Many ASH attendees — particularly those who recall the frantic July evenings spent crunching numbers for the impending ASH abstract submission — are well-acquainted with the statistical challenges posed by “interaction effects.” This term describes when the impact of one variable on an outcome changes depending on the value of another variable. Just as late July is often marked by scrambling through the complexities of variance and regression analyses, resolving these interaction effects also remains a complex task in science. Today, the Scientific Committee on Immunology and Host Defense is hosting Host Factors Driving Anti-Leukemia Immunotherapy Outcomes (2:00 p.m. to 3:15 p.m., Marriott Marquis, Pacific Ballroom Salons 18-19). This session will delve into the interactions between the host immune microenvironment, allogeneic hematopoietic stem cell transplantation (allo-HSCT), and chimeric antigen receptor T-cell (CAR-T) therapy, addressing a central question in the field: how to optimize donor-host immune interactions to enhance leukemia eradication.
“There is increasing evidence that host factors determine the efficacy and the risk for side effects of cellular immunotherapy,” said session chair Robert Zeiser, MD. “Our understanding of the host immune activation status and the microbiome that determine efficacy of allo-HSCT and CAR T cells has made huge strides in the last decade. For example, we recently showed that host-derived microglia determine the severity of CAR-T immune effector cell-associated neurotoxicity syndrome.”1 While challenges such as graft-versus-host disease (GVHD) and relapse persist, the field is making strides in identifying the key factors driving the immune mechanisms that govern these outcomes, paving the way for innovative approaches that would reduce relapse rates post-allo-HSCT while minimizing GVHD.
Bringing an “omics” perspective, Catherine J. Wu, MD, will discuss single-cell transcriptomics, DNA sequencing, and spatial analysis of serial leukemia samples taken before and after allogeneic transplant or donor lymphocyte infusions. Her work reveals novel approaches for tracking clones pre- and post-allograft and examines the key cellular players and spatial organization driving the graft-versus-leukemia (GVL) effect.
Takanori Teshima, MD, PhD, will explore how modulating the host tumor microenvironment can enhance GvL. “The host alloimmune response is a double-edged sword,” Dr. Teshima said. “The concept of the tumor immune microenvironment (TIME) in leukemia is relatively recent but understanding TIME has important implications for developing precision intervention strategies in leukemia.”
The separation of GVL from GVHD has been a topic of intense research to improve transplant outcomes, and one promising approach is selective modulation of the immune environment in GVHD target tissues. “Location, location, location!” Dr. Teshima emphasizes. “Target tissues of acute GVHD are the skin, liver, and intestine, while leukemic stem cells reside in the bone marrow. We know that intestinal stem cells acquire inflammatory memory in GVHD, fueling the inflammatory fire. This represents a therapeutic opportunity — [sphingosine-1-phosphate] inhibitors, for example, prevent donor T cell migration to GVHD target tissues, but not to the bone marrow.” These approaches open new avenues for selectively targeting GVHD while preserving the critical GVL response.
The immune microenvironment is key to other immunotherapeutic approaches, such as CAR-T therapy. While CD19-directed CAR-T has shown impressive results in B-cell acute lymphoblastic leukemia (ALL), challenges such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, T cell exhaustion, and the limited durability of responses remain. Additionally, myeloid leukemias remain a major therapeutic hurdle.
Franziska Blaeschke, MD, PhD, is optimistic about the promise of CAR-T. “The field sits at the intersection of tumor biology, therapy, and novel omics, and the pace of change is remarkable,” she said. “New targets for CAR-T cell therapy in acute myeloid leukemia (AML) have been identified that are very promising in preclinical models.2 Omics are driving the field forward — novel single-cell RNA sequencing-based screening algorithms will help design the ideal CAR for AML.3 We are also just starting to better understand the differences between ALL and AML in the context of immunotherapy, e.g., the role of therapy-induced cytokines in the bone marrow microenvironment that can lead to CAR-T cell exhaustion.”4
Dr. Blaeschke will showcase the power of CRISPR screens to build the next generation of CAR T cells, providing updates on recent work deploying a non-viral knockin of BATF-TFAP4 to enhance fitness and anti-cancer function of CAR T cells.5 “I am really excited to tell you more about the current CRISPR screening toolbox and how these novel technologies can help us build better cell therapies,” Dr. Blaeschke said.
These insights underscore the transformative potential of integrating novel technologies with the field of immunotherapy to overcome current challenges and pave the way for more effective leukemia treatments.
REFERENCES
1 Vinnakota JM, Biavasco F, Schwabenland M, et al. Targeting TGFβ-activated kinase-1 activation in microglia reduces CAR T immune effector cell-associated neurotoxicity syndrome. Nat Cancer. 2024;5(8):1227-1249.
2 Sauer T, Parikh K, Sharma S, et al. CD70-specific CAR T cells have potent activity against acute myeloid leukemia without HSC toxicity. Blood. 2021;138(4):318-330.
3 Gottschlich A, Thomas M, Grünmeier R, et al. Single-cell transcriptomic atlas-guided development of CAR-T cells for the treatment of acute myeloid leukemia. Nat Biotechnol. 2023;41(11):1618-1632.
4 Bhagwat AS, Torres L, Shestova O, et al. Cytokine-mediated CAR T therapy resistance in AML. Nat Med. Published online September 27, 2024. doi: 10.1038/s41591-024-03271-5.
5 Blaeschke F, Chen YY, Apathy R, et al. Modular pooled discovery of synthetic knockin sequences to program durable cell therapies. Cell. 2023;186(19):4216-4234.e33.
