Special Scientific Symposia
The following information is preliminary and subject to change. All times are listed in Central time.
Biology and Translation of NK Cells
Saturday, December 10, 2022, 2:00 p.m. - 3:15 p.m.
Ernest N. Morial Convention Center, 293-294
Cellular immunotherapy has revolutionized our approach to managing cancer, giving hope to patients with otherwise limited prognosis and survival. The use of chimeric antigen receptor (CAR) T cells has been at the forefront of recent advances in cancer immunotherapy. CAR T cells have been mostly effective in B cell malignancies and their use is associated with major toxicities including cytokine release syndrome (CRS), neurotoxicity, and the potential for causing graft versus host disease (GVHD) with allogeneic products. Natural Killer (NK) cells have an intrinsic propensity to target malignant cells, which can be further enhanced by activating them with cytokines to induce a memory-like phenotype and/or by arming them with novel CAR constructs. Cytokine-engineered and CAR-armed NK cells have demonstrated excellent safety with promising efficacy signal in recent clinical trials, making them attractive alternatives to T cell-based approaches. Recently CRISPR-based gene-editing techniques have been successfully applied to NK cells to further enhance their anti-tumor responses. Furthermore, novel NK cell engagers have shown promising activity in preclinical and early phase clinical trials. Based on these major recent advances we believe that the hematology community will benefit from a symposium highlighting the basic biology and translation of the NK cell-based therapies to the clinic. This proposal is supported by the Subcommittee on Emerging Gene & Cell Therapies.
Chair:
Katy Rezvani, MD
The University of Texas M D Anderson Cancer Center
Houston, TX
Speakers:
Rizwan Romee, MD
Dana-Farber Cancer Institute
Boston, MA
Fundamentals of NK Cell Biology
Eric Vivier, DVM, Phd, [email protected]
Centre d'Immunologie de Marseille-Luminy (CIML)
Marseille, France
Antibody-Based NK Cell Engager Therapeutics
Jeffrey S. Miller, MD, MD
University of Minnesota
Minneapolis, MN
Novel Immunomodulatory Agents to Harness NK Cell Mediated Anti-Tumor Responses
Building Dietary Evidence for Hematologic Malignancies - Mechanistic Insights
Sunday, December 11, 2022, 9:30 a.m. - 10:45 a.m.
Ernest N. Morial Convention Center, 217-219
Dietary research in blood cancers is an unmet need. This is often the most asked question by patients and the least likely to be addressed by hematologists and oncologists. With the increasing number of patients diagnosed with precursor disorders due to better testing strategies and the reduced cancer specific mortality due to novel therapies, there is an opportunity to improve outcomes further with evidence-based nutrition guidance in hematologic malignancies.
Epidemiologic studies have shown associations between unhealthy dietary patterns and the risk of hematologic malignancies although mechanistic data are sparse. With recent advances in methods to study metabolism, microbiome, and the immune system, it is possible to gain a deeper mechanistic understanding into dietary effects. Currently, there are a limited number of dietary intervention trials in hematologic malignancies and their precursor disorders, although interest is growing.
This session will focus on mechanistic insights and biomarker strategies that aide in nutrition in blood cancer research. We will discuss metabolic, microbiome, and immune mechanisms by which diet may affect/modulate hematologic malignancies.
Dr. Catherine Marinac will review the epidemiological evidence linking dietary patterns, metabolic disease (such as obesity and diabetes), and hematologic malignancies. Additional metabolic biomarkers such as markers of insulin resistance and its association with hematologic malignancies will be discussed. She will discuss ongoing and future strategies to translate epidemiological findings to interventional trials in the clinic.
Dr. Matteo Bellone will discuss the evidence linking diet, microbiome, and hematologic malignancies. The gut microbiome composition modulates the host immune response (innate and adaptive) and eventually impacts tumor growth. There will be special emphasis on dietary patterns (such as plant based high fiber diets and western high fat and protein diets) that affect the gut microbiome composition (specifically species and genus). This will be discussed in the context of translational studies with myeloma mouse models. The gut microbiome or its related metabolites may also be manipulated to improve the efficacy of checkpoint blockers.
Dr. Urvi Shah will present the evidence linking diet, the immune system, and hematologic malignancies (with a special focus on plasma cell disorders). The talk will discuss the potential impact of dietary patterns on the immune microenvironment and the immune system and thus disease course. Lastly, the role of dietary interventions in clinical trials studying disease progression, overall response rates, and potential synergy with immunotherapies will also be examined.
Chair:
Urvi A Shah, MD
Memorial Sloan Kettering Cancer Center
New York, NY
Speakers:
Catherine R. Marinac, PhD
Dana-Farber Cancer Institute
Boston, MA
Nutrition Metabolism Connection (Epidemiologic Focus)
Matteo Bellone, MD
IRCCS Ospedale San Raffaele
Milan, MI, Italy
Nutrition Gut Microbiome Connection (Translational Focus)
Urvi A Shah, MD
Memorial Sloan Kettering Cancer Center
New York,
Nutrition Immune Connection (Clinical Focus)
Genetic and Functional Heterogeneity in Megakaryocytes and Platelets
Saturday, December 10, 2022, 2:00 p.m. - 3:15 p.m.
