Engineering allorejection-resistant CAR-NKT cells from hematopoietic stem cells for off-the-shelf cancer immunotherapy.

The clinical potential of current FDA-approved chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy is encumbered by its autologous nature, which presents notable challenges related to manufacturing complexities, heightened costs, and limitations in patient selection. Therefore, there is a growing demand for off-the-shelf universal cell therapies. In this study, we have generated universal CAR-engineered NKT (UCAR-NKT) cells by integrating iNKT TCR engineering and HLA gene editing on hematopoietic stem cells (HSCs), along with an ex vivo, feeder-free HSC differentiation culture. The UCAR-NKT cells are produced with high yield, purity, and robustness, and they display a stable HLA-ablated phenotype that enables resistance to host cell-mediated allorejection. These UCAR-NKT cells exhibit potent antitumor efficacy to blood cancers and solid tumors, both in vitro and in vivo, employing a multifaceted array of tumor-targeting mechanisms. These cells are further capable of altering the tumor microenvironment by selectively depleting immunosuppressive tumor-associated macrophages and myeloid-derived suppressor cells. In addition, UCAR-NKT cells demonstrate a favorable safety profile with low risks of graft-versus-host disease and cytokine release syndrome. Collectively, these preclinical studies underscore the feasibility and significant therapeutic potential of UCAR-NKT cell products and lay a foundation for their translational and clinical development.

Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

The treatment of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) has evolved to include several new options. The NCCN Guidelines for WM/LPL provide a framework on which to base decisions regarding diagnosis, treatment, assessment of response to treatment, and follow-up of both newly diagnosed and previously treated WM/LPL.

Treatment-free remission after dasatinib in patients with chronic myeloid leukaemia in chronic phase with deep molecular response: Final 5-year analysis of DASFREE.

Patients with chronic myeloid leukaemia in chronic phase (CML-CP) who have a sustained deep molecular response (DMR) are eligible to discontinue treatment and attempt treatment-free remission (TFR). In the DASFREE study (ClinicalTrials.gov; NCT01850004), the 2-year TFR rate after dasatinib discontinuation was 46%; here we present the 5-year update. Patients with a stable DMR after ≥2 years of dasatinib therapy discontinued treatment and were followed for 5 years. At a minimum follow-up of 60 months, in 84 patients discontinuing dasatinib, the 5-year TFR rate was 44% (n = 37). No relapses occurred after month 39 and all evaluable patients who relapsed and restarted dasatinib (n = 46) regained a major molecular response in a median of 1.9 months. The most common adverse event during the off-treatment period was arthralgia (18%, 15/84); a total of 15 withdrawal events were reported in nine patients (11%). At the 5-year final follow-up, almost half of the patients who discontinued dasatinib after a sustained DMR maintained TFR. All evaluable patients who experienced a relapse quickly regained a DMR after restarting dasatinib, demonstrating that dasatinib discontinuation is a viable and potentially long-term option in patients with CML-CP. The safety profile is consistent with the previous report.

Systemic Light Chain Amyloidosis, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology.

Primary systemic light chain amyloidosis (SLCA) is characterized by production of light chains that get converted to amyloid fibrils with an affinity for visceral organs and causing organ dysfunction. The therapy for SLCA is directed to recovering the function of the affected organs by targeting the abnormal plasma cell clone and slowing deposition of amyloid fibrils. The NCCN Guidelines for SLCA provide recommendations for workup, diagnosis, and treatment of primary as well as previously treated SLCA.

Multiple Myeloma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

The treatment of relapsed/refractory multiple myeloma (MM) has evolved to include several new options. These include new combinations with second generation proteasome inhibitors (PI); second generation immunomodulators, monoclonal antibodies, CAR T cells, bispecific antibodies, selinexor, venetoclax, and many others. Most patients with MM undergo several cycles of remissions and relapse, and therefore need multiple lines of combination therapies. Selecting treatment options for relapsed/refractory MM requires consideration of resistance status to specific classes, and patient-specific factors such as age and other comorbidities should be considered. The NCCN Guidelines for MM provide a framework on which to base decisions regarding workup, treatment, and follow-up of newly diagnosed and previously treated MM. This manuscript outlines the recommendations from NCCN Guidelines for MM specific to relapsed/refractory disease.

