Identification, characterisation and therapeutic targeting of leukaemic stem/propagating cells in Acute Myeloid Leukaemia

Lead Research Organisation: University of Oxford
Department Name: UNLISTED

Abstract

There are ~3000 new cases a year in the UK of Acute Myeloid Leukaemia (AML). This is the most common aggressive leukaemia. Despite advances in treating patients under the age of 60 years, 50% of these patients still die of their disease. Furthermore, 80% of patients are over the age of 60 and in this age group only 5% of patients are cured. Thus, we need to improve therapy. AML mainly arises sporadically through acquisition of genetic changes in DNA in multiple genes that regulate the complex process of blood cell production. In some patients there is a preleukaemia condition called Myelodysplasia (MDS). One way to further our understanding AML is to define the compendium of genetic changes throughout all our DNA in both AML and MDS and assess how changes deregulate normal blood stem and progenitor cells and transform them into cancerous populations. This necessary information provides a rational platform for future developments to directly benefit patient care. Furthermore study of MDS and AML provides a model to discover general principles in cancer biology and therapy.

Technical Summary

Our aim is to characterise the heterogeneous populations of leukaemia propagating cells (LPC) in adult and childhood Acute Myeloid Leukaemia (AML) at functional, genetic, epigenetic and molecular levels, eventually at a single cell level, to improve our basic understanding of leukaemia initiation and propagation. The ultimate aim is to translate this knowledge to improve survival rates in patients. Recent studies from our laboratory and other laboratories have shown that, within any one patient’s tumour, there is functional, molecular and genetic heterogeneity of tumour propagating populations. Though not yet formally demonstrated, layered upon this will likely be epigenetic heterogeneity. Thus, our key questions centre around understanding: a) the nature of this heterogeneity; b) how it arises and c) how different aspects of heterogeneity impact on each other. From a tumour biology perspective, a central hypothesis we will work towards testing is that there are specific molecular attributes present in AML LPC, but absent in downstream progeny, that explain LPC’s ability to propagate tumours whereas downstream progeny cannot. Experimentally, these studies will initially be cell population based. We will purify distinct immunophenotypic primary human AML populations, test their in vivo function, and determine their molecular, genetic and epigenetic profiles. This will be an iterative process. But, ultimately, these studies will have to be conducted at the single cell level,. To begin with, we will overlay single cell molecular and genetic analysis on the cell population-based studies. From a translational standpoint, our key hypotheses are: A) AML LPC are the chemoresistant relapse-driving populations. B) LPC can be therapeutically targeted. Only if both hypotheses are proven correct will be able to improve survival for patients. To test the first hypothesis, we will track LPC from diagnosis through therapy. To address the second hypothesis, we will continue work with Stanford to develop a combination of therapeutic antibodies targeting LPC antigens. Once again, there are huge challenges here, that include: a) defining a window between efficacy and toxicity given that many LPC markers are widely expressed b) defining cocktails of antibodies that target all chemoresistant LPCs.

Publications

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Ossenkoppele G (2020) BCL-2 Inhibitor and Conventional Chemotherapy Combinations for Acute Myeloid Leukemia: Shifting From the Unfit to the Fit Patient With AML. in Journal of clinical oncology : official journal of the American Society of Clinical Oncology

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Roberts I (2021) Sowing the seeds of leukemia before birth. in Science (New York, N.Y.)

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Sallman DA (2023) Magrolimab in Combination With Azacitidine in Patients With Higher-Risk Myelodysplastic Syndromes: Final Results of a Phase Ib Study. in Journal of clinical oncology : official journal of the American Society of Clinical Oncology

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Sweeney C (2019) The Graft-Versus-Leukemia Effect in AML. in Frontiers in oncology

Related Projects

Project Reference Relationship Related To Start End Award Value
MC_UU_00016/1 31/03/2017 30/03/2022 £3,035,000
MC_UU_00016/2 Transfer MC_UU_00016/1 31/03/2017 30/03/2022 £3,411,000
MC_UU_00016/3 Transfer MC_UU_00016/2 31/03/2017 30/03/2022 £1,366,000
MC_UU_00016/4 Transfer MC_UU_00016/3 31/03/2017 30/03/2020 £3,017,000
MC_UU_00016/5 Transfer MC_UU_00016/4 31/03/2017 30/03/2020 £497,000
MC_UU_00016/6 Transfer MC_UU_00016/5 31/03/2017 30/03/2022 £2,530,000
MC_UU_00016/7 Transfer MC_UU_00016/6 31/03/2017 30/03/2022 £2,018,000
MC_UU_00016/8 Transfer MC_UU_00016/7 31/03/2017 30/03/2018 £1,131,000
MC_UU_00016/9 Transfer MC_UU_00016/8 31/03/2017 30/03/2022 £2,500,000
MC_UU_00016/10 Transfer MC_UU_00016/9 31/03/2017 30/03/2018 £1,171,000
MC_UU_00016/11 Transfer MC_UU_00016/10 31/03/2017 30/03/2022 £1,387,000
MC_UU_00016/12 Transfer MC_UU_00016/11 31/03/2017 30/03/2022 £446,000
 
Description NHSBT Non Executive Director
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact Ensuring quality and safe provision of blood and organs - Stem cells for England.
 
