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.
Organisations
People |
ORCID iD |
Paresh Vyas (Principal Investigator) |
Publications
Daver N
(2022)
AML-262 Pivekimab Sunirine (PVEK, IMGN632) Triplet With Azacitidine and Venetoclax Shows Broad Activity in Adverse Genetic Subsets of Relapsed/Refractory Acute Myeloid Leukemia and Reduced Infusion-Related Reactions
in Clinical Lymphoma Myeloma and Leukemia
Rajakumaraswamy N
(2023)
Real-world Effectiveness of Azacitidine in Treatment-Naive Patients With Higher-risk Myelodysplastic Syndromes.
in Clinical lymphoma, myeloma & leukemia
Jakobsen NA
(2018)
From genomics to targeted treatment in haematological malignancies: a focus on acute myeloid leukaemia.
in Clinical medicine (London, England)
Vyas P
(2020)
Disease Models & Mechanisms announces a new Editor-in-Chief.
in Disease models & mechanisms
Symeonidou V
(2022)
Heterogeneous genetic and non-genetic mechanisms contribute to response and resistance to azacitidine monotherapy
in eJHaem
Josa-Culleré L
(2023)
Phenotypic screening identifies a trisubstituted imidazo[1,2-a]pyridine series that induces differentiation in multiple AML cell lines.
in European journal of medicinal chemistry
Sweeney C
(2019)
The Graft-Versus-Leukemia Effect in AML.
in Frontiers in oncology
Turkalj S
(2023)
An Overview of Targeted Therapies in Acute Myeloid Leukemia.
in HemaSphere
Stoilova B
(2019)
The Inflammasome: More Than a Protective Innate Immune Mechanism.
in Immunity
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... |