NCCN Guidelines® Insights: Multiple Myeloma, Version 3.2022.

The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, initial workup, treatment, follow-up, and supportive care for patients with various plasma cell neoplasms, including multiple myeloma. These NCCN Guidelines Insights highlight some of the important updates/changes specific to the treatment of patients with multiple myeloma in the 2022 version of the guidelines.

Cost-Health Literacy as an Educational Objective in Fellowship Training.

Physicians are encouraged to communicate with their patients about financial concerns, but are infrequently taught skills necessary to do so. This study describes a curriculum for oncology fellows aimed to improve skills of cost-health literacy, and provides assessment of the curriculum impact on self-perceived cost communication practices. Oncology fellows at a large academic program in 2019 participated in a cost-health literacy curriculum over 3 months. The curriculum consisted of a didactic on financial toxicity (45 min), a problem-based learning case highlighting financial toxicity risk factors and areas for intervention (30 min), and a group discussion (30 min) to review and consolidate strategies to navigate financial toxicity in direct patient care. A cost-health literacy survey was administered at baseline and at the conclusion of the curriculum to evaluate the impact of the program. Of 19 participants, 16 completed both the pre-survey and post-survey and were included in the analysis. After the intervention, participants were more likely to report comfort discussing out-of-pocket costs (50% vs. 19%, p = 0.002) and to feel they could help a patient experiencing financial toxicity (62% vs. 6%, p = 0.005). There was no improvement in the subjective assessment of patient financial distress (57% v 50%, p = 0.759). Oncology fellows can improve self-reported cost-health literacy skills through participation in a targeted, brief curriculum. Further studies are warranted to determine how this approach can be applied in other settings and if it objectively impacts cost communication practices.

Long-term behavioral effects observed in mice chronically exposed to static ultra-high magnetic fields.

PURPOSE: The primary goal of this study was to investigate whether chronic exposures to ultra-high B0 fields can induce long-term cognitive, behavioral, or biological changes in C57BL/6 mice. METHODS: C57BL/6 mice were chronically exposed to 10.5-T or 16.4-T magnetic fields (3-h exposures, two exposure sessions per week, 4 or 8 weeks of exposure). In vivo single-voxel 1 H magnetic resonance spectroscopy was used to investigate possible neurochemical changes in the hippocampus. In addition, a battery of behavioral tests, including the Morris water-maze, balance-beam, rotarod, and fear-conditioning tests, were used to examine long-term changes induced by B0 exposures. RESULTS: Hippocampal neurochemical profile, cognitive, and basic motor functions were not impaired by chronic magnetic field exposures. However, the balance-beam-walking test and the Morris water-maze testing revealed B0 -induced changes in motor coordination and balance. The tight-circling locomotor behavior during Morris water-maze tests was found as the most sensitive factor indexing B0 -induced changes. Long-term behavioral changes were observed days or even weeks subsequent to the last B0 exposure at 16.4 T but not at 10.5 T. Fast motion of mice in and out of the 16.4-T magnet was not sufficient to induce such changes. CONCLUSION: Observed results suggest that the chronic exposure to a magnetic field as high as 16.4 T may result in long-term impairment of the vestibular system in mice. Although observation of mice may not directly translate to humans, nevertheless, they indicate that studies focused on human safety at very high magnetic fields are necessary.

Multiple Myeloma, Version 3.2021, NCCN Clinical Practice Guidelines in Oncology.

Multiple myeloma is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure. This manuscript discusses the management of patients with solitary plasmacytoma, smoldering multiple myeloma, and newly diagnosed multiple myeloma.

Syndactyly in a novel Fras1(rdf) mutant results from interruption of signals for interdigital apoptosis.

