune surveillance and cancer vaccine failure. Immunosuppression is mediated by the STAT-3 transcription factor, which potentiates signaling in tumor and immune cells. Because immunosuppression continues to be a major inhibitor of cancer vaccine efficacy, we examined in this study whether therapeutically targeted delivery of a synthetic STAT-3 inhibitor to the TME, combined with an HER-2 DNA vaccine can improve immune surveillance against HER-2 þ breast cancer and prevent its recurrence. To this end, we developed a novel ligand-targeted nanoparticle (NP) encapsulating a CDDO-Im payload capable of specific delivery to the TME, which showed an effective therapeutic inhibition of STAT-3 activation in primary tumors. Furthermore, we showed that treatment with these NPs resulted in priming of the immune TME, characterized by increased IFN-g, p-STAT-1, GM-CSF, IL-2, IL-15, and IL-12b and reduced TGF-b, IL-6, and IL-10 protein expression. In addition, we found significantly increased tumor infiltration by activated CD8 þ T cells, M1 macrophages, and dendritic cells. These changes correlated with delayed growth of orthotopic 4TO7 breast tumors and, when combined with an HER-2 DNA vaccine, prevented HER-2 þ primary tumor recurrence in immunocompetent mice. Furthermore, antitumor T-cell responses were enhanced in splenocytes isolated from mice treated with this combination therapy. Together, these data show effective protection from cancer recurrence through improved immune surveillance against a tumor-specific antigen. Cancer Res; 71(17); 5688-96. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 99%

Targeted Therapeutic Remodeling of the Tumor Microenvironment Improves an HER-2 DNA Vaccine and Prevents Recurrence in a Murine Breast Cancer Model

et al. 2011

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“…The injection of large cell numbers has many drawbacks. The procedure is expensive and labor intensive, results in the transfer of later passage cells that are likely less potent effectors and is complicated by T cell trapping in the lungs that can cause respiratory distress (35) and vascular leak syndrome (36). The use of effLuc in models of adoptive immunotherapy will hopefully provide the technology necessary to resolve these side effects and allow the identification of a small subset(s) of T cells, which are responsible for anti-tumor activity.…”

Section: Discussionmentioning

confidence: 99%

Visualizing fewer than 10 mouse T cells with an enhanced firefly luciferase in immunocompetent mouse models of cancer

Rabinovich

Yang

Etto

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

184

168

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Antigen specific T cell migration to sites of infection or cancer is critical for an effective immune response. In mouse models of cancer, the number of lymphocytes reaching the tumor is typically only a few hundred, yet technology capable of imaging these cells using bioluminescence has yet to be achieved. A combination of codon optimization, removal of cryptic splice sites and retroviral modification was used to engineer an enhanced firefly luciferase (ffLuc) vector. Compared with ffLuc, T cells expressing our construct generated >100 times more light, permitting detection of as few as three cells implanted s.c. while maintaining long term coexpression of a reporter gene (Thy1.1). Expression of enhanced ffLuc in mouse T cells permitted the tracking of <3 ؋ 10 4 adoptively transferred T cells infiltrating sites of vaccination and preestablished tumors. Penetration of light through deep tissues, including the liver and spleen, was also observed. Finally, we were able to enumerate infiltrating mouse lymphocytes constituting <0.3% of total tumor cellularity, representing a significant improvement over standard methods of quantitation including flow cytometry.bioluminescence ͉ immunology ͉ molecular biology

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“…Although this new therapeutic modality offers hope for the future, a multitude of toxicities limit the total dose and duration of the therapy. The toxic side-effects include severe hypotension resulting in a decrease in systemic vascular resistance and hypoperfusion of vital organs, and in the development of vascular leak syndrome [6][7][8]10,21]. Rosenstein et al [22] reported that the vascular leakage is dependent on the dose and duration of IL-2 treatment.…”

Section: Discussionmentioning

confidence: 99%

Pyridoxalated haemoglobin polyoxyethylene conjugate, a nitric oxide scavenger, decreases dose-limiting hypotension associated with interleukin-2 (IL-2) therapy

Murakami

Privalle²,

Enkhbaatar

et al. 2003

Clinical Science

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Interleukin-2 (IL-2), a cytokine that induces natural killer cells termed lymphokine-activated killer (LAK) cells, is in use as an anticancer agent. During IL-2 therapy, adverse effects, such as vasodilatation and hypotension, are common. Previous studies suggest that these effects are due to nitric oxide (NO). Therefore a model of IL-2-induced hyperdynamic response in sheep was developed to test the effect of pyridoxalated haemoglobin polyoxyethylene conjugate (PHP; a NO scavenger), which is currently in clinical development for the treatment of shock associated with systemic inflammatory response syndrome. Twelve female sheep were divided into four groups (n =3 per group): sham control (Ringer's lactate solution), PHP alone (20 mg x kg(-1) x h(-1) for 96 h), IL-2 alone (recombinant human IL-2; 1,440,000 units/kg intravenously every 8 h) and a combination of PHP and IL-2. All of the sheep received Ringer's lactate solution to maintain haematocrit at baseline levels. The sheep had free access to food and water. A fall in the mean arterial pressure and systemic vascular resistance index by 20% was observed in the IL-2 group, but not in the PHP+IL-2 group. The fluid requirement to maintain the haematocrit was higher in the IL-2 group (5 ml x kg(-1) x h(-1)) than in the PHP+IL-2 group (4 ml x kg(-1) x h(-1)). The sham group showed no changes in any of the parameters. Scavenging NO by PHP prevented the hyperdynamic reaction induced by IL-2 administration in sheep. This activity of PHP may prevent the early discontinuation of IL-2 therapy that results because of these adverse events.

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Review: Cardiopulmonary Toxicity of Adoptive Immunotherapy

Cited by 22 publications

References 41 publications

Targeted Therapeutic Remodeling of the Tumor Microenvironment Improves an HER-2 DNA Vaccine and Prevents Recurrence in a Murine Breast Cancer Model

Targeted Therapeutic Remodeling of the Tumor Microenvironment Improves an HER-2 DNA Vaccine and Prevents Recurrence in a Murine Breast Cancer Model

Visualizing fewer than 10 mouse T cells with an enhanced firefly luciferase in immunocompetent mouse models of cancer

Pyridoxalated haemoglobin polyoxyethylene conjugate, a nitric oxide scavenger, decreases dose-limiting hypotension associated with interleukin-2 (IL-2) therapy

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