Ernest N. Morial Convention Center, 252-254
Platelets have important roles in not only hemostasis but also other key biological and pathological processes such as immunoregulation, malignancy, angiogenesis, and wound healing. Historically, megakaryocytes have been considered a phenotypically homogenous population that produce a uniform population of platelets. However, recent studies have challenged this paradigm and created a fundamental shift in how we view both megakaryocytes and their platelet progeny. This session will focus on heterogeneity in the development and function of platelets and their precursor cells, megakaryocytes.
Dr. Krause will present cell and molecular insights into the fate specification of primary human megakaryocytic-erythroid progenitors (MEP). While much is known about how megakaryoblasts and erythroblasts progress to maturation, the signaling, transcriptomic, and epigenetic changes that occur during MEP fate specification are still largely unknown. Dr. Krause will present data revealing roles for differential transcription, epigenetics and the cell cycle in MEP fate specification based on functional assays and high throughput molecular approaches as well as recently published timelapse microscopy studies.
Dr. Alastair Poole will present evidence showing emergence of megakaryocytes into vasculature including an in vitro heart-lung system that has been developed to allow perfusion of megakaryocytes through the pulmonary vasculature. High efficiency of in vitro platelet generation in lung vasculature is shown and demonstration that in vitro microfluidic chambers mimic this vasculature, enabling large scale functional platelet generation in vitro.
Dr. Anandi Krishnan will discuss how platelet transcriptomic signatures not only capture information from parent megakaryocytes and progenitor hematopoietic stem cells but also underlying disease states. In cancer, substantive body of research in patients with solid tumors have identified distinct signatures in ‘tumor educated platelets’, reflecting influences of the tumor, stroma and vasculature on splicing, sequestration of tumor-derived RNAs and potentially cytokine and microvesicle influences on megakaryocytes. Dr. Krishnan’s lab has identified platelet RNA expression as a highly sensitive approach to profiling chronic progressive hematologic malignancies, where the combination of large data cohorts and machine-learning algorithms enable precise feature selection and potential prognostication. This talk will also highlight actionable steps required toward advancing the utility of the platelet transcriptome as a highly sensitive biomarker in cancer and emphasize the immense opportunities for personalized medicine.
Chair:
Kellie R. Machlus, PhD
Harvard Medical School and Boston Children's Hospital
Boston, MA
Speakers:
Diane S. Krause
Yale University
New Haven, CT
Differentiation of Bipotent Progenitors to the Megakaryocytic versus Erythroid Lineages
Alastair W. Poole, Vet.MB, MA, PhD
School of Medical Sciences
Bristol, United Kingdom
Highly Efficient In Vitro Platelet Generation in Lung Vasculature Reproduced by Microfluidics
Anandi Krishnan, PhD
Stanford University School of Medicine
Palo Alto, CA
Genetic Heterogeneity in Platelets - Towards Personalized Medicine
Special Symposium on the Basic Science of Hemostasis and Thrombosis
Monday, December 12, 2022, 4:30 p.m. - 6:05 p.m.
Ernest N. Morial Convention Center, 208-210
Sepsis is a leading cause of infection-related hospitalization and mortality caused by a systemic inflammatory response. The multiple organ failure associated with sepsis is driven by overactivation of the immune system, coagulation pathways, and various blood cell populations. The confluence and crosstalk between these events are often referred to as thrombo-inflammation. This session will highlight new mechanisms in sepsis induced thrombo-inflammation including new roles for platelets, the contact pathway, and the endothelium that are potential therapeutic targets.
Dr. Julie Rayes will focus on novel mechanisms by which NETosis, in general, and S100A8/A9, in particular, induce the formation of procoagulant platelets through platelet adhesion receptor GPIba with a supporting role for CD36. This immune-driven platelet activation potentiates neutrophil recruitment, amplifying thrombo-inflammation. During infection, neutrophil activation is essential for pathogen clearance through phagocytosis, degranulation, and extracellular trap formation. NETosis is associated with the release of damage-associated molecular patterns including S100A8/A9 and S100A12 promoting a prothrombotic and proinflammatory environment. Increases in S100A8/A9 and S100A12 levels are associated with thrombotic complications and higher mortality in septic patients.
Dr. Evi Stavrou will present novel insights into the contribution of coagulation factor XII (FXII) in sepsis. FXII sits at the nexus of coagulation, inflammation, innate immunity, and microbial defense systems. Several prior studies have uncovered diverse mechanisms by which FXII modulates infectious burden and host outcomes. Dr. Stavrou’s lab has identified FXII-mediated signaling networks that initiate and propagate neutrophil thromboinflammatory responses. This talk will discuss how viral- and bacterial-derived factors interact with FXII, the structural and functional modifications arising from this crosstalk and the signaling pathways they intersect, identifying potential homeostatic functions for FXII.