BACKGROUND: Fras1 encodes an extracellular matrix protein that is critical for the establishment of the epidermal basement membrane during gestation. In humans, mutations in FRAS1 cause Fraser Syndrome (FS), a pleiotropic condition with many clinical presentations such as limb, eye, kidney, and craniofacial deformations. Many of these defects are mimicked by loss of Fras1 in mice, and are preceded by the formation of epidermal blisters in utero. RESULTS: In this study, we identified a novel ENU-derived rounded foot (rdf) mouse mutant with highly penetrant hindlimb soft-tissue syndactyly, among other structural defects. Mapping and sequencing revealed that rdf is a novel loss-of-function nonsense allele of Fras1 (Fras1(rdf)). Focusing on the limb, we found that the Fras1(rdf) syndactyly phenotype originates from loss of interdigital cell death (ICD). Despite normal expression of bone morphogenetic protein (BMP) ligands and their receptors, the BMP downstream target gene Msx2, which is also necessary and sufficient to promote ICD, was down-regulated in the interdigital regions of Fras1(rdf) hindlimb buds. CONCLUSIONS: The close correlation between limb bud epidermal blistering, decreased Msx2 expression, and reduced ICD in the Fras1(rdf) hindlimb buds suggests that epithelium detachment from the mesenchyme may create a physical gap that interrupts the transmission of BMP, among other signals, resulting in soft tissue syndactyly.

American Indian and Alaska Native recruitment strategies for health-related randomized controlled trials: A scoping review.

BACKGROUND: Significant health disparities exist among American Indian and Alaska Natives (AI/ANs), yet AI/ANs are substantially underrepresented within health-related research, including randomized controlled trials (RCTs). Although research has previously charted representation inequities, there is however a gap in the literature documenting best practice for recruitment techniques of AI/ANs into RCTs. Therefore, the aim of this review was to systematically gather and analyze the published literature to identify common strategies for AI/AN participant recruitment for RCTs in the US. METHODS: A scoping review methodology was engaged with a systematic search operationalized within relevant databases to February 19, 2022, with an additional updated search being carried out up until January 1, 2023: PubMed, Embase, Web of Science, PsycINFO, CINAHL, and Google Scholar. A two-stage article review process was engaged with double reviewers using Covidence review software. Content analysis was then carried out within the included articles by two reviewers using NVivo software to identify common categories within the data on the topic area. RESULTS: Our review identified forty-one relevant articles with the main categories of recruitment strategies being: 1) recruitment methods for AI/ANs into RCTs (passive advertising recruitment approaches, individual-level recruitment approaches, relational methods of recruitment); 2) recruitment personnel used within RCTs; and, 3) relevant recruitment setting. The majority of the included studies used a culturally relevant intervention, as well as a community-involved approach to operationalizing the research. CONCLUSION: Increasing AI/AN representation in RCTs is essential for generating evidence-based interventions that effectively address health disparities and improve health outcomes. Researchers and funding agencies should prioritize the engagement, inclusion, and leadership of AI/AN communities throughout the RCT research process. This includes early community involvement in study design, implementation of culturally tailored recruitment strategies, and dissemination of research findings in formats accessible to AI/AN communities.

Truth and Reconcilition Commissions and Health Care System Responses for Indigenous Peoples: A Scoping Review.

Grounded in human rights approaches, truth and reconciliation commissions (TRCs) explore an event or process that did widespread and systematic intentional harm to a group of people. Health as a fundamental right is an important component addressed by TRCs. Yet despite TRCs often having recommendations for health care systems, it is unknown how well these recommendations are being translated within health care settings. Therefore, the overarching purpose of our scoping review was to identify academic articles that discussed health care system discourse or responses to TRCs in the context of Indigenous Peoples. Our thematic analysis of the included articles identified three main themes for health care system responses to TRCs: (1) the acknowledgment of multiple ways of knowing, being, and doing in health systems; (2) current interventions as responses within health systems; and (3) suggestions for change within health systems. Although a TRC may create a specific road map and mandate for health care systems, we found considerable variability in the uptake of these actions across institutions. Concerted efforts within and around health care systems and across sectors are therefore necessary to achieve large-scale, meaningful change for Indigenous Peoples post-TRCs and to maintain accountability as a foundational human rights principle.

Postnatal myelomeningocele closure in smallest reported neonate: illustrative case.