Description NHSBT Non-Executive Director
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact Ensuring quality and safe provision of blood and organs.
 
Description NHSBT Non-Executive Director
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact Ensuring quality and safe provision of blood and organs - Stem cells for England.
 
Description 0011150 CF
Amount £241,600 (GBP)
Organisation University of Oxford 
Department John Fell Fund
Sector Academic/University
Country United Kingdom
Start 11/2021 
End 09/2022
 
Description Amendment 4 Collaboration CyTOF Panels Mount Sinai
Amount £43,800 (GBP)
Organisation Bristol-Myers Squibb 
Department Celgene
Sector Private
Country United States
Start 09/2019 
End 09/2022
 
Description BD - Celgene Fellowship Agreement for Supat Thongjuea entitled "Single-Cell Computational Biology for Translational Medicine
Amount £519,623 (GBP)
Organisation Bristol-Myers Squibb 
Department Celgene
Sector Private
Country United States
Start 11/2019 
End 10/2022
 
Description BRC3 - Precision Medicine cluster funding
Amount £112,500 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 03/2019 
End 03/2020
 
Description Blood Cancer UK - Programme Continuity Grant
Amount £300,000 (GBP)
Organisation Blood Cancer UK 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2020 
End 04/2024
 
Description Celgene Translational Science Proposal
Amount £1,065,908 (GBP)
Organisation Bristol-Myers Squibb 
Department Celgene
Sector Private
Country United States
Start 09/2019 
End 01/2023
 
Description HIDI Award
Amount £25,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 07/2018 
End 07/2019
 
Description Oxford Comprehensive Biomedical Research Centre
Amount £60,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 03/2018 
End 04/2022
 
Description WIMM - Lymphoma Biobank
Amount £44,500 (GBP)
Organisation Oxford University Hospitals NHS Foundation Trust 
Sector Academic/University
Country United Kingdom
Start 11/2021 
End 10/2022
 
Description WIMM - TAL Wolfson Donation
Amount £750,000 (GBP)
Organisation The Wolfson Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2021 
End 05/2023
 
Description WIMM Celgene Fellowship
Amount £519,623 (GBP)
Organisation Bristol-Myers Squibb 
Sector Private
Country United Kingdom
Start 03/2019 
End 03/2024
 
Description WIMM LadyTata- A Groom
Amount £75,000 (GBP)
Organisation Lady Tata Memorial Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2021 
End 09/2023
 
Description WIMM-Celgene F'ship 21-2
Amount £543,000 (GBP)
Organisation Bristol-Myers Squibb 
Department Celgene
Sector Private
Country United States
Start 03/2021 
End 10/2022
 
Title METHOD AND COMPOSITION 
Description The invention relates to a method of selecting an immunotherapeutic agent for treating a disease in an individual, and to treatment of the disease by administering the immunotherapeutic agent or the cognate peptide antigen for the immunotherapeutic agent. The invention also relates to an antigen binding molecule that binds to the peptide antigen. 
IP Reference WO2022223970 
Protection Patent / Patent application
Year Protection Granted 2022
Licensed Yes
Impact n a pilot experiment, we stimulated PBMCs from one patient with overlapping putative GvL peptides identified by IFNy ELISpot mapping (see Figure 3), or control peptides, FACS-sorted responding T cells (identified by IFNy-secretion using a catch reagent) and successfully subjected them to parallel single cell TCR/transcriptome sequencing (10X genomics platform) (Keskin, D.B. et al. Neoantigen vaccine generates intratumoral T cell responses in phase lb glioblastoma trial. Nature, 2019. 565(7738): p. 234-239). Analysis of the data has enabled identification of TCRs highly enriched in the peptide-responsive population, and simultaneous interrogation of their gene expression profile. Bulk TCR sequencing was also performed on an unstimulated ex vivo sample from the same patient, to enable determination of the frequency of each peptide-responsive TCR within the in vivo T cell repertoire. This established a workflow in our laboratory that can readily be applied to the larger sample set from the AMADEUS trial.
 
