← Blood Podcast
Blood Podcast
Interleukin-1 signaling pathways in myelodysplastic syndromes, the immune checkpoint regulator VISTA as a target in graft-vs-host disease, and epcoritamab plus chemotherapy in transplant-ineligible relapsed/refractory diffuse large B-cell lymphoma
00:20:59
Loading summary
Transcript1 lines
- [00:02]
A
Welcome to the April 10, 2025 episode of Blood Podcast, your source for innovative ideas and cutting edge information. Our topics are based on articles published in Blood A Journal of the American Society of Hematology. Today we'll learn more about the role of interleukin 1 signaling in the bone marrow microenvironment in the development of myelodysplastic syndromes, the immune checkpoint regulator VISTA as a potential target for preventing graft versus host disease and epcoritamab plus gemcitabine and oxaliplatin in transplant ineligible relapsed refractory diffuse large B cell lymphoma. We first examined data in the blood article entitled IL1, R1 and IL18 signals regulate mesenchymal stromal cells in aged murine model of myelodysplastic syndromes by Yuko Kawano from the University of Rochester School of Medicine and dentistry in Rochester, New York and colleagues. Myelodysplastic syndromes, or MDs, are a diverse group of hematopoietic stem cell disorders characterized by bone marrow dysfunction and an increased risk for developing acute myeloid leukemia. MDS is associated with advanced age, typically developing in people over the age of 70. Multiple lines of evidence suggest that MDS is related to inflammation. Patients with MDS have higher levels of pro inflammatory cytokines in their blood compared to people without this disorder. In addition, preclinical studies have shown that pro inflammatory cytokines have direct effects on hematopoietic stem cell proliferation and differentiation as well as indirect effects on the bone marrow microenvironment that regulates and supports these cells. The authors of the paper we'll discuss first investigated how pro inflammatory cytokines might contribute to MDS development indirectly through their effects on a rare type of cell in the bone marrow microenvironment known as mesenchymal stromal cells or MSCs. They first investigated the types of cytokines found in plasma from patients with mds. They found several differences compared to plasma from healthy bone marrow donors, including higher levels of proteins that participate in the pro inflammatory interleukin 1 or IL1 pathway. These included soluble interleukin 1 receptor and and IL18, another member of the IL1 family. These differences were not seen when plasma from younger healthy donors was compared to that of older donors. These results reinforced the idea that MDS is associated with a pro inflammatory environment and identified IL1 as a potentially important signaling pathway. Turning to cell cultures, the the authors investigated the effects of IL1b, a form of IL1 previously implicated in MDS and IL18 on MSCs. Both cytokines had considerable effects on MSCs, altering their ability to support hematopoietic stem cell growth and differentiation. In MSC enriched bone marrow CO cultures, both IL1B and IL18 led to increased numbers of hematopoietic stem cells including multipotent progenitor cells, granulocyte macrophage progenitors and erythroid progenitor cells. IL1B and IL18 had minimal effects on bone marrow cells in the absence of CO cultured MSCs, suggesting that these effects of IL1 signaling were indirect occurring via IL1's effects on the MSCs. IL1b and IL18 stimulated signaling pathways in MSCs that were likely to be involved in these effects. In an immortalized mouse MSC cell line, IL1B stimulated NF Kappab signaling while IL18 did not. In primary bone marrow MSC cultures from wild Type mice, both IL1b and IL18 stimulated P38 MAPK and PI3k AKT signaling pathways involved in both inflammation and oncogenesis. To further investigate IL1 signaling in MSCS, the authors looked at messenger RNA expression for interleukin 1 receptor associated kinase 4 or IRAC4 and nod LRR and pyrin domain containing protein 3 or NLRP3. IRAC4 is involved in IL1 receptor signaling while NLRP3 is a component of the inflammasome, an intracellular structure that regulates IL1 and IL18 secretion. IRAC4 expression was increased in primary MSCs cultured from a mouse MDS model, while NLRP3 expression was increased in primary MSCS cultured from older mice. The authors developed an age appropriate mouse model of MDS by transplanting bone marrow from an MDS mouse model into older wild type mice. After the transplanted mice developed MDS, they were treated with IL1 signaling inhibitors. Both the IRAC4 and the NLRP3 inhibitor reversed the proliferation of dysfunctional MSCs and improved MSC functionality in bone marrow from these mice. The IRAC4 inhibitor selectively suppressed MDS cells while sparing non MDS cells in the bone marrow of the transplanted mice. This inhibitor also improved white blood cell and lymphocyte counts compared with untreated mice. Taken together with additional results from cell culture experiments, these findings suggested that inhibiting IL1 signaling through IRAC4 alters the types and number of MSCs present in the bone marrow microenvironment in older mice, restoring the bone marrow to a state in which MDS would be less likely to develop. Overall, the Authors concluded that IL1b and IL18 regulation of MSCs in the bone marrow microenviron plays a role in both MDS and the age related skewing towards myeloid lineages that can precede