title: A novel immunomodulatory molecularly targeted strategy for refractory Hodgkin's lymphoma.
abstract: Although Hodgkin's lymphoma (HL) was one of the first human cancers to be cured by chemotherapy, no new agents other than brentuximab vedotin (Adcetris®, CD 30 directed antibody drug conjugate) have received US Food and Drug Administration (FDA) approval for HL since 1977. Subsets of young adult patients with HL continue to relapse, even after stem cell transplantation, warranting new approaches. Against this background, we report a dramatic response in a young patient with advanced HL refractory to the standard treatment who responded to the combination of a pan-histone deacetylase inhibitor (vorinostat, suberoylanilide hydroxamic acid, SAHA) and mammalian target of rapamycin (mTOR) inhibitor therapy (sirolimus,rapamume). In-depth immunohistochemical and morphoproteomic analyses of this exceptional responder to targeted therapy have yielded potential insights into the biology of advanced HL. The PI3K/AKT/mTOR pathway is a commonly activated pathway in multiple tumor types including HL. The patient was treated using therapy based on mechanistic in vitro data demonstrating that combined histone deacetylase (HDAC) and mTOR inhibition act together on this pathway, resulting in inhibition of reciprocal feedback networks, leading to better anti-proliferative activity. The in vivo response signature from this patient's tissue sample sheds light on immune dysregulation in HL. We describe the response signature achieved from targeting immune dysregulation in addition to targeting the key oncogenic PI3K/AKT/mTOR pathway. We also expand on the role of rapamycin analogs in oncology. This study supports a role for an immune-type pathogenesis that is amenable to immune modulating targeted therapy in refractory HL.
  
  
  CONCLUSIONS
  We report an exceptional responder to molecularly targeted and immune modulator therapy in advanced Hodgkin's lymphoma. The morphoproteomic/morphometric findings in this "unusual responder" patient's relapsed HL that correlate best, as a response signature with the subsequent clinical remission following rapamycin (sirolimus) and vorinostat (SAHA) therapies, center on an immune dysregulation involving an imbalance between effector and functional T regulatory cells in addition to targeting the mTOR pathway. This underscores the need for an approach illustrated in our study--namely of focusing on pathogenetic mechanisms and combinatorial therapies that target both the pathogenesis and adaptive responses to contemplated therapies.
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Vivek
authors.initials: V
authors.lastname: Subbiah
authors.forename: Robert E
authors.initials: RE
authors.lastname: Brown
authors.forename: Mary F
authors.initials: MF
authors.lastname: McGuire
authors.forename: Jamie
authors.initials: J
authors.lastname: Buryanek
authors.forename: Filip
authors.initials: F
authors.lastname: Janku
authors.forename: Anas
authors.initials: A
authors.lastname: Younes
authors.forename: David
authors.initials: D
authors.lastname: Hong
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D005260:Female; D006689:Hodgkin Disease / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D007155:Immunologic Factors / Q000008:administration & dosage; D058990:Molecular Targeted Therapy; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D000077337:Vorinostat
chemical_list: D006877:Hydroxamic Acids; D007155:Immunologic Factors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000077337:Vorinostat; C401859:temsirolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus