Adiposity induces lethal cytokine storm after systemic administration of stimulatory immunotherapy regimens in aged mice

Mirsoian, Annie; Bouchlaka, Myriam N.; Sckisel, Gail D.; Chen, Mingyi; Pai, Chien Chun Steven; Maverakis, Emanual; Spencer, Richard G.; Fishbein, Kenneth W.; Siddiqui, Sana; Monjazeb, Arta M.; Martin, Bronwen; Maudsley, Stuart; Hesdorffer, Charles; Ferrucci, Luigi; Longo, Dan L.; Blazar, Bruce R.; Wiltrout, Robert H.; Taub, Dennis D.; Murphy, William J.

doi:10.1084/jem.20140116

Cited by 120 publications

(103 citation statements)

References 16 publications

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“…antibody is more toxic in aged mice and mice with obesity 76 . Treatment with etanercept to block TNF in young, obese mice receiving the same immunotherapy prevented the toxic effects of cytokine storm 77 . Many epidemiologic studies indicate that vitamin D deficiency is associated with an increased risk of cancer incidence and mortality 78 .…”

Section: Box 1 Adoptive T Cell Therapymentioning

confidence: 98%

Is autoimmunity the Achilles' heel of cancer immunotherapy?

June

Warshauer

Bluestone

2017

Nat Med

388

315

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Section: Box 1 Adoptive T Cell Therapymentioning

confidence: 98%

Is autoimmunity the Achilles' heel of cancer immunotherapy?

June

Warshauer

Bluestone

2017

Nat Med

388

315

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“…5). Toxicities with our regimen are consistent with high-dose IL-2 (although not as severe), with an initial cytokine storm syndrome that can be fatal in aged mice [17, 25]. However, the fact that we tailored our regimen to utilize anti-CTLA-4 to delay contraction and therefore administered it at a late time point avoided any added toxicities that may have occurred as a result of co-administration.…”

Section: Discussionmentioning

confidence: 54%

“…In some of the pioneering studies involving anti-CTLA-4 in which it was co-administered in a B16 melanoma model with a GM-CSF-expressing tumor vaccine, significant vitiligo was noted [24]. Since in our studies we were also administering it in combination with another immunotherapy (αCD40/IL-2) which we have also published to exhibit key toxicities under certain scenarios [17, 25], we wanted to be sure that co-administration with anti-CTLA-4 did not further exacerbate toxicities within our model. Therefore, in addition to evaluating immune parameters, we also monitored weight loss, liver enzymes, and organ pathology for any evidence of toxicity.…”

Section: Resultsmentioning

confidence: 94%

Late administration of murine CTLA-4 blockade prolongs CD8-mediated anti-tumor effects following stimulatory cancer immunotherapy

Sckisel

Mirsoian

Bouchlaka

et al. 2015

Cancer Immunol Immunother

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We have demonstrated that immunostimulatory therapies such as interleukin-2 (IL-2) and anti-CD40 (αCD40) can be combined to deliver synergistic anti-tumor effects. While this strategy has shown success, efficacy varies depending on a number of factors including tumor type and severe toxicities can be seen. We sought to determine whether blockade of negative regulators such as cytotoxic T lymphocyte antigen-4 (CTLA-4) could simultaneously prolong CD8+ T cell responses and augment T cell anti-tumor effects. We devised a regimen in which anti-CTLA-4 was administered late so as to delay contraction and minimize toxicities. This late administration both enhanced and prolonged CD8 T cell activation without the need for additional IL-2. The quality of the T cell response was improved with increased frequency of effector/effector memory phenotype cells along with improved lytic ability and bystander expansion. This enhanced CD8 response translated to improved anti-tumor responses both at the primary and metastatic sites. Importantly, toxicities were not exacerbated with combination. This study provides a platform for rational design of immunotherapy combinations to maximize anti-tumor immunity while minimizing toxicities.

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“…It is, therefore, reasonable to expect that toxicities will escalate with the development of increasingly potent immune therapies. In addition, as the use of immunotherapy becomes more widespread, patients with underlying susceptibilities to autoimmune sequelae, notably obese and older individuals, will be encountered with increased frequency (6,7). Consequently, unless we do something to lower known toxicities, we will not be able to fully exploit the therapeutic potential of the immune modality.…”

Section: Toxicity: a Major Challenge For Immunomodulationmentioning

confidence: 99%

Reducing Toxicity of Immune Therapy Using Aptamer-Targeted Drug Delivery

Gilboa

Berezhnoy

Schrand

2015

Cancer Immunology Research

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Modulating the function of immune receptors with antibodies is ushering in a new era in cancer immunotherapy. With the notable exception of PD-1 blockade used as monotherapy, immune modulation can be associated with significant toxicities that are expected to escalate with the development of increasingly potent immune therapies. A general way to reduce toxicity is to target immune potentiating drugs to the tumor or immune cells of the patient. This Crossroads article discusses a new class of nucleic acid-based immune-modulatory drugs that are targeted to the tumor or to the immune system by conjugation to oligonucleotide aptamer ligands. Cell-free chemically synthesized short oligonucleotide aptamers represent a novel and emerging platform technology for generating ligands with desired specificity that offer exceptional versatility and feasibility in terms of development, manufacture, and conjugation to an oligonucleotide cargo. In proof-of-concept studies, aptamer ligands were used to target immune-modulatory siRNAs or aptamers to induce neoantigens in the tumor cells, limit costimulation to the tumor lesion, or enhance the persistence of vaccine-induced immunity. Using increasingly relevant murine models, the aptamer-targeted immune-modulatory drugs engendered protective antitumor immunity that was superior to that of current "gold-standard" therapies in terms of efficacy and lack of toxicity or reduced toxicity. To overcome immune exhaustion aptamer-targeted siRNA conjugates could be used to downregulate intracellular mediators of exhaustion that integrate signals from multiple inhibitory receptors. Recent advances in aptamer development and second-generation aptamer-drug conjugates suggest that we have only scratched the surface.

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Adiposity induces lethal cytokine storm after systemic administration of stimulatory immunotherapy regimens in aged mice

Cited by 120 publications

References 16 publications

Is autoimmunity the Achilles' heel of cancer immunotherapy?

Is autoimmunity the Achilles' heel of cancer immunotherapy?

Late administration of murine CTLA-4 blockade prolongs CD8-mediated anti-tumor effects following stimulatory cancer immunotherapy

Reducing Toxicity of Immune Therapy Using Aptamer-Targeted Drug Delivery

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