mds. These findings support the rationale for investigating anti inflammatory agents as MDS therapies. In an accompanying commentary, Yan Liao and Chie Guo Kai of the University of Chinese Academy of Sciences in Hangzhou, China, called this study a significant advancement in our understanding of the inflammatory bone marrow niche in MDs, providing an important foundation for future research. They noted that considerable challenges remain, however, before these findings can be translated into clinical practice. Next up we'll discuss findings from the Blood article entitled Targeting cell surface VISTA expression on allospecific naive T cells promotes tolerance by Brent Cohen of the University of Minnesota in Minneapolis and colleagues. Despite multidrug regimens intended to prevent it, graft versus host disease, or gvhd remains a significant problem in patients who receive allogeneic transplants to treat hematological malignancies. GVHD is caused by donor T cell alloreactivity against antigens found in normal host tissues. This process depends on T cell activation, which is regulated by CO inhibitory and CO stimulatory immune checkpoint regulators. Vista, which stands for V domain immunoglobulin suppressor of T cell activation, is a negative checkpoint regulator that can act as either a ligand or or a receptor to modulate T cell effect or function. VISTA is an important immunoregulator for maintaining peripheral self tolerance, enforcing T cell quiescence when T cell receptor signaling is present. Previous studies had found that a single dose of an agonistic monoclonal antibody directed at VISTA protected transplanted mice from gvhd. The authors of the paper will be discussing next investigated the mechanism of this effect further, as well as factors that might influence its ability to be translated for use in a clinical setting. They used several mouse models in which transplant of bone marrow from one mouse strain into another induced gvhd. Using a range of tracking methods, they were able to follow and determine the fate of donor and host T cells to carefully analyze the mechanism of this protective effect. The authors confirmed that a single dose of a commercially available agonistic VISTA targeted antibody known as 8G8 prevented acute GVHD in multiple mouse GVHD transplant models, including major histocompatibility, disparate minor histocompatibility and haploidentical models. Using a green fluorescence protein tracking system, they showed that 8G8 treatment dramatically and preferentially reduced the number of allureactive donor CD4T cells. Vista acts transiently to CO inhibit only the very earliest stages of T cell activation. Investigating the kinetics of T cell depletion, the Authors found that 8g8 only protected against GVHD when it was given during a narrow 10 to 16 hour window around the time of transplant. Targeting vista on donor CD8 positive T cells or on host cells, on the other hand, was not effective at preventing gvhd. T cell depletion can occur via T cell intrinsic mechanisms such as programmed cell death or extrinsic mechanisms that involve other cell types. Using inhibitors of FC crosslinking and phagocytic macrophages, the authors established that 8G 8 marks VISTA bearing CD4T cells for elimination via antibody dependent cellular phagocytosis. Additional experiments mostly ruled out intrinsic mechanisms for donor CD4T cell depletion. Importantly, depletion of donor CD4 positive T cells did not prevent graft versus lymphoma activity. This might be because activated CD8T effector cells expressed lower levels of VISTA and thus were relatively unaffected by anti VISTA antibody mediated phagocytosis. To investigate whether the ability of the VISTA targeted antibody to prevent GVHD was compatible with clinical transplant conditions, the authors treated transplanted mice with the calcineurin inhibitor tacrolimus or the MTOR inhibitor rapamycin. Tacrolimus given around the time of transplant abrogated GVHD prevention, although this agent could be given later without interfering with GVHD prevention. Rapamycin did not interfere with GVHD prevention. These results suggested that calcineurin signaling is needed for VISTA upregulation and or for T cell depletion via antibody dependent cellular phagocytosis. To investigate whether VISTA targeted antibodies might also protect against GVHD in humans, the authors created a xenogeneic GVHD mouse model in which human peripheral blood mononuclear cells were transplanted into irradiated immunodeficient mice. Treatment with an antibody targeted at human VISTA in this system also resulted in robust GVHD protection. The authors concluded that targeting VISTA CO inhibitory pathways on alloreactive donor T cells might be translatable to humans as a means of preventing GVHD while still preserving graft versus lymphoma activity in human allogeneic stem cell transplants. In an accompanying commentary, Takanori Teshima of the Hokkaido University Faculty of Medicine in Sapporo, Japan, concluded that antivista therapy holds promise as a preventative treatment for gvhd. Although he said that many questions remain, he noted that it would be technically difficult to recapitulate this work in humans, which is necessary to confirm similar kinetics and selective depletion of CD4 T cells. In addition, it would be necessary to confirm that VISTA targeted agents do not inhibit donor cell engraftment in humans. In the final part of today's podcast, we'll discuss findings in the Blood article entitled Epcoritamab Gemox in transplant