BACKGROUND: Myelomeningocele (MMC) is the most serious form of spina bifida, a congenital defect in neural tube development. Defect closure in a patient with an extremely low birth weight presents unique challenges and risks; lower birth weight is associated with multiple organ system concerns, homeostasis is difficult, and local tissue is underdeveloped. To the authors' knowledge, the present case is the lowest reported weight (490 g) for a neonate with postnatal MMC repair. OBSERVATIONS: A preterm male with a prenatally diagnosed lumbosacral MMC and associated Chiari malformation type II was born at 23 weeks 1 day to a 29-year-old mother, gravidity 6 parity 4. The patient was medically stabilized and underwent MMC closure on day of life 5. His weight was 490 g at the time of this repair, and he did not have any surgical complications. At age 16 months, he underwent endoscopic third ventriculostomy with choroid plexus cauterization; he has not required any further hydrocephalus treatments since the last follow-up at 30 months of age. LESSONS: To the authors' knowledge, this case is the lowest birth weight ex utero MMC closure reported in the literature. Challenges of prematurity and size required appropriate preoperative stabilization, careful hemostasis and temperature regulation, and meticulous surgical technique.

Historical changes in wind-driven ocean circulation drive pattern of Pacific warming.

The tropical Pacific warming pattern since the 1950s exhibits two warming centers in the western Pacific (WP) and eastern Pacific (EP), encompassing an equatorial central Pacific (CP) cooling and a hemispheric asymmetry in the subtropical EP. The underlying mechanisms of this warming pattern remain debated. Here, we conduct ocean heat decompositions of two coupled model large ensembles to unfold the role of wind-driven ocean circulation. When wind changes are suppressed, historical radiative forcing induces a subtropical northeastern Pacific warming, thus causing a hemispheric asymmetry that extends toward the tropical WP. The tropical EP warming is instead induced by the cross-equatorial winds associated with the hemispheric asymmetry, and its driving mechanism is southward warm Ekman advection due to the off-equatorial westerly wind anomalies around 5°N, not vertical thermocline adjustment. Climate models fail to capture the observed CP cooling, suggesting an urgent need to better simulate equatorial oceanic processes and thermal structures.

Generation of allogeneic CAR-NKT cells from hematopoietic stem and progenitor cells using a clinically guided culture method.

Cancer immunotherapy with autologous chimeric antigen receptor (CAR) T cells faces challenges in manufacturing and patient selection that could be avoided by using 'off-the-shelf' products, such as allogeneic CAR natural killer T (AlloCAR-NKT) cells. Previously, we reported a system for differentiating human hematopoietic stem and progenitor cells into AlloCAR-NKT cells, but the use of three-dimensional culture and xenogeneic feeders precluded its clinical application. Here we describe a clinically guided method to differentiate and expand IL-15-enhanced AlloCAR-NKT cells with high yield and purity. We generated AlloCAR-NKT cells targeting seven cancers and, in a multiple myeloma model, demonstrated their antitumor efficacy, expansion and persistence. The cells also selectively depleted immunosuppressive cells in the tumor microenviroment and antagonized tumor immune evasion via triple targeting of CAR, TCR and NK receptors. They exhibited a stable hypoimmunogenic phenotype associated with epigenetic and signaling regulation and did not induce detectable graft versus host disease or cytokine release syndrome. These properties of AlloCAR-NKT cells support their potential for clinical translation.

A phase 2 multicenter study of lenalidomide in relapsed or refractory classical Hodgkin lymphoma.

Relapsed or refractory (rel/ref) classical Hodgkin lymphoma (cHL) remains a clinical challenge, with limited effective treatment options available after stem cell transplantation. In a multicenter phase 2 study, the efficacy of lenalidomide in rel/ref cHL patients was evaluated at a dose of 25 mg/d on days 1-21 of a 28-day cycle. Patients remained on lenalidomide until disease progression or an unacceptable adverse event (AE) occurred. Thirty-eight cHL patients were enrolled with a median of 4 (range, 2-9) prior therapies; 87% had undergone prior stem cell transplantation and 55% of patients did not respond to their last prior therapy. Of 36 evaluable patients, responses were 1 complete remission (CR), 6 partial remissions (PRs), and 5 patients with stable disease (SD) for ≥ 6 months resulting in an International Working Committee (IWC) objective overall response rate (ORR) of 19% and a cytostatic ORR of 33%. Decreased chemokine (CCL17 and CCL22) plasma levels at 2 weeks were associated with a subsequent response. The treatment was well tolerated, and the most common grade 3/4 AEs were neutropenia (47%), anemia (29%), and thrombocytopenia (18%). Four patients discontinued lenalidomide because of rash, elevated transaminases/bilirubin, and cytopenias. We provide preliminary evidence of lenalidomide's activity in patients with rel/ref cHL, and therefore exploration of lenalidomide in combination with other active agents is warranted. This trial is registered at www.ClinicalTrials.gov as NCT00540007.

