Obesity and cancer immunotherapy toxicity

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Date: Apr. 2015
From: Immunotherapy(Vol. 7, Issue 4)
Publisher: Future Medicine Ltd.
Document Type: Report
Length: 2,320 words
Lexile Measure: 2090L

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Author(s): Annie Mirsoian aff1 , William J Murphy aff1 aff2

Keywords:

cancer; cytokines; immunotherapy; inflammation; obesity; toxicity

Within the past decade the usage of cancer immunotherapy has gained momentum, achieving successes within various advanced-staged malignancies and is beginning to be explored as a primary therapeutic rather than secondary to traditional cytoreductive therapies. Immunotherapeutic antitumor approaches have included systemic stimulatory therapies, blocking checkpoint inhibitory pathways, direct induction of T-cell stimulatory pathways and adoptive cell transfer strategies, among others [1 ]. However, the wide-spread application of immunotherapy has been limited by the induction of dose-limiting, and often times life-threatening, immune-related adverse reaction events (irAEs). These reactions are best exemplified by stimulatory systemic therapies, such as IL-2 and high-dose IFN, that can result in cytokine-release syndrome, multiorgan failure and require their usage to be limited to highly specialized centers capable of providing continuous care [2 ].

More recently, novel immunotherapies have similarly resulted in the induction of irAEs ranging from mild, requiring dose and scheduling adjustments, to life-threatening. Immune checkpoint blockade therapies such as anti-CTLA-4 and anti-PD-1 induce a generalized expansion and activation of T cells that can adversely result in autoimmunity. Toxicities with checkpoint blockade therapies have included dermatitis, enterocolitis, endocrinopathies and life-threatening liver toxicities, and/or pneumonitis [3-5 ]. Likewise, a Phase II clinical trial using agonistic CD137 antibody to overcome T-cell inhibition through direct binding and activation of 4-1BB co-stimulatory receptor resulted in grade 4 hepatitis that halted the continuance of the trial [6 ]. Recently, great promise in antitumor efficacy has been demonstrated through autologous infusion of engineered T cells that express chimeric antigen receptors (CARs). Low-dose administration of CAR-T cells expressing CD137 and targeting CD19 into three patients with chemotherapy-resistant chronic lymphocytic leukemia resulted in all three demonstrating strong antitumor responses with two patients having complete remission [7 ]. However, CAR-T-cell therapy is accompanied by cytokine release syndrome and/or macrophage activation syndrome that can culminate in the development of severe respiratory and cardiac dysfunction, requiring specialized care throughout treatment [7-9 ].

Of importance is the commonality that preclinical modeling has often failed to reveal toxicities that are observed in human clinical trials. The vast majority of preclinical studies make usage of young, lean, specific-pathogen free (SPF) inbred mouse models that are not reflective of the human cancer patient phenotype, which are usually much older. Another variable is body mass. Within the US the CDC estimates that greater than a third of all adults are currently obese (BMI [greater than]30); a figure estimated to rise to be between 42-67% by 2030 [10 ]. Alarmingly, obesity is also becoming an epidemic of younger ages with a current estimated prevalence of 17% in children and adolescents [11 ]. In their 2014 position statement, the American Society of Clinical Oncology attributed obesity to be a major unrecognized risk factor for cancer. The American Society of Clinical Oncology highlights that obesity is quickly surpassing tobacco as a leading, preventable, cause of cancer [ 12 ]. These statistics underscore that the phenotype of the 'typical' cancer patient may be changing....

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Gale Document Number: GALE|A411322527