Genomic, Immunologic, and Functional Evolution of Resistance to Immunotherapy in a Melanoma Exceptional Responder

David Liu*, Jia-Ren Lin* (equal contribution), Gyulnara G Kasumova, Alex Heyde, Alvin Shi, Adam Kraya, Gao Zhang, Tabea Moll, Dennie T Frederick, Yu-An Chen, Denis Schapiro, Shu Wang, Kevin Bi, Avinash Sahu, Shaolin Mei, Benchun Miao, Tatyana Sharova, Tommy Kim, Riley Fadden, Donald Lawrence, Mai P Hoang, Daniel P Cahill, Mohsen Malehmir, Christine Lian, Eytan Ruppin, Benjamin Izar, Meenhard Herlyn, Martin A Nowak, Eliezer M Van Allen, Katherine Nathanson, Keith T Flaherty, Ryan J Sullivan, Manolis Kellis, Peter K Sorger, Genevieve M Boland

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1169 -22 -55 -62 -1381 27 39 62 76 83 92 109 1028 4 days radiation 1 day radiation MAP2K1 IDH1 Genome doubling Genomedoubling Chr2q partial loss Chr15q loss (B2M) Genome doubling CDKN2A homozygous deletionC15 muts (n=4) C13 Muts (n=17) Chr19q partial loss C24 Muts (n=9) PTEN homozygous deletion Genome doubling Chr11 loss Partial response Partial response Partial response Treatment: Response: Day -30 -60 -1381 0 1169 1849 1862 Nivolumab Nivolumab Anti-PD1TLR-9 Nivolumab Ipilimumab 180 30 60 120 150 720 1028 90 1760 2066 1790 1820 1850 Progression 2066 2 1 4 5 6 3 0 T4 T1 T3 T2 T5 T6 T11 T13 T14 T15 T18 T19 T21 T12 T9 T10 T20 T22 R1 R3.2 R2 T16 T17 T8 T7 AS4 AB1 AS3 AS1 AL3 AS2 AL4 AV1 AB2 AL1 AL2 R3.1

Biopsies

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Day -55, Skin Left Forearm

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Day -22, L2 - Skin Right Nasolabial Fold

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Day 27, L6 - Skin Chin

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Day 27, L4 - Skin Upper Lip

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Day 27, L5 - Skin Left Brow

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Day 27, L5 - Skin Right Ear

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Day 39, L2 - Skin Left Arm

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Day 39, L2 - Skin Right Posterior Scalp

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Day 39, L2 - Skin Posterior Neck

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Day 39, L3 - Skin Left Posterior Scalp

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Day 62, L1 - Skin Right Neck

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Day 62, L1 - Skin Left Wrist

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Day 76, L1 - Skin Left Leg

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Day 76, L4 - Skin Right Neck

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Day 76, L4 - Skin Right Nasolabial Fold

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Day 83, L1 - Skin Left Posterior Shoulder

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Day 92, L6 - Skin Left Groin

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Day 92, L1 - Skin Left Neck

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Day 92, L3 - Skin Right Upper Lip

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Day 109, L1 - Skin Left Ring Finger

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Day 1028, L3 - Jejunum

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Day 1849, L3 - Skin Left Neck

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Day 1862, L3 - Skin Left Neck

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Autopsies

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Autopsy - Lung, Right Lower Lobe

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Autopsy - Lung, Right Upper Lobe

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Autopsy - Lung, Left Upper Lobe

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Autopsy - Lung, Left Lower Lobe

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Autopsy - Subcutaneous Lesion, Left Mastoid

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Autopsy - Subcutaneous Lesion, left inguinal region

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Autopsy - Subcutaneous Lesion, left scalp

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Autopsy - Subcutaneous Lesion, Left Temporal Bone

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Autopsy - Visceral Organ, Right Adrenal

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