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The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Myeloma Intergroup conducted a workshop on Immune and Cellular Therapy in Multiple Myeloma on January 7, 2022. This workshop included presentations by basic, translational, and clinical researchers with expertise in plasma cell dyscrasias. Four main topics were discussed: platforms for myeloma disease evaluation, insights into pathophysiology, therapeutic target and resistance mechanisms, and cellular therapy for multiple myeloma. Here we provide a comprehensive summary of these workshop presentations.

PDF file - 151 KB, Supplemental text including supplemental methods, supplemental figure and table legends, and supplemental references.

PDF file - 29 KB, Comparison of metabolic readouts in AP and AKP cell lines

XLS file - 25 KB, Top 5 Ingenuity Pathway Analysis biological functions represented in GEMM AP vs AKP signature

Purpose:Immune dysregulation is described in multiple myeloma. While preclinical models suggest a role for altered T-cell immunity in disease progression, the contribution of immune dysfunction to clinical outcomes remains unclear. We aimed to characterize marrow-infiltrating T cells in newly diagnosed patients and explore associations with outcomes of first-line therapy.Experimental Design:We undertook detailed characterization of T cells from bone marrow (BM) samples, focusing on immune checkpoints and features of immune dysfunction, correlating with clinical features and progression-free survival.Results:We found that patients with multiple myeloma had greater abundance of BM regulatory T cells (Tregs) which, in turn, expressed higher levels of the activation marker CD25 compared with healthy donors. Patients with higher frequencies of Tregs had shorter PFS and a distinct Treg immune checkpoint profile (increased PD-1, LAG-3) compared with patients with lower frequencies of Tregs. Analysis of CD4 and CD8 effectors revealed that low CD4effector (CD4eff):Treg ratio and increased frequency of PD-1–expressing CD4eff cells were independent predictors of early relapse over and above conventional risk factors, such as genetic risk and depth of response. Ex vivo functional analysis and RNA sequencing revealed that CD4 and CD8 cells from patients with greater abundance of CD4effPD-1+ cells displayed transcriptional and secretory features of dysfunction.Conclusions:BM-infiltrating T-cell subsets, specifically Tregs and PD-1–expressing CD4 effectors, negatively influence clinical outcomes in newly diagnosed patients. Pending confirmation in larger cohorts and further mechanistic work, these immune parameters may inform new risk models, and present potential targets for immunotherapeutic strategies.

Supplementary tables and figures

Purpose: Effective therapies for KRAS-mutant colorectal cancer (CRC) are a critical unmet clinical need. Previously, we described genetically engineered mouse models (GEMM) for sporadic Kras-mutant and non-mutant CRC suitable for preclinical evaluation of experimental therapeutics. To accelerate drug discovery and validation, we sought to derive low-passage cell lines from GEMM Kras-mutant and wild-type tumors for in vitro screening and transplantation into the native colonic environment of immunocompetent mice for in vivo validation.Experimental Design: Cell lines were derived from Kras-mutant and non-mutant GEMM tumors under defined media conditions. Growth kinetics, phosphoproteomes, transcriptomes, drug sensitivity, and metabolism were examined. Cell lines were implanted in mice and monitored for in vivo tumor analysis.Results:Kras-mutant cell lines displayed increased proliferation, mitogen-activated protein kinase signaling, and phosphoinositide-3 kinase signaling. Microarray analysis identified significant overlap with human CRC-related gene signatures, including KRAS-mutant and metastatic CRC. Further analyses revealed enrichment for numerous disease-relevant biologic pathways, including glucose metabolism. Functional assessment in vitro and in vivo validated this finding and highlighted the dependence of Kras-mutant CRC on oncogenic signaling and on aerobic glycolysis.Conclusions: We have successfully characterized a novel GEMM-derived orthotopic transplant model of human KRAS-mutant CRC. This approach combines in vitro screening capability using low-passage cell lines that recapitulate human CRC and potential for rapid in vivo validation using cell line-derived tumors that develop in the colonic microenvironment of immunocompetent animals. Taken together, this platform is a clear advancement in preclinical CRC models for comprehensive drug discovery and validation efforts. Clin Cancer Res; 19(11); 2929–40. ©2013 AACR.

