title: HESI/FDA workshop on immunomodulators and cancer risk assessment: Building blocks for a weight-of-evidence approach.
abstract: Profound immunosuppression (e.g., AIDS, transplant therapy) is epidemiologically associated with an increased cancer risk, and often with oncogenic viruses. It is currently unclear how broadly this association translates to therapeutics that modulate immunity. A workshop co-sponsored by the FDA and HESI examined how perturbing the immune system may contribute to carcinogenesis, and highlighted priorities for improving non-clinical risk assessment of targeted immunomodulatory therapies. Conclusions from the workshop were as follows. 1) While profound altered immunity can promote tumorigenesis, not all components of the immune system are equally important in defense against or promotion of cancer and a similar cancer risk for all immunomodulatory molecules should not be assumed. 2) Rodent carcinogenicity studies have limitations and are generally not reliable predictors of cancer risk associated with immunosuppression. 3) Cancer risk needs to be evaluated based on mechanism-based weight-of-evidence, including data from immune function tests most relevant to tumor immunosurveillance or promotion. 4) Information from nonclinical experiments, clinical epidemiology and immunomodulatory therapeutics show that immunosurveillance involves a complex network of cells and mediators. To support a weight-of-evidence approach, an increased focus on understanding the quantitative relationship between changes in relevant immune function tests and cancer risk is needed.
authors.affiliation: Amgen Inc, 1120 Veterans Blvd, South San Francisco, CA 94080, USA. Electronic address: hlebrec@amgen.com.
authors.forename: H
authors.initials: H
authors.lastname: Lebrec
authors.affiliation: UCB-Celltech, 208 Bath Road, Slough SL1 3WE, UK.
authors.forename: F R
authors.initials: FR
authors.lastname: Brennan
authors.affiliation: Bristol-Myers Squibb Company, 1 Squibb Dr., New Brunswick, NJ 08903, USA.
authors.forename: H
authors.initials: H
authors.lastname: Haggerty
authors.affiliation: Merck & Co Inc, 770 Sumneytown Pike, PO Box 4, MS WP45-233, West Point, PA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Herzyk
authors.affiliation: Pfizer Inc, Eastern Point Rd, Groton, CT 063340, USA.
authors.forename: C
authors.initials: C
authors.lastname: Kamperschroer
authors.affiliation: GlaxoSmithKline, 709 Swedeland Rd, King of Prussia, PA 19406, USA.
authors.forename: C C
authors.initials: CC
authors.lastname: Maier
authors.affiliation: Amgen Inc, 1120 Veterans Blvd, South San Francisco, CA 94080, USA.
authors.forename: R
authors.initials: R
authors.lastname: Ponce
authors.affiliation: Amgen Inc, 1120 Veterans Blvd, South San Francisco, CA 94080, USA.
authors.forename: B D
authors.initials: BD
authors.lastname: Preston
authors.affiliation: Janssen Research & Development, LLC, Welsh & McKean Roads, Spring House, PA 19477, USA.
authors.forename: D
authors.initials: D
authors.lastname: Weinstock
authors.affiliation: Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, MD 20993, USA.
authors.forename: R D
authors.initials: RD
authors.lastname: Mellon
mesh_terms: D000818:Animals; D006801:Humans; D007155:Immunologic Factors / Q000009:adverse effects*; D009369:Neoplasms / Q000139:chemically induced* / Q000453:epidemiology / Q000276:immunology; D018570:Risk Assessment / Q000331:legislation & jurisprudence; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology
chemical_list: D007155:Immunologic Factors; D014409:Tumor Necrosis Factor-alpha
keywords: Cancer; Carcinogenicity; Immunomodulation; Immunosuppression; Immunotoxicity; Immunotoxicology; Risk assessment