Biology and Treatment of Human Myeloid Cancers
Lead Research Organisation:
University of Oxford
Department Name: UNLISTED
Abstract
Blood cancers are the 5th most common cancers. This program studies the biology of the most common
aggressive adult leukemia, acute myeloid leukemia and blood disorders related to it. The programme is tracing
these cancers from the first events that establish the foundations for these cancers to develop late in life, to the
events that lead to fully formed cancers. The programme is also to devlope new treatments that harms the power
of the immune sustem to cure these cancers.
aggressive adult leukemia, acute myeloid leukemia and blood disorders related to it. The programme is tracing
these cancers from the first events that establish the foundations for these cancers to develop late in life, to the
events that lead to fully formed cancers. The programme is also to devlope new treatments that harms the power
of the immune sustem to cure these cancers.
Technical Summary
Approximately 10 billion new, polyclonal, human myeloid blood cells terminally differentiate daily.
We aim to understand mechanisms by which recurrent genetic mutations, epigenetic change, and
an altered microenvironment, subtly disrupt this differentiation cascade causing clonal haemopoiesis
of indeterminant potential (CHIP) initially, and then the clinical disorders, myelodysplastic
syndromes (MDS) and acute myeloid leukaemia (AML). Over the last 5 years, we have defi ned
aspects of the complex normal hierarchy of early human blood stem/progenitor cells. We have
purifi ed and characterised the transcriptional profi les of functional AML leukaemic stem cells and
shown they are arrested at progenitor and precursor stages of haemopoiesis. We have functionally
tested the spectrum of oncogenic mutations that lead to AML transformation. Finally, we
have used this information, and sequential human bone marrow samples, interrogated by single
cell analyses, to understand how therapy modulates the clonal landscape of preleukaemic and
leukaemic clones leading to AML therapy response and therapy failure. This is vital information to
develop new rational therapy combinations. Over the next 5 years, we will determine the timing of
acquisition of mutations causing CHIP, and the timing of mutations associated with with MDS and
transformation to AML. Using human samples and mouse models, we will model the quantitative
advantage conferred by CHIP/MDS/AML mutations to mutant blood stem cells, and the impact
sequential genetic mutations, and epigenetic changes on differentiation that causes MDS and transformation to AML. Finally, we have an ambitious program to develop novel immune therapies in AML.
We aim to understand mechanisms by which recurrent genetic mutations, epigenetic change, and
an altered microenvironment, subtly disrupt this differentiation cascade causing clonal haemopoiesis
of indeterminant potential (CHIP) initially, and then the clinical disorders, myelodysplastic
syndromes (MDS) and acute myeloid leukaemia (AML). Over the last 5 years, we have defi ned
aspects of the complex normal hierarchy of early human blood stem/progenitor cells. We have
purifi ed and characterised the transcriptional profi les of functional AML leukaemic stem cells and
shown they are arrested at progenitor and precursor stages of haemopoiesis. We have functionally
tested the spectrum of oncogenic mutations that lead to AML transformation. Finally, we
have used this information, and sequential human bone marrow samples, interrogated by single
cell analyses, to understand how therapy modulates the clonal landscape of preleukaemic and
leukaemic clones leading to AML therapy response and therapy failure. This is vital information to
develop new rational therapy combinations. Over the next 5 years, we will determine the timing of
acquisition of mutations causing CHIP, and the timing of mutations associated with with MDS and
transformation to AML. Using human samples and mouse models, we will model the quantitative
advantage conferred by CHIP/MDS/AML mutations to mutant blood stem cells, and the impact
sequential genetic mutations, and epigenetic changes on differentiation that causes MDS and transformation to AML. Finally, we have an ambitious program to develop novel immune therapies in AML.
Organisations
People |
ORCID iD |
| Paresh Vyas (Principal Investigator) |
Publications
Chen J
(2022)
MDS-482 Impact Of Magrolimab in Combination With Azacitidine on Red Blood Cells (RBCs) in Patients With Higher-Risk Myelodysplastic Syndromes (HR MDS)
in Clinical Lymphoma Myeloma and Leukemia
Daver N
(2022)
AML-464 Tolerability and Efficacy of the First-In-Class Anti-CD47 Antibody Magrolimab Combined With Azacitidine in Frontline Patients With TP53-Mutated Acute Myeloid Leukemia (AML): Phase 1b Results
in Clinical Lymphoma Myeloma and Leukemia
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
Daver NG
(2022)
TP53-Mutated Myelodysplastic Syndrome and Acute Myeloid Leukemia: Biology, Current Therapy, and Future Directions.
in Cancer discovery
Daver NG
(2023)
Tolerability and Efficacy of the Anticluster of Differentiation 47 Antibody Magrolimab Combined With Azacitidine in Patients With Previously Untreated AML: Phase Ib Results.
in Journal of clinical oncology : official journal of the American Society of Clinical Oncology
DiNardo C
(2022)
AML-432 Overall Survival (OS) by Mutant Allele (R140 or R172) in Patients With Late-Stage, Mutant- Relapsed/Refractory Acute Myeloid Leukemia (AML) Treated With Enasidenib or Conventional Care Regimens (CCR) in the Randomized, Open-Label, Phase 3 IDHENTIFY Trial
in Clinical Lymphoma Myeloma and Leukemia
Gooding S
(2022)
Loss of COP9 signalosome genes at 2q37 is associated with IMiD resistance in multiple myeloma.
in Blood
Related Projects
| Project Reference | Relationship | Related To | Start | End | Award Value |
|---|---|---|---|---|---|
| MC_UU_00029/1 | 31/03/2022 | 30/03/2027 | £4,671,000 | ||
| MC_UU_00029/2 | Transfer | MC_UU_00029/1 | 31/03/2022 | 30/03/2027 | £2,140,000 |
| MC_UU_00029/3 | Transfer | MC_UU_00029/2 | 31/03/2022 | 30/03/2027 | £3,857,000 |
| MC_UU_00029/4 | Transfer | MC_UU_00029/3 | 31/03/2022 | 30/03/2027 | £1,339,000 |
| MC_UU_00029/5 | Transfer | MC_UU_00029/4 | 31/03/2022 | 30/03/2027 | £2,875,000 |
| MC_UU_00029/6 | Transfer | MC_UU_00029/5 | 31/03/2022 | 30/03/2027 | £1,968,000 |
| MC_UU_00029/7 | Transfer | MC_UU_00029/6 | 31/03/2022 | 30/03/2027 | £1,450,000 |
| MC_UU_00029/8 | Transfer | MC_UU_00029/7 | 31/03/2022 | 30/03/2027 | £2,507,000 |
| MC_UU_00029/9 | Transfer | MC_UU_00029/8 | 31/03/2022 | 30/03/2027 | £3,688,000 |
| Description | WIMM Celgene Fellowship |
| Amount | £519,623 (GBP) |
| Organisation | Bristol-Myers Squibb |
| Sector | Private |
| Country | United Kingdom |
| Start | 03/2019 |
| End | 03/2024 |
| 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 | 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 | 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... |