Functional Precision Medicine Provides Clinical Benefit in Advanced Aggressive Hematologic Cancers and Identifies Exceptional Responders

Christoph Kornauth; Tea Pemovska; Gregory I. Vladimer; Günther Bayer; Michael Bergmann; Sandra Eder; Ruth Eichner; Martin Erl; Harald Esterbauer; Ruth Exner; Verena Felsleitner-Hauer; Maurizio Forte; Alexander Gaiger; Klaus Geissler; Hildegard T. Greinix; Wolfgang Gstöttner; Marcus Hacker; Bernd Lorenz Hartmann; Alexander W. Hauswirth; Tim Heinemann; Daniel Heintel; Mir Alireza Hoda; Georg Hopfinger; Ulrich Jaeger; Lukas Kazianka; Lukas Kenner; Barbara Kiesewetter; Nikolaus Krall; Gerhard Krajnik; Stefan Kubicek; Trang Le; Simone Lubowitzki; Marius E. Mayerhoefer; Elisabeth Menschel; Olaf Merkel; Katsuhiro Miura; Leonhard Müllauer; Peter Neumeister; Thomas Noesslinger; Katharina Ocko; Leopold Öhler; Michael Panny; Alexander Pichler; Edit Porpaczy; Gerald W. Prager; Markus Raderer; Robin Ristl; Reinhard Ruckser; Julius Salamon; Ana-Iris Schiefer; Ann-Sofie Schmolke; Ilse Schwarzinger; Edgar Selzer; Christian Sillaber; Cathrin Skrabs; Wolfgang R. Sperr; Ismet Srndic; Renate Thalhammer; Peter Valent; Emiel van der Kouwe; Katrina Vanura; Stefan Vogt; Cora Waldstein; Dominik Wolf; Christoph C. Zielinski; Niklas Zojer; Ingrid Simonitsch-Klupp; Giulio Superti-Furga; Berend Snijder; Philipp B. Staber

doi:10.1158/2159-8290.CD-21-0538

Functional Precision Medicine Provides Clinical Benefit in Advanced Aggressive Hematologic Cancers and Identifies Exceptional Responders

Christoph Kornauth, Tea Pemovska, Gregory I. Vladimer, Günther Bayer, Michael Bergmann, Sandra Eder, Ruth Eichner, Martin Erl, Harald Esterbauer, Ruth Exner, Verena Felsleitner-Hauer, Maurizio Forte, Alexander Gaiger, Klaus Geissler, Hildegard T. Greinix, Wolfgang Gstöttner, Marcus Hacker, Bernd Lorenz Hartmann, Alexander W. Hauswirth, Tim HeinemannDaniel Heintel, Mir Alireza Hoda, Georg Hopfinger, Ulrich Jaeger, Lukas Kazianka, Lukas Kenner, Barbara Kiesewetter, Nikolaus Krall, Gerhard Krajnik, Stefan Kubicek, Trang Le, Simone Lubowitzki, Marius E. Mayerhoefer, Elisabeth Menschel, Olaf Merkel, Katsuhiro Miura, Leonhard Müllauer, Peter Neumeister, Thomas Noesslinger, Katharina Ocko, Leopold Öhler, Michael Panny, Alexander Pichler, Edit Porpaczy, Gerald W. Prager, Markus Raderer, Robin Ristl, Reinhard Ruckser, Julius Salamon, Ana-Iris Schiefer, Ann-Sofie Schmolke, Ilse Schwarzinger, Edgar Selzer, Christian Sillaber, Cathrin Skrabs, Wolfgang R. Sperr, Ismet Srndic, Renate Thalhammer, Peter Valent, Emiel van der Kouwe, Katrina Vanura, Stefan Vogt, Cora Waldstein, Dominik Wolf, Christoph C. Zielinski, Niklas Zojer, Ingrid Simonitsch-Klupp, Giulio Superti-Furga, Berend Snijder, Philipp B. Staber

Division of Internal Medicine 1 (University Hospital St. Pölten)

