breakthroughs in epigenetics

8/20/2019 Breakthroughs in Epigenetics

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Use of Epigenetic Therapy toEnhance the Benets of Cancer

Immunotherapy

Stephen B. Baylin


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4/19

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


5/19

Sharma an" #llison$ Cancer Immunol$ Immunother$

Cancer Cells an" Immune Tolerance

'arachaliou et al$ Cancer Biol

Immune

Tolerance

Immunecellactivation


6/19

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


7/19

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)


8/19

a""ington >an"scape < Epigenetic Control of0evelopment

Iovini an" Cavalli$ Cell$


9/19

5egulation of theEpigenome

#hu a et al #nn 5ev (e" in

@ar"0rive

Softare


10/19%aylin and Schuebel, Nature &&'( )&'-*, +

EpigenomicsGenome har" "rive Softare

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CpG

to(eCpGCpG


11/19Baylin 4ones$ Col" Spring @ar

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


12/19@anahan an" einerg$

The @allmar*s of Cancer an" Therapy Target

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programcontriutes totumorigenesis+

5esponses

5esistance


13/19

otential for Epigenetic 5F riming to Immune ToleranceTherapy

rangle$ ang$ Easaran etBeing teste" in ongoing trials


14/19Schreier et al Science

Tolerance

@ypothesis < Epigenetic Therapy Is Ane otential(eans to 5everse Cancer Immune Evasion


15/19


16/19Cho ' et al$ Shoc*$


17/19

Chiappinelli$ et al$5oulois et al$ Cell$


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19/19

IFNα,IFNβ

IFNGR1

CTA Peptide

MHC Class IT CelI

Receptor

Tumor Cell

ImmuneCell

IFNy

NFkB,

PI3!i"#ali#"

CTAs$R%s,

dsRNA

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Epigenetic Therapy :iral (imicry;Improve" Immunotherapy

1) /unctionalconteFt forepigenetic 5F Kimmunechec*pointtherapy

) Basal genesignature D

breakthroughs in epigenetics

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