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Use of Epigenetic Therapy toEnhance the Benets of Cancer
Immunotherapy
Stephen B. Baylin
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Epigenetic Therapy to Improve Immunotherap
General concepts
Several small clinical trial observations, and a building body of pre-clinical data
suggest that epigenetic therapy strategies may prime for concurrent or subsequent therapiesand especially immunotherapies.
Specic concepts 1) Epigenetic therapies may reverse multiple components of cancer immune evasion
) Above includes that DNA demethylating agents can induce a “viral mimicry response in
human cancer cells !hich results in upregulation of activity from copies of viral DNA !hichhave become part of our genomes over long periods of evolution " this can potentially increasethe “immunogenicity of tumor cells
!) #ombinatorial epigenetic therapy strategies may optimi$e the above
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Sharma an" #llison$ Cancer Immunol$ Immunother$
Cancer Cells an" Immune Tolerance
'arachaliou et al$ Cancer Biol
Immune
Tolerance
Immunecellactivation
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hat Is Immune Chec*point Therapy+
Brea*sTolerance
#ctive anti,tumor
immune cell
1) -o /0# approve" fora"vance" melanoma$ lungcancer$ renal cancer) But$ hile enetting 2
&%3 of patients ithmelanoma$ only 2 %3 or less'ono$ 4 Stem Cell an" 5egenerative (e"$ %16
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Epigenetics
Classic 0enition
The ranch of iology hich stu"iesthecausal interactions eteen genes an"theirpro"ucts$ hich ring the phenotypeintoeing. 7 #ll of our cells have the samegenetics ut there are "i8erent types)
(o"ern 0enition
The stu"y of heritale changes7mitotic or meiotic) ingene function hich create a nephenotype ithouta correspon"ing change in 0-#se9uence. 7 ie$ all of our cells have the
same 0-# ut there are "i8erenttypes)
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a""ington >an"scape < Epigenetic Control of0evelopment
Iovini an" Cavalli$ Cell$
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5egulation of theEpigenome
#hu a et al #nn 5ev (e" in
@ar"0rive
Softare
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EpigenomicsGenome har" "rive Softare
A-
A//
CpG
to(eCpGCpG
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The position of mutations an" the anormal epigenome intumor progressionCancer D "isease of anormal retention of self,reneal an""efective lineage commitment
utations " epigenomeregulating genes
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The @allmar*s of Cancer an" Therapy Target
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//#normalepigenetic
programcontriutes totumorigenesis+
5esponses
5esistance
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otential for Epigenetic 5F riming to Immune ToleranceTherapy
rangle$ ang$ Easaran etBeing teste" in ongoing trials
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Tolerance
@ypothesis < Epigenetic Therapy Is Ane otential(eans to 5everse Cancer Immune Evasion
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Chiappinelli$ et al$5oulois et al$ Cell$
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IFNα,IFNβ
IFNGR1
CTA Peptide
MHC Class IT CelI
Receptor
Tumor Cell
ImmuneCell
IFNy
NFkB,
PI3!i"#ali#"
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dsRNA
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IRF+
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P
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Epigenetic Therapy :iral (imicry;Improve" Immunotherapy
1) /unctionalconteFt forepigenetic 5F Kimmunechec*pointtherapy
) Basal genesignature D
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