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Outline : • Definition and goals of PM Precisely What the Doctor Ordered? • Background

• Applications

TRIA Orthopaedic and Sports Medicine Conference • Opportunities February 9, 2018 • Challenges

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Personalized Medicine Definition Personalized Medicine Goals

•Also called precision, genomic or individualized medicine •Improve clinical outcomes for individual patients •NIH definition: “…an emerging approach for disease treatment and prevention that •Minimize unnecessary side effects for takes into account individual variability in those unlikely to respond to a particular genes, environment, and lifestyle for each treatment person”

https://ghr.nlm.nih.gov/primer/precisionmedicine/definition. Accessed 1/30/2018. Jameson, JL, Longo, DL. Precision Medicine—Personalized, Problematic, and Promising. N Engl J Med 2015; 372:2229‐2234.

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Is Personalized Medicine New? Pisum sativum (Garden pea)

• Personal and family medical history How is personalized • Ethnicity medicine related to peas? • Exposures: environmental, occupational, socioeconomic

• Biochemical profile

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“Father of ” Drivers of Personalized Medicine Growth

• Diagnostic and treatment advances Gregor Mendel, 1822‐1884 • Falling costs

Czech, Augustinian Friar • Electronic health records

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Genomics in Human Personalized Medicine • Philadelphia Chromosome, 1959

• Allelic variation of Cytochrome P450 2D6 demonstrated, 1980s

• Mapping of human genome, 2003

• Direct‐to‐consumer genetic testing, 2007

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Genetic Testing Options Single‐Nucleotide Polymorphism

• Whole Genome Sequencing (3 billion+ base pairs)

• Whole Exome Sequencing (~1.5% of genome)

• Genotyping (assay of selected bases The upper DNA molecule differs from the lower DNA molecule where variations often occur) at a single base‐pair location (a C/A polymorphism)

Image Credit: SNP model by David Eccles (gringer)/Wikipedia.org. Accessed 1/30/2018.

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Personalized Medicine Personalized Medicine Applications Opportunities • Diagnosis and Prognosis • Treatment guidance • BCR‐ABL+ CML: imatinib • HER‐2+ breast : trastuzumab • CD‐19 receptor+ DLBCL, ALL: CAR‐T • ALK+ non‐small cell lung cancer: ALK inhibitor • Microbiome study and intervention

Jameson, JL, Longo, DL. Precision Medicine—Personalized, Problematic, and Promising. N Engl J Med 2015; 372:2229‐2234. Jameson, JL, Longo, DL. Precision Medicine—Personalized, Problematic, and Promising. N Engl J Med 2015; 372:2229‐2234.

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Conclusions Personalized Medicine Challenges • PM is an emerging approach to disease • Cost of diagnosis and treatment prevention and treatment • Diagnostic and treatment advances, • Interpretation‐‐imperfect risk prediction declining cost, and EHR will drive growth • Opportunities include diagnosis, • Right to know vs. unnecessary worry prognosis, targeted treatment, and microbiome study and intervention • Regulatory: privacy, research consent, • Challenges include cost, interpretation, approval of treatment privacy issues, and regulation

Jameson, JL, Longo, DL. Precision Medicine—Personalized, Problematic, and Promising. N Engl J Med 2015; 372:2229‐2234.

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Sample Genome Report

Thank you!

[email protected] Vassy JL et al for the MedSeq Project. Public Health Genomics. 2015; 18(2): 123–129.

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CAR‐T Cell Adoptive Transfer

Schematic of the treatment of a patient with chimeric antigen receptor (CAR) T cells. (1) Isolation of peripheral T cells from patient via apheresis. (2) Transfection of T cells with a lentivirus containing genes for CAR directed against the tumor target antigen: binding of virus to T‐cell membrane, fusion of virus with cell membrane, reverse transcription, DNA integration, and transcription/protein expression of CAR genes, and insertion of CAR into cell membrane. (3) Adoptive transfer of autologous CAR‐T cells via infusion with or without prior lymphodepleting conditioning. (4) Patient monitoring for treatment response, and for persistence of CAR‐T cells. Professional illustration by A. Y. Chen.

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