Research output: Journal article (peer-reviewed) › Journal article

79 Citations (Scopus)

Abstract

Personalized medicine aims to match the right drug with the right patient by using specific features of the individual patient’s tumor. However, current strategies of personalized therapy matching provide treatment opportunities for less than 10% of patients with cancer. A promising method may be drug profiling of patient biopsy specimens with single-cell resolution to directly quantify drug effects. We prospectively tested an image-based single-cell functional precision medicine (scFPM) approach to guide treatments in 143 patients with advanced aggressive hematologic cancers. Fifty-six patients (39%) were treated according to scFPM results. At a median follow-up of 23.9 months, 30 patients (54%) demonstrated a clinical benefit of more than 1.3-fold enhanced progression-free survival compared with their previous therapy. Twelve patients (40% of responders) experienced exceptional responses lasting three times longer than expected for their respective disease. We conclude that therapy matching by scFPM is clinically feasible and effective in advanced aggressive hematologic cancers. SIGNIFICANCE: This is the first precision medicine trial using a functional assay to instruct n-of-one therapies in oncology. It illustrates that for patients lacking standard therapies, high-content assaybased scFPM can have a significant value in clinical therapy guidance based on functional dependencies of each patient’s cancer.

Original language	English
Pages (from-to)	372-387
Number of pages	16
Journal	Cancer Discovery
Volume	12
Issue number	2
DOIs	https://doi.org/10.1158/2159-8290.CD-21-0538
Publication status	Published - 01 Feb 2022

Keywords

Adult
Aged
Aged, 80 and over
Austria
Cohort Studies
Female
Hematologic Neoplasms/drug therapy
Humans
Male
Middle Aged
Molecular Targeted Therapy
Precision Medicine
Progression-Free Survival
Young Adult

ASJC Scopus subject areas

Oncology

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10.1158/2159-8290.CD-21-0538

Cite this

Kornauth, C., Pemovska, T., Vladimer, G. I., Bayer, G., Bergmann, M., Eder, S., Eichner, R., Erl, M., Esterbauer, H., Exner, R., Felsleitner-Hauer, V., Forte, M., Gaiger, A., Geissler, K., Greinix, H. T., Gstöttner, W., Hacker, M., Hartmann, B. L., Hauswirth, A. W., ... Staber, P. B. (2022). Functional Precision Medicine Provides Clinical Benefit in Advanced Aggressive Hematologic Cancers and Identifies Exceptional Responders. Cancer Discovery, 12(2), 372-387. https://doi.org/10.1158/2159-8290.CD-21-0538

@article{bc02f8a14fa04d77a4ab4d18700996d0,

title = "Functional Precision Medicine Provides Clinical Benefit in Advanced Aggressive Hematologic Cancers and Identifies Exceptional Responders",

abstract = "Personalized medicine aims to match the right drug with the right patient by using specific features of the individual patient{\textquoteright}s tumor. However, current strategies of personalized therapy matching provide treatment opportunities for less than 10% of patients with cancer. A promising method may be drug profiling of patient biopsy specimens with single-cell resolution to directly quantify drug effects. We prospectively tested an image-based single-cell functional precision medicine (scFPM) approach to guide treatments in 143 patients with advanced aggressive hematologic cancers. Fifty-six patients (39%) were treated according to scFPM results. At a median follow-up of 23.9 months, 30 patients (54%) demonstrated a clinical benefit of more than 1.3-fold enhanced progression-free survival compared with their previous therapy. Twelve patients (40% of responders) experienced exceptional responses lasting three times longer than expected for their respective disease. We conclude that therapy matching by scFPM is clinically feasible and effective in advanced aggressive hematologic cancers. SIGNIFICANCE: This is the first precision medicine trial using a functional assay to instruct n-of-one therapies in oncology. It illustrates that for patients lacking standard therapies, high-content assaybased scFPM can have a significant value in clinical therapy guidance based on functional dependencies of each patient{\textquoteright}s cancer.",

keywords = "Adult, Aged, Aged, 80 and over, Austria, Cohort Studies, Female, Hematologic Neoplasms/drug therapy, Humans, Male, Middle Aged, Molecular Targeted Therapy, Precision Medicine, Progression-Free Survival, Young Adult",

