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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01169-22-5527396276839210910284 days of XRT1 day radiationMAP2K1IDH1Genome doublingGenomedoublingChr2q partial lossChr15q loss (B2M)Genome doublingCDKN2A homozygous deletionAdditional deletionsC5 Muts (n=13)Chr19q partial lossC11 Mutations (n=6)PTEN homozygous deletionMixed responseMixed responsePartial responseTreatmentResponseDay-30-600116918491862NivolumabNivolumabAnti-PD1TLR-9NivolumabPre-treatmentIpilimumab18030601201507201028901760179018201850Progressive disease

Biopsies

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Day -55, L6 - Skin Left Forearm

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Day -22, L2 - Skin Right Nasolabial Fold

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Day 27, L1 - 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, L1 - 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, L6 - Skin Left Neck

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Day 1862, L6 - 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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