Description American Association of Cancer Research Myeloid Meeting 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Title: "Molecular Features Associated with Response to Combination Therapy with Enasidenib (ENA) Plus Azacitidine (AZA) in Newly Diagnosed IDH2-Mutated Acute Myeloid Leukemia (AML)"


Co-authors: Alberto Risueño, PhD, Wendy L. See, PhD, Courtney D. DiNardo, MD, MSCE, Hartmut Döhner, MD, Eytan Stein, MD5, Amir T. Fathi, MD6, Paresh Vyas, DPhil, FRCP, FRCPath, MRCP, MRCPath, Lynn Quek, MD PhD, Thomas Prebet, MD, PhD, Anita K. Gandhi, PhD9 and Maroof Hasan, MD
Year(s) Of Engagement Activity 2023
URL https://ash.confex.com/ash/2022/webprogram/Session22525.html
 
Description Belgian Academy of Sciences 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Paresh VYAS (Professor of Haematology at the University of Oxford, Oxford, UK) : Paresh Vyas : Clonal Cell Heterogeneity in Tissues With Aging Alters Function: Using Whole Genome Sequencing and Single Cell Sequencing To Study These Processes In Blood Cells As An Exemplar

Ruud Delwel (Professor "Molecular Leukemogenesis", Department of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands): How good genes can become Evil in leukemia

Steven O. Smith (Professor - Director of Structural Biology, Department of Biochemistry and Cell Biology Stony Brook, NY USA) : Lessons from brain-derived amyloid fibril structures from Alzheimer's Disease patients

https://www.youtube.com/watch?v=GjyrzYunfPU

See also: https://www.facebook.com/probramedecine/
Year(s) Of Engagement Activity 2022
URL https://www.youtube.com/watch?v=GjyrzYunfPU
 
Description Conference / Exposition: American Association of Cancer Research Myeloid Meeting 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Title: "Molecular Features Associated with Response to Combination Therapy with Enasidenib (ENA) Plus Azacitidine (AZA) in Newly Diagnosed IDH2-Mutated Acute Myeloid Leukemia (AML)"

Co-authors: Alberto Risueño, PhD, Wendy L. See, PhD, Courtney D. DiNardo, MD, MSCE, Hartmut Döhner, MD, Eytan Stein, MD5, Amir T. Fathi, MD6, Paresh Vyas, DPhil, FRCP, FRCPath, MRCP, MRCPath, Lynn Quek, MD PhD, Thomas Prebet, MD, PhD, Anita K. Gandhi, PhD9 and Maroof Hasan, MD
Year(s) Of Engagement Activity 2023
URL https://ash.confex.com/ash/2022/webprogram/Session22525.html
 
Description Conference / Exposition: University of Texas South Western 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact PLENARY SESSION 8: CELL AND IMMUNE TARGETING IN MYELOID MALIGNANCIES SESSION CHAIR: PARESH VYAS, UNIVERSITY OF OXFORD, OXFORD, UNITED KINGDOM 12:00 P.M.-1:45 P.M.

Talk title: "Graft versus Leukemia (GvL): Identification and characterization of alloreactive antigens and cognate T cell responses in acute myeloid leukemia"
Year(s) Of Engagement Activity 2023
URL https://www.aacr.org/meeting/acute-myeloid-leukemia-and-myelodysplastic-syndrome/program/
 
Description EHA (European Haematology Association) Annual Meeting. 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact TOLERABILITY AND EFFICACY OF THE FIRST-IN-CLASS ANTI-CD47 ANTIBODY MAGROLIMAB COMBINED WITH AZACITIDINE IN FRONTLINE PATIENTS WITH TP53-MUTATED ACUTE MYELOID LEUKEMIA: PHASE 1B RESULTS
Dr. Naval G Daver
Author(s): Naval G Daver, Paresh Vyas, Suman Kambhampati, Monzr M Al Malki, Richard Larson, Adam Asch, Gabriel Mannis, Wanxing Chai-Ho, Tiffany Tanaka, Terrence Bradley, Deepa Jeyakumar, Eunice Wang, Guan Xing, Mark Chao, Giri Ramsingh, Camille Renard, Indu Lal, Joshua Zeidner, David Sallman
(Abstract release date: 05/26/22) EHA Library. G Daver N. 06/10/2022; 356996; S132
Year(s) Of Engagement Activity 2022
URL https://library.ehaweb.org/eha/2022/eha2022-congress/356996/naval.g.daver.tolerability.and.efficacy....
 
Description ESH (European Society of Haematology) Treatment of Leukaemias (Virtual) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact (Latest session from 2022 not recorded. Earlier talk from 2019 recorded at URL provided below):

The AML Global Portal were delighted to speak to Paresh Vyas, University of Oxford, Oxford, UK, during the European School of Hematology (ESH) Translational Research Conference on AML. We asked Paresh Vyas: When do you use single-cell MRD assessment in AML?