Relapsed/refractory (R/r) T cell acute lymphoblastic leukemia (T-ALL) has a dismal prognosis, with an unmet need for effective novel therapies. The successes seen in chimeric antigen receptor (CAR)-T cell therapy for B-ALL have yet to be fully translated to T-ALL. Most strategies have targeted pan-T antigens (CD7, CD5) but these may be limited by T cell aplasia and fratricide, requiring elimination of CAR-T antigen expression during manufacture and salvage hematopoietic stem cell transplantation (HSCT). Here, we describe CD21 as a novel immunotherapeutic strategy for the treatment of T-ALL. CD21 is largely confined to malignant T cells with expression in 57% of diagnostic T-ALL but only on a minor fraction of mature T cells (10%). While anti-CD21 CAR-T targeting membrane distal epitopes were ineffective, CAR-T cells utilising a novel Fab-CAR architecture and binding to membrane proximal epitopes showed no fratricide and were potent against low antigen density cell line and patient-derived xenograft models of T-ALL in vitro and in vivo. Further, we showed that CD21 expression in T-ALL can be upregulated by inhibition of the PI3K/ axis. CD21 is a novel target for CAR-T cell therapy in T-ALL, avoiding the fratricide and T cell aplasia seen with many T-ALL CAR-T strategies.

In this article, a section of the Alpha-Text Esther story (1:10–15) is brought to the foreground to reveal the hitherto unrecognized hints that point to the Hebrew Vorlage, the literary Tendenz, and the scribal negligence unparalleled in either the Septuagint or the Masoretic text. All these literary phenomena suggest that the Alpha-Text and the Masoretic text versions reflect two variant archetypes of a Hebrew text, but this does not mean that both archetypes cannot overlap at places. When the archetypes do overlap, some of the unique readings in the Alpha-Text actually reflect later exegeses or misunderstandings that are dependent on the readings preserved in both the Masoretic text and the Septuagint. The later exegeses in particular help locate the Sitz im Leben of Alpha-Text Esth 1:10–15 in the Hasmonean period and thereafter when the Jewish-gentile relationship is strained.

Autologous stem cell transplantation (ASCT) is standard of care in biologically fit, newly diagnosed multiple myeloma (MM) patients, offering better therapeutic outcomes and improved quality of life (QoL). However, with the UK’s 1st national lockdown on 23/03/2020, several guidelines recommended deferring ASCT due to risks of infection, with resource limitations forcing some units to suspend ASCT entirely. Such changes to patients’ treatment plans inevitably altered their lived experience during these uncertain times with expected impact on QoL. We conducted a qualitative study using semi-structured interviews to gain insight into MM patients’ understanding of their disease, initial therapy and ASCT, and their response to therapy changes. A clinical snapshot of how COVID-19 affected the MM ASCT service in a single UK institution is also provided, including changes to chemotherapy treatment plans, timing, and prioritisation of ASCT. Framework analysis identified 6 overarching themes: (1) beliefs about ASCT, (2) perceptions of information provided about MM and ASCT, (3) high levels of fear and anxiety due to COVID-19, (4) feelings about ASCT disruption or delay due to COVID-19, (5) perceptions of care, and (6) importance of social support. Example subthemes were beliefs that ASCT would provide a long-remission/best chance of normality including freedom from chemotherapy and associated side-effects, disappointment, and devastation at COVID-related treatment delays (despite high anxiety about infection) and exceptionally high levels of trust in the transplant team. Such insights will help us adjust our service and counselling approaches to be more in tune with patients’ priorities and expectations.

Virtual environments and immersive technologies are growing in popularity for human factors purposes. Whether it is training in a low-risk environment or using simulated environments for testing future automated vehicles, virtual environments show promise for the future of our field. The purpose of this session is to have current human factors practitioners and researchers demonstrate their immersive technologies. This is the eighth iteration of the “Me and My VE” interactive session. Presenters in this session will provide a brief introduction of their virtual reality, augmented reality, or virtual environment work before engaging with attendees in an interactive demonstration period. During this period, the presenters will each have a multimedia display of their immersive technology as well as discuss their work and development efforts. The selected demonstrations cover issues of designing immersive interfaces, military and medical training, and using simulation to better understand complex tasks. This includes a mix of government, industry, and academic-based work. Attendees will be virtually immersed in the technologies and research presented allowing for interaction with the work being done in this field.

Autologous stem cell transplantation (ASCT) is standard of care in biologically fit, newly diagnosed multiple myeloma (MM) patients, offering better therapeutic outcomes and improved quality of life (QoL). However, with the UK’s 1st national lockdown on 23/03/2020, several guidelines recommended deferring ASCT due to risks of infection, with resource limitations forcing some units to suspend ASCT entirely. Such changes to patients’ treatment plans inevitably altered their lived experience during these uncertain times with expected impact on QoL. We conducted a qualitative study using semi-structured interviews to gain insight into MM patients’ understanding of their disease, initial therapy and ASCT, and their response to therapy changes. A clinical snapshot of how COVID-19 affected the MM ASCT service in a single UK institution is also provided, including changes to chemotherapy treatment plans, timing, and prioritisation of ASCT. Framework analysis identified 6 overarching themes: 1) beliefs about ASCT, 2) perceptions of information provided about MM and ASCT, 3) high levels of fear and anxiety due to COVID-19, 4) feelings about ASCT disruption or delay due to COVID-19, 5) perceptions of care and 6) importance of social support. Example subthemes were beliefs that ASCT would provide a long-remission/best chance of normality including freedom from chemotherapy and associated side-effects, disappointment, and devastation at COVID-related treatment delays (despite high anxiety about infection) and exceptionally high levels of trust in the transplant team. Such insights will help us adjust our service and counselling approaches to be more in tune with patients’ priorities and expectations.