Large vertebral artery pseudoaneurysm masquerading as a schwannoma: illustrative case.

BACKGROUND: Extracranial vertebral aneurysms or pseudoaneurysms are rare and result primarily from trauma. Large pseudoaneurysms can masquerade as mass lesions, making it challenging to identify the correct diagnosis. OBSERVATIONS: This is a case report in which a large vertebral pseudoaneurysm posed as a schwannoma and biopsy was attempted. It was later identified as a vascular lesion and treated appropriately with no complications. LESSONS: Vascular etiologies should always be included in the differential diagnosis of spine and nerve pathologies especially lesions that are in the vicinity of major vascular channels such as the transverse foramina of the cervical spine.

Regional sex differences in neurochemical profiles of healthy mice measured by magnetic resonance spectroscopy at 9.4 tesla.

Objective: To determine sex differences in the neurochemical concentrations measured by in vivo proton magnetic resonance spectroscopy (1H MRS) of healthy mice on a genetic background commonly used for neurodegenerative disease models. Methods: 1H MRS data collected from wild type mice with C57BL/6 or related genetic backgrounds in seven prior studies were used in this retrospective analysis. To be included, data had to be collected at 9.4 tesla magnetic field using advanced 1H MRS protocols, with isoflurane anesthesia and similar animal handling protocols, and a similar number of datasets from male and female mice had to be available for the brain regions analyzed. Overall, 155 spectra from female mice and 166 spectra from male mice (321 in total), collected from six brain regions (brainstem, cerebellum, cortex, hippocampus, hypothalamus, and striatum) at various ages were included. Results: Concentrations of taurine, total creatine (creatine + phosphocreatine), ascorbate, glucose and glutamate were consistently higher in male vs. female mice in most brain regions. Striatum was an exception with similar total creatine in male and female mice. The sex difference pattern in the hypothalamus was notably different from other regions. Interaction between sex and age was significant for total creatine and taurine in the cerebellum and hippocampus. Conclusion: Sex differences in regional neurochemical levels are small but significant and age-dependent, with consistent male-female differences across most brain regions. The neuroendocrine region hypothalamus displays a different pattern of sex differences in neurochemical levels. Differences in energy metabolism and cellular density may underlie the differences, with higher metabolic rates in females and higher osmoregulatory and antioxidant capacity in males.

CD19/CD20 Bispecific Chimeric Antigen Receptor (CAR) in Naive/Memory T Cells for the Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma.

To address antigen escape and loss of T-cell functionality, we report a phase I clinical trial (NCT04007029) evaluating autologous naive and memory T (TN/MEM) cells engineered to express a bispecific anti-CD19/CD20 chimeric antigen receptor (CAR; CART19/20) for patients with relapsed/refractory non-Hodgkin lymphoma (NHL), with safety as the primary endpoint. Ten patients were treated with 36 × 106 to 165 × 106 CART19/20 cells. No patient experienced neurotoxicity of any grade or over grade 1 cytokine release syndrome. One case of dose-limiting toxicity (persistent cytopenia) was observed. Nine of 10 patients achieved objective response [90% overall response rate (ORR)], with seven achieving complete remission [70% complete responses (CR) rate]. One patient relapsed after 18 months in CR but returned to CR after receiving a second dose of CART19/20 cells. Median progression-free survival was 18 months and median overall survival was not reached with a 17-month median follow-up. In conclusion, CART19/20 TN/MEM cells are safe and effective in patients with relapsed/refractory NHL, with durable responses achieved at low dosage levels. SIGNIFICANCE: Autologous CD19/CD20 bispecific CAR-T cell therapy generated from TN/MEM cells for patients with NHL is safe (no neurotoxicity, maximum grade 1 cytokine release syndrome) and demonstrates strong efficacy (90% ORR, 70% CR rate) in a first-in-human, phase I dose-escalation trial. This article is highlighted in the In This Issue feature, p. 517.