author = "Christoph Kornauth and Tea Pemovska and Vladimer, {Gregory I.} and G{\"u}nther Bayer and Michael Bergmann and Sandra Eder and Ruth Eichner and Martin Erl and Harald Esterbauer and Ruth Exner and Verena Felsleitner-Hauer and Maurizio Forte and Alexander Gaiger and Klaus Geissler and Greinix, {Hildegard T.} and Wolfgang Gst{\"o}ttner and Marcus Hacker and Hartmann, {Bernd Lorenz} and Hauswirth, {Alexander W.} and Tim Heinemann and Daniel Heintel and Hoda, {Mir Alireza} and Georg Hopfinger and Ulrich Jaeger and Lukas Kazianka and Lukas Kenner and Barbara Kiesewetter and Nikolaus Krall and Gerhard Krajnik and Stefan Kubicek and Trang Le and Simone Lubowitzki and Mayerhoefer, {Marius E.} and Elisabeth Menschel and Olaf Merkel and Katsuhiro Miura and Leonhard M{\"u}llauer and Peter Neumeister and Thomas Noesslinger and Katharina Ocko and Leopold {\"O}hler and Michael Panny and Alexander Pichler and Edit Porpaczy and Prager, {Gerald W.} and Markus Raderer and Robin Ristl and Reinhard Ruckser and Julius Salamon and Ana-Iris Schiefer and Ann-Sofie Schmolke and Ilse Schwarzinger and Edgar Selzer and Christian Sillaber and Cathrin Skrabs and Sperr, {Wolfgang R.} and Ismet Srndic and Renate Thalhammer and Peter Valent and {van der Kouwe}, Emiel and Katrina Vanura and Stefan Vogt and Cora Waldstein and Dominik Wolf and Zielinski, {Christoph C.} and Niklas Zojer and Ingrid Simonitsch-Klupp and Giulio Superti-Furga and Berend Snijder and Staber, {Philipp B.}",

note = "Funding Information: We thank the patients and their families for their trust in taking part in this study. The study was academically funded and supported by the Medical University Vienna, the General Hospital Vienna, and the Research Center for Molecular Medicine (CeMM) of the Funding Information: G.I. Vladimer reports other support from Allcyte GmbH and other support from Exscientia GmbH during the conduct of the study; other support from Allcyte GmbH; and other support from Exsci-entia GmbH outside the submitted work; in addition, G.I. Vladimer has a patent for EP 3 704 484 A1 pending and licensed to Exscientia GmbH and a patent for EP 3 198 276 A1 pending and licensed to Exscientia GmbH; much of the screening work was performed while a postdoc at CeMM; manuscript drafting/data interpretation during employment, shareholder, and founder of Allcyte, which used the techniques described in this manuscript for translational research (not involved in clinical data collection). After final submission but before acceptance, Allcyte GmbH was acquired by Exscientia. M. Bergmann reports personal fees from Boehringer Ingelheim; grants from Boehringer Ingelheim, and grants from Bristol Myers Squibb outside the submitted work. K. Geissler reports personal fees from Novartis, personal fees from Celgene, and personal fees from Jazz outside the submitted work. B.L. Hartmann reports personal fees and nonfinancial support from Janssen, personal fees and nonfinancial support from Amgen, personal fees and nonfinancial support from Takeda, and personal fees and nonfinancial support from AbbVie during the conduct of the study. T. Heinemann reports grants from the Deutsche Forschungsgemeinschaft (DFG; German Research Foundation—project number 389640585) and grants from the Swiss National Science Foundation (PP00P3_163961) during the conduct of the study. N. Krall reports grants from WWTF, grants from Marie Curie Fellowship, and grants from SNF Postdoc Fellowship during the conduct of the study; and reports being an employee of Allcyte GmbH and an employee of Exscientia GmbH, outside the submitted work; in addition, N. Krall has a patent for EP 3 704 484 A1 pending, assigned to Exscientia GmbH, and a patent for EP 3 198 276 A1 pending, assigned to Exscientia GmbH; and is a founder and shareholder of Allcyte GmbH. Allcyte GmbH was bought by Funding Information: We thank the patients and their families for their trust in taking part in this study. The study was academically funded and supported by the Medical University Vienna, the General Hospital Vienna, and the Research Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences. We gratefully acknowledge funding from the Vienna Science and Technology Fund; (LS16-034, to G. Superti-Furga and U. Jaeger), the Austrian Science Fund (F4704-B20, to P. Valent; F4711-B20, to G. Superti-Furga; and P27132-B20, to P.B. Staber), and the European Molecular Biology Organization Long Term Fellowship (1543-2012, to G.I. Vladimer; 733-2016 to T. Pemovska). B. Snijder acknowledges funding from the ETH Zurich, the Swiss National Science Foundation (PP00P3_163961, PP00P3_194809, and CRSII5_193832), and the European Research Council (SCIPER; 803063). Funding Information: Austrian Academy of Sciences. We gratefully acknowledge funding from the Vienna Science and Technology Fund; (LS16-034, to G. Superti-Furga and U. Jaeger), the Austrian Science Fund (F4704-B20, to P. Valent; F4711-B20, to G. Superti-Furga; and P27132-B20, to P.B. Staber), and the European Molecular Biology Organization Long Term Fellowship (1543-2012, to G.I. Vladimer; 733-2016 to T. Pemovska). B. Snijder acknowledges funding from the ETH Zurich, the Swiss National Science Foundation (PP00P3_163961, PP00P3_194809, and CRSII5_193832), and the European Research Council (SCIPER; 803063). Publisher Copyright: {\textcopyright}2021 The Authors; Published by the American Association for Cancer Research.",