Paresh Vyas discusses the role of measurable residual disease (MRD) monitoring in informing clinical practice and reviews different approaches such as next-generation sequencing (NGS), flow cytometry and single-cell measurement of disease.
Year(s) Of Engagement Activity 2022
URL https://aml-hub.com/medical-information/esh-2019-or-when-do-you-use-single-cell-mrd-assessment-in-am...
 
Description Hosted Work Experience Programme 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Other audiences
Results and Impact Run a session on haematology for students in the MRC WIMM work experience programme. Included go fish game, activities on gene expression using legos and microscopy and leukaemia diagnosis
Year(s) Of Engagement Activity 2019
 
Description MRC Festival 2019 on Cancer immunotherapy - Grigore 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Part of working group that developed activities for MRC Festival 2019 on Cancer immunotherapy
Year(s) Of Engagement Activity 2019
 
Description Myeloid Workshop (Cincinnati, USA) 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Since 1995, the Workshop on Molecular Aspects of Myeloid Stem Cell Development and Leukemia has offered a highly successful presentation series from approximately 40-50 renowned national and international researchers and clinicians.

The goal of these biennial workshops is to bring together investigators with expertise in complementary aspects of stem cell biology and myelopoiesis - from normal myelopoiesis to myeloid leukemias and myelodysplastic/myeloproliferative syndromes. Basic researchers and clinician investigators from both sides of the Atlantic, Australia and Japan come together biennially to discuss their latest findings in a close and informal setting. The workshop brings together scientists with expertise in normal and abnormal hematopoiesis and clinicians who treat leukemia/MDS/MPD patients and also have active research programs in these diseases.

Participants achieve a better understanding of critical steps/factors that regulate hematopoiesis, their impact in leukemogenesis, and potential relevance in clinical settings. Although there are other workshops and meetings dedicated to understanding the regulation of hematopoiesis or clinical advances in leukemia, this workshop uniquely brings together both clinicians and scientists in a relaxed forum.

Speakers: (See URL)
Year(s) Of Engagement Activity 2022
URL https://myeloidmeeting.org
 
Description OXFORD & NATIONWIDE SUPPORT GROUP MEETING - MDS UK Members 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Speaker at OXFORD & NATIONWIDE SUPPORT GROUP MEETING - MDS UK Members
Year(s) Of Engagement Activity 2021
 
Description Patient Support Group 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Patients, carers and/or patient groups
Results and Impact Giving support and advice to patients, families and carers.
Year(s) Of Engagement Activity 2019
 
Description Science in the supermarket, MRC Festival 2019 - Douzi & Grigore 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Science in the supermarket, MRC Festival 2019
Year(s) Of Engagement Activity 2019
 
Description University of Texas South Western 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact PLENARY SESSION 8: CELL AND IMMUNE TARGETING IN MYELOID MALIGNANCIES SESSION CHAIR: PARESH VYAS, UNIVERSITY OF OXFORD, OXFORD, UNITED KINGDOM 12:00 P.M.-1:45 P.M.

TITLE: "Graft versus Leukemia (GvL): Identification and characterization of alloreactive antigens and cognate T cell responses in acute myeloid leukemia"
Year(s) Of Engagement Activity 2023
URL https://www.aacr.org/meeting/acute-myeloid-leukemia-and-myelodysplastic-syndrome/program/
 
Description iWAL (International Workshop on Acute Leukemia) Workshop (Nice, France): iWAL 2022 Session V: Mechanisms of resistance to targeted therapies in AML 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact iwAL 2022 Session V: Mechanisms of resistance to targeted therapies in AML
Tuesday Dec 06, 2022

The 4th International Workshop on Acute Leukemias (iwAL) 2022 took place in Nice, France, and brought together leading experts in the field as they discussed several topics. In this podcast series, you will hear the latest updates in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) and gain an insight into the sessions that took place at this year's meeting.

In this podcast, Naval Daver, MD, The University of Texas MD Anderson Cancer Center, Houston, TX, Paresh Vyas, MRCP, FRCP, FRCPath, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK, Alexander Perl, MD, University of Pennsylvania, Philadelphia, PA, and Carsten Müller-Tidow, MD, University Hospital Heidelberg, Heidelberg, Germany, discuss mechanisms of resistance to targeted therapies in AML, and the role of epigenetics.
Year(s) Of Engagement Activity 2022
URL https://vjhemonc.podbean.com/e/iwal-2022-session-v-mechanisms-of-resistance-to-targeted-therapies-in...