ineligible relapsed refractory DLBCL results from the EPCOR NHL 2 trial by Joshua Brody of the Mount Sinai School of Medicine in New York, NY and colleagues. Patients with relapsed refractory diffuse large B cell lymphoma or DLBCL who are ineligible for autologous stem cell transplant have limited further treatment options and poor outcomes. Outcomes are particularly poor for patients who are treatment refractory. Overall response rates or ORRs to subsequent therapies are about 26% and only about 7% have complete responses or CRS. These factors lead to a median overall survival or OS of about six months in these patients. Given these circumstances, interest has been high in developing new treatments for relapsed refractory dlbcl, particularly combination regimens that have the potential to overcome resistance by targeting multiple disease pathways. In 2023, the CD20 directed CD3T cell engaging bispecific antibody epcoritamab received FDA approval for treating adult patients with relapsed refractory DLBCL who have received two or more prior lines of systemic therapy. Bispecific antibodies such as epcoritamab represent an off the shelf option for transplant ineligible patients with dlbcl, many of whom are ineligible for CAR T cell therapies as well. The non randomized Phase 1B2 EPCOR NHL 2 trial is currently investigating epcoritamab in combination with the chemotherapeutic agents gemcitabine and doxaliplatin in patients with CD20 positive non Hodgkin lymphoma. These chemotherapeutic agents have historically been used together with the anti CD20 monoclonal antibody rituximab for treating transplant ineligible DLBCL. The study we'll be discussing last reported the results for ARM 5 of this trial, which enrolled patients with DLBCL who had relapsed or were refractory to at least one prior line of therapy. The trial included patients with de novo disease and those whose DLBCL was transformed from follicular or nodal marginal zone lymphoma. Patients were ineligible for transplant because of age, performance status, comorbidities, or an insufficient response to prior therapy or had a previous transplant failure. The authors enrolled 105 patients, many of whom had high risk characteristics or other challenging features. 35% were 75 years old or older, 19% had bulky disease, 61% had Ann Arbor stage 4 disease, and 10% had double or triple hit lymphoma. 52% of these patients had primary refractory disease and 70% were refractory to their last systemic therapy. The majority, about 60%, had received two or more prior lines of therapy, 28% had received prior CAR t cell therapy. The current publication reported efficacy and safety results for patients treated with the 48mg dose of epcoritamab in either the dose escalation or dose expansion phases of the trial at a median follow up of 13.2 months. Combination therapy with epcoritamab, gemcitabine and oxaliplatin resulted in an ORR of 85% and a CR rate of 61% for the entire ARM5 cohort. The median duration of response was 23.6 months. The authors noted that patients who had received only one prior line of therapy had a CR rate of 74% compared with 53% for those who had received two or more prior lines. Median progression free survival for the entire cohort was 11.2 months and 26.7 months for patients who had a cross. Median OS for the Entire cohort was 21.6 months and had not been reached in patients with a cr. The most common treatment emergent adverse events in this trial were hematologic events, infections, and cytokine release syndrome or CRS. Hematologic adverse events included 73% of patients with thrombocytopenia, 65% with neutropenia, and 59% with anemia. The majority of these events were grade 3 or higher. CRS, which occurred in 52% of patients, was grade 1 or grade 2 except for one patient with grade 3, 23% of patients received tocilizumab and 17% received corticosteroids beyond those used for prophylaxis. For CRS, three patients developed immune effector cell associated neurotoxicity syndrome. All three cases resolved, but one patient had to discontinue treatment. 72% of patients developed infections, primarily COVID 19, upper respiratory tract pneumonia, and urinary tract infections. The study was largely enrolled during the COVID 19 pandemic and COVID 19 accounted for five of the 13 deaths. During the study, 57% of patients discontinued treatment in this trial. By design, epcoritamab was continued following completion of chemotherapy until disease progression 31% of patients discontinued because of progressive disease 19% of patients discontinued because of adverse events, predominantly infections. The authors concluded that treatment with epcoritamab plus gemcitabine and oxaliplatin resulted in deep and durable responses in this cohort of transplant ineligible patients with relapsed refractory dlbcl, many of whom had high risk disease. In an accompanying commentary, Carmelo Carlos Della of Humanitas University in Milan, Italy, said that this study establishes epcoritamab chemotherapy as a potential clinically meaningful option for transplant ineligible patients with relapsed refractory dlbcl. He noted that longer follow up and a more extensive assessment of minimal residual disease will be needed to completely evaluate the efficacy and safety of this combination therapy. For a list of additional authors as well as more detailed articles and commentaries on which this podcast is based, please go to bloodjournal.org be sure to join us next week for another episode of Blood Podcast. Thank you for listening.