year = "2022",

month = feb,

day = "1",

doi = "10.1158/2159-8290.CD-21-0538",

language = "English",

volume = "12",

pages = "372--387",

journal = "Cancer Discovery",

issn = "2159-8274",

publisher = "American Association for Cancer Research Inc.",

number = "2",

}

Kornauth, C, Pemovska, T, Vladimer, GI, Bayer, G, Bergmann, M, Eder, S, Eichner, R, Erl, M, Esterbauer, H, Exner, R, Felsleitner-Hauer, V, Forte, M, Gaiger, A, Geissler, K, Greinix, HT, Gstöttner, W, Hacker, M, Hartmann, BL, Hauswirth, AW, Heinemann, T, Heintel, D, Hoda, MA, Hopfinger, G, Jaeger, U, Kazianka, L, Kenner, L, Kiesewetter, B, Krall, N, Krajnik, G, Kubicek, S, Le, T, Lubowitzki, S, Mayerhoefer, ME, Menschel, E, Merkel, O, Miura, K, Müllauer, L, Neumeister, P, Noesslinger, T, Ocko, K, Öhler, L, Panny, M, Pichler, A, Porpaczy, E, Prager, GW, Raderer, M, Ristl, R, Ruckser, R, Salamon, J, Schiefer, A-I, Schmolke, A-S, Schwarzinger, I, Selzer, E, Sillaber, C, Skrabs, C, Sperr, WR, Srndic, I, Thalhammer, R, Valent, P, van der Kouwe, E, Vanura, K, Vogt, S, Waldstein, C, Wolf, D, Zielinski, CC, Zojer, N, Simonitsch-Klupp, I, Superti-Furga, G, Snijder, B & Staber, PB 2022, 'Functional Precision Medicine Provides Clinical Benefit in Advanced Aggressive Hematologic Cancers and Identifies Exceptional Responders', Cancer Discovery, vol. 12, no. 2, pp. 372-387. https://doi.org/10.1158/2159-8290.CD-21-0538

TY - JOUR

T1 - Functional Precision Medicine Provides Clinical Benefit in Advanced Aggressive Hematologic Cancers and Identifies Exceptional Responders

AU - Kornauth, Christoph

AU - Pemovska, Tea

AU - Vladimer, Gregory I.

AU - Bayer, Günther

AU - Bergmann, Michael

AU - Eder, Sandra

AU - Eichner, Ruth

AU - Erl, Martin

AU - Esterbauer, Harald

AU - Exner, Ruth

AU - Felsleitner-Hauer, Verena

AU - Forte, Maurizio

AU - Gaiger, Alexander

AU - Geissler, Klaus

AU - Greinix, Hildegard T.

AU - Gstöttner, Wolfgang

AU - Hacker, Marcus

AU - Hartmann, Bernd Lorenz

AU - Hauswirth, Alexander W.

AU - Heinemann, Tim

AU - Heintel, Daniel

AU - Hoda, Mir Alireza

AU - Hopfinger, Georg

AU - Jaeger, Ulrich

AU - Kazianka, Lukas

AU - Kenner, Lukas

AU - Kiesewetter, Barbara

AU - Krall, Nikolaus

AU - Krajnik, Gerhard

AU - Kubicek, Stefan

AU - Le, Trang

AU - Lubowitzki, Simone

AU - Mayerhoefer, Marius E.