Objective This study aimed to describe two cases of acute respiratory distress syndrome (ARDS) secondary to novel coronavirus disease 2019 (COVID-19) in pregnant women requiring extracorporeal membrane oxygenation (ECMO), and resulting in premature delivery. Study Design The clinical course of two women hospitalized with ARDS due to COVID-19 care in our intensive care (ICU) is summarized; both participants provided consent to be included in this case series. Results Both women recovered with no clinical sequelae. Neonatal outcomes were within the realm of expected for prematurity with the exception of coagulopathy. There was no vertical transmission to the neonates. Conclusion This case series highlights that ECMO is a feasible treatment in the pregnant woman with severe COVID-19 and that delivery can be performed safely on ECMO with no additional risk to the fetus. While ECMO carries its natural risks, it should be considered a viable option during pregnancy and the postpartum period. Key Points COVID-19 may present with a more severe course in pregnancy. ECMO may be used in pregnant woman with severe COVID-19. Delivery can be performed on ECMO without added fetal risk.

Purpose: Immune dysregulation is described in multiple myeloma. While preclinical models suggest a role for altered T-cell immunity in disease progression, the contribution of immune dysfunction to clinical outcomes remains unclear. We aimed to characterize marrow-infiltrating T cells in newly diagnosed patients and explore associations with outcomes of first-line therapy. Experimental Design: We undertook detailed characterization of T cells from bone marrow (BM) samples, focusing on immune checkpoints and features of immune dysfunction, correlating with clinical features and progression-free survival. Results: We found that patients with multiple myeloma had greater abundance of BM regulatory T cells (Tregs) which, in turn, expressed higher levels of the activation marker CD25 compared with healthy donors. Patients with higher frequencies of Tregs had shorter PFS and a distinct Treg immune checkpoint profile (increased PD-1, LAG-3) compared with patients with lower frequencies of Tregs. Analysis of CD4 and CD8 effectors revealed that low CD4effector (CD4eff):Treg ratio and increased frequency of PD-1–expressing CD4eff cells were independent predictors of early relapse over and above conventional risk factors, such as genetic risk and depth of response. Ex vivo functional analysis and RNA sequencing revealed that CD4 and CD8 cells from patients with greater abundance of CD4effPD-1+ cells displayed transcriptional and secretory features of dysfunction. Conclusions: BM-infiltrating T-cell subsets, specifically Tregs and PD-1–expressing CD4 effectors, negatively influence clinical outcomes in newly diagnosed patients. Pending confirmation in larger cohorts and further mechanistic work, these immune parameters may inform new risk models, and present potential targets for immunotherapeutic strategies.

The present article seeks to describe, analyze, and evaluate the modern scholarly attempts to grapple with the moral issues about good and evil in the Hebrew Esther story. The first part of the article examines the anti-Semitic sentiments looming behind the pre-World War II European, especially the Protestant, commentators’ ethics assessments of the book of Esther and its Jewish characters, before pointing out a blind spot in these assessments. The second part of the article offers a systematic analysis of the gradual change of attitude induced mainly by the Jewish scholars in the aftermath of the Second World War. Lastly, the paper turns the spotlight on the Esther studies conducted by recent feminist and other marginalized biblical scholars. Attempts are made to demonstrate how their works, coming from different social contexts, enrich the academic discussions about good and evil in the book of Esther.

Community health workers (CHWs) have been effectively utilised in resource-limited settings to combat a growing demand for health access that cannot be met by the current workforce. The purpose of this study was to evaluate a CHW training programme in Malawi that integrated technology into rehabilitation care delivery. This was a retrospective cross-sectional study of a training programme conducted in December 2018. The participants were a convenience sample of all active home-based palliative care CHWs at St. Gabriel's Hospital (n = 60). The data collected included the following: a written pre- and post-knowledge test, skills competency checklist and a post-training programme survey. Descriptive frequencies described skill competency and quantitative responses from the post-training programme survey. Paired t test (α = 0.05) analysis determined the significance of knowledge acquisition. Themes in the narrative responses in the post-training survey were identified. Both training programme groups showed significantly greater knowledge on the post-test (M = 9.50, SD = 0.861; M = 9.43, SD = 0.971) compared to the pre-test (M = 7.97, SD = 1.351; M = 7.90, SD = 1.900); t(29) = 6.565, p