Dr. Robert Flaumenhaft will describe the prothrombotic transformation of the endothelium in sepsis and discuss how stimulation of endothelial-intrinsic cytoprotective pathways can reverse this prothrombotic phenotype. Endothelial function is frequently pathologically altered in the context of sepsis, resulting in maladaptive responses that endanger the host. Among these responses, the formation of microvascular thrombi, which wall off invading pathogens from accessing the circulation, can gravely threaten vital organs during systemic infection. Loss of endothelial anticoagulant properties, expression of prothrombotic membrane proteins, and exocytosis of soluble prothrombotic factors promote clot formation. Normalization of the endothelium by stimulation of cytoprotective pathways substantially reduces this prothrombotic transformation. Unlike systemic anticoagulants, antiplatelet agents and/or antifibrinolytics targeting the endothelium provide the unique opportunity to simultaneously prevent thrombosis and promote hemostasis.
If you are attending the meeting in New Orleans, following this session, please join ASH leadership and your colleagues at the ASH Networking Reception for the Hemostasis and Thrombosis Community, taking place at the down the hallway at the Ernest N Morial Convention Center in Rivergate Terrace, from 6:30 p.m. - 7:30 p.m.
Co-Chairs:
Kellie R. Machlus, PhD
Harvard Medical School and Boston Children's Hospital
Boston, MA
Keith B. Neeves, PhD
University of Colorado Denver
Aurora, CO
Wilbur A. Lam, MD, PhD
Emory University, Georgia Tech, Children's Healthcare of Atlanta
Atlanta, GA
Speakers:
Julie Rayes, PhD
University of Birmingham
Birmingham, United Kingdom
Coordinated Platelet Activation and Netosis Drive Thrombo-Inflammation during Sepsis
Evi X. Stavrou, MD
Louis Stokes Cleveland VA Medical Center
Cleveland, OH
Role of Factor XII in Sepsis
Robert Flaumenhaft, MD, PhD
Beth Israel Deaconess Medical Center and Harvard Medical School
Newton, MA
Targeting the Endothelium to Prevent Thrombus Formation in Sepsis
Sean Quinn, PhD
Children's Hospital of Philadelphia
Philadelphia, PA
An Antibody Targeting Human FV Promotes Thrombin Generation and Reduces Bleeding in a Hemophilic Mouse Model
Targeting Endogenous Retroelements and Viral Mimicry in Therapy of Hematologic Malignancies
Sunday, December 11, 2022, 9:30 a.m. - 10:45 a.m.
Ernest N. Morial Convention Center, 288-290
Despite comprising a large fraction of the human genome, the biology and function of endogenous retroelements remains poorly understood. Endogenous retroelements are largely silenced through epigenetic mechanisms, however these retroelements can be re-expressed in malignancy or via epigenetic therapies. Recent studies indicate that re-activation of retroelements can promote anti-cancer immune responses through inflammation and viral mimicry. This session will cover new topics in re-activation of endogenous retroelements and viral mimicry, through hypomethylating agents (HMAs) and other mechanisms, as an emerging area of intense focus for cancer therapy.
Dr. Gabriel Griffin will discuss the topic of reactivation of epigenetically controlled immunogenicity for tumor therapy, including his perspective on the current state of this field and future key directions. He will focus on the function of endogenous retroviruses (ERV) and other transposable elements (TE) as latent immunostimulatory ligands in cancer cells. Dr. Griffin will review epigenetic mechanisms of ERV and TE silencing, as well as the cellular and immunologic sequelae of their activation in cancer cells. Finally, Dr. Griffin will discuss the potential for epigenetic therapies to enhance the efficacy and scope of cancer immunotherapy, including for hematologic cancers.
Dr. Lipka will review the potential mechanisms mediating response to HMAs and discuss the impact of endogeneous retroelement reactivation and viral mimicry upon sensitivity of myeloid neoplasms to HMAs. Understanding these mechanisms is important since HMAs are currently widely used in the treatment of hematologic malignancies, but their exact mechanism of action remains elusive.
Dr. Chiappinelli will present recent work on transcriptional regulation of transposable elements by epigenetic mechanisms and the tumor suppressor P53 and how transposable element RNA can activate the type I interferon response. Transposable elements make up half of the genome and are silenced by epigenetic modifications in most differentiated normal cells. In cancer cells, silencing of transposable elements is altered, and this can further be perturbed by therapies that target epigenetic regulators.
Chair:
Megan E. McNerney, MD,PhD
The University of Chicago
Chicago, IL
Speakers:
Gabriel K. Griffin, MD
Dana-Farber Cancer Institute
Boston, MA
Introduction to Endogenous Retroelements and the Viral Mimicry Response in Cancer Therapy
Daniel B. Lipka, MD
German Cancer Research Center (DKFZ)
Heidelberg, Germany
Viral Mimicry Induced By Hypomethylating Agents in Acute Myeloid Leukemia
Katherine Bakshian Chiappinelli, PhD
The George Washington University, The GW Cancer Center
WASHINGTON, DC
New Therapeutic Approaches to Engage Viral Mimicry Response