AU - Menschel, Elisabeth

AU - Merkel, Olaf

AU - Miura, Katsuhiro

AU - Müllauer, Leonhard

AU - Neumeister, Peter

AU - Noesslinger, Thomas

AU - Ocko, Katharina

AU - Öhler, Leopold

AU - Panny, Michael

AU - Pichler, Alexander

AU - Porpaczy, Edit

AU - Prager, Gerald W.

AU - Raderer, Markus

AU - Ristl, Robin

AU - Ruckser, Reinhard

AU - Salamon, Julius

AU - Schiefer, Ana-Iris

AU - Schmolke, Ann-Sofie

AU - Schwarzinger, Ilse

AU - Selzer, Edgar

AU - Sillaber, Christian

AU - Skrabs, Cathrin

AU - Sperr, Wolfgang R.

AU - Srndic, Ismet

AU - Thalhammer, Renate

AU - Valent, Peter

AU - van der Kouwe, Emiel

AU - Vanura, Katrina

AU - Vogt, Stefan

AU - Waldstein, Cora

AU - Wolf, Dominik

AU - Zielinski, Christoph C.

AU - Zojer, Niklas

AU - Simonitsch-Klupp, Ingrid

AU - Superti-Furga, Giulio

AU - Snijder, Berend

AU - Staber, Philipp B.

N1 - Funding Information: We thank the patients and their families for their trust in taking part in this study. The study was academically funded and supported by the Medical University Vienna, the General Hospital Vienna, and the Research Center for Molecular Medicine (CeMM) of the Funding Information: G.I. Vladimer reports other support from Allcyte GmbH and other support from Exscientia GmbH during the conduct of the study; other support from Allcyte GmbH; and other support from Exsci-entia GmbH outside the submitted work; in addition, G.I. Vladimer has a patent for EP 3 704 484 A1 pending and licensed to Exscientia GmbH and a patent for EP 3 198 276 A1 pending and licensed to Exscientia GmbH; much of the screening work was performed while a postdoc at CeMM; manuscript drafting/data interpretation during employment, shareholder, and founder of Allcyte, which used the techniques described in this manuscript for translational research (not involved in clinical data collection). After final submission but before acceptance, Allcyte GmbH was acquired by Exscientia. M. Bergmann reports personal fees from Boehringer Ingelheim; grants from Boehringer Ingelheim, and grants from Bristol Myers Squibb outside the submitted work. K. Geissler reports personal fees from Novartis, personal fees from Celgene, and personal fees from Jazz outside the submitted work. B.L. Hartmann reports personal fees and nonfinancial support from Janssen, personal fees and nonfinancial support from Amgen, personal fees and nonfinancial support from Takeda, and personal fees and nonfinancial support from AbbVie during the conduct of the study. T. Heinemann reports grants from the Deutsche Forschungsgemeinschaft (DFG; German Research Foundation—project number 389640585) and grants from the Swiss National Science Foundation (PP00P3_163961) during the conduct of the study. N. Krall reports grants from WWTF, grants from Marie Curie Fellowship, and grants from SNF Postdoc Fellowship during the conduct of the study; and reports being an employee of Allcyte GmbH and an employee of Exscientia GmbH, outside the submitted work; in addition, N. Krall has a patent for EP 3 704 484 A1 pending, assigned to Exscientia GmbH, and a patent for EP 3 198 276 A1 pending, assigned to Exscientia GmbH; and is a founder and shareholder of Allcyte GmbH. Allcyte GmbH was bought by Funding Information: We thank the patients and their families for their trust in taking part in this study. The study was academically funded and supported by the Medical University Vienna, the General Hospital Vienna, and the Research Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences. We gratefully acknowledge funding from the Vienna Science and Technology Fund; (LS16-034, to G. Superti-Furga and U. Jaeger), the Austrian Science Fund (F4704-B20, to P. Valent; F4711-B20, to G. Superti-Furga; and P27132-B20, to P.B. Staber), and the European Molecular Biology Organization Long Term Fellowship (1543-2012, to G.I. Vladimer; 733-2016 to T. Pemovska). B. Snijder acknowledges funding from the ETH Zurich, the Swiss National Science Foundation (PP00P3_163961, PP00P3_194809, and CRSII5_193832), and the European Research Council (SCIPER; 803063). Funding Information: Austrian Academy of Sciences. We gratefully acknowledge funding from the Vienna Science and Technology Fund; (LS16-034, to G. Superti-Furga and U. Jaeger), the Austrian Science Fund (F4704-B20, to P. Valent; F4711-B20, to G. Superti-Furga; and P27132-B20, to P.B. Staber), and the European Molecular Biology Organization Long Term Fellowship (1543-2012, to G.I. Vladimer; 733-2016 to T. Pemovska). B. Snijder acknowledges funding from the ETH Zurich, the Swiss National Science Foundation (PP00P3_163961, PP00P3_194809, and CRSII5_193832), and the European Research Council (SCIPER; 803063). Publisher Copyright: ©2021 The Authors; Published by the American Association for Cancer Research.

PY - 2022/2/1

Y1 - 2022/2/1

N2 - Personalized medicine aims to match the right drug with the right patient by using specific features of the individual patient’s tumor. However, current strategies of personalized therapy matching provide treatment opportunities for less than 10% of patients with cancer. A promising method may be drug profiling of patient biopsy specimens with single-cell resolution to directly quantify drug effects. We prospectively tested an image-based single-cell functional precision medicine (scFPM) approach to guide treatments in 143 patients with advanced aggressive hematologic cancers. Fifty-six patients (39%) were treated according to scFPM results. At a median follow-up of 23.9 months, 30 patients (54%) demonstrated a clinical benefit of more than 1.3-fold enhanced progression-free survival compared with their previous therapy. Twelve patients (40% of responders) experienced exceptional responses lasting three times longer than expected for their respective disease. We conclude that therapy matching by scFPM is clinically feasible and effective in advanced aggressive hematologic cancers. SIGNIFICANCE: This is the first precision medicine trial using a functional assay to instruct n-of-one therapies in oncology. It illustrates that for patients lacking standard therapies, high-content assaybased scFPM can have a significant value in clinical therapy guidance based on functional dependencies of each patient’s cancer.

AB - Personalized medicine aims to match the right drug with the right patient by using specific features of the individual patient’s tumor. However, current strategies of personalized therapy matching provide treatment opportunities for less than 10% of patients with cancer. A promising method may be drug profiling of patient biopsy specimens with single-cell resolution to directly quantify drug effects. We prospectively tested an image-based single-cell functional precision medicine (scFPM) approach to guide treatments in 143 patients with advanced aggressive hematologic cancers. Fifty-six patients (39%) were treated according to scFPM results. At a median follow-up of 23.9 months, 30 patients (54%) demonstrated a clinical benefit of more than 1.3-fold enhanced progression-free survival compared with their previous therapy. Twelve patients (40% of responders) experienced exceptional responses lasting three times longer than expected for their respective disease. We conclude that therapy matching by scFPM is clinically feasible and effective in advanced aggressive hematologic cancers. SIGNIFICANCE: This is the first precision medicine trial using a functional assay to instruct n-of-one therapies in oncology. It illustrates that for patients lacking standard therapies, high-content assaybased scFPM can have a significant value in clinical therapy guidance based on functional dependencies of each patient’s cancer.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Austria

KW - Cohort Studies

KW - Female

KW - Hematologic Neoplasms/drug therapy

KW - Humans

KW - Male

KW - Middle Aged

KW - Molecular Targeted Therapy

KW - Precision Medicine

KW - Progression-Free Survival

KW - Young Adult

UR - http://www.scopus.com/inward/record.url?scp=85124443134&partnerID=8YFLogxK

U2 - 10.1158/2159-8290.CD-21-0538

DO - 10.1158/2159-8290.CD-21-0538

M3 - Journal article

C2 - 34635570

SN - 2159-8274

VL - 12

SP - 372

EP - 387

JO - Cancer Discovery

JF - Cancer Discovery

IS - 2

ER -

Functional Precision Medicine Provides Clinical Benefit in Advanced Aggressive Hematologic Cancers and Identifies Exceptional Responders

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