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Despite improvement in treatment options for myeloma patients, including targeted immunotherapies, multiple myeloma remains a mostly incurable malignancy. High CS1 (SLAMF7) expression on myeloma cells and limited expression on normal cells makes it a promising target for CAR-T therapy. The CS1 protein has two extracellular domains – the distal Variable (V) domain and the proximal Constant 2 (C2) domain. We generated and tested CS1-CAR-T targeting the V domain of CS1 (Luc90-CS1-CAR-T) and demonstrated anti-myeloma killing in vitro and in vivo using two mouse models. Since fratricide of CD8 + cells occurred during production, we generated fratricide resistant CS1 deficient Luc90- CS1- CAR-T (ΔCS1-Luc90- CS1- CAR-T). This led to protection of CD8 + cells in the CAR-T cultures, but had no impact on efficacy. Our data demonstrate targeting the distal V domain of CS1 could be an effective CAR-T treatment for myeloma patients and deletion of CS1 in clinical production did not provide an added benefit using in vivo immunodeficient NSG preclinical models.

Hematopoietic stem cell transplantation (HSCT) conditioning using antibody-drug conjugates (ADC) is a promising alternative to conventional chemotherapy- and irradiation-based conditioning regimens. The drug payload bound to an ADC is a key contributor to its efficacy and potential toxicities; however, a comparison of HSCT conditioning ADCs produced with different toxic payloads has not been performed. Indeed, ADC optimization studies in general are hampered by the inability to produce and screen multiple combinations of antibody and drug payload in a rapid, cost-effective manner. Herein, we used Click chemistry to covalently conjugate four different small molecule payloads to streptavidin; these streptavidin-drug conjugates can then be joined to any biotinylated antibody to produce stable, indirectly conjugated ADCs. Evaluating CD45-targeted ADCs produced with this system, we found the pyrrolobenzodiazepine (PBD) dimer SGD-1882 was the most effective payload for targeting mouse and human hematopoietic stem cells (HSCs) and acute myeloid leukemia cells. In murine syngeneic HSCT studies, a single dose of CD45-PBD enabled near-complete conversion to donor hematopoiesis. Finally, human CD45-PBD provided significant antitumor benefit in a patient-derived xenograft model of acute myeloid leukemia. As our streptavidin-drug conjugates were generated in-house with readily accessible equipment, reagents, and routine molecular biology techniques, we anticipate this flexible platform will facilitate the evaluation and optimization of ADCs for myriad targeting applications.

National Comprehensive Cancer Network guidelines consider 18F-fluciclovine PET-CT for prostate cancer biochemical recurrence localisation after radical prostatectomy, whereas European Association of Urology guidelines recommend prostate-specific membrane antigen (PSMA) PET-CT. To the best of our knowledge, no prospective head-to-head comparison between these tests has been done so far. The aim of this study was to compare prospectively paired 18F-fluciclovine and PSMA PET-CT scans for localising biochemical recurrence of prostate cancer after radical prostatectomy in patients with low prostate-specific antigen (PSA) concentrations (<2·0 ng/mL). This was a prospective, single-centre, open-label, single-arm comparative study done at University of California Los Angeles (Los Angeles, CA, USA). Patients older than 18 years of age with prostate cancer biochemical recurrence after radical prostatectomy and PSA levels ranging from 0·2 to 2·0 ng/mL without any prior salvage therapy and with a Karnofsky performance status of at least 50 were eligible. Patients underwent 18F-fluciclovine (reference test) and PSMA (index test) PET-CT scans within 15 days. Detection rate of biochemical recurrence at the patient level and by anatomical region was the primary endpoint. A statistical power analysis demonstrated that a sample size of 50 patients was needed to show a 22% difference in detection rates in favour of PSMA (test for superiority). Each PET scan was interpreted by three independent masked readers and a consensus majority interpretation was generated (two vs one) to determine positive findings. This study is registered with ClinicalTrials.gov, number NCT03515577, and is complete. Between Feb 26, 2018, and Sept 20, 2018, 143 patients were screened for eligibility, of whom 50 patients were enrolled into the study. Median follow-up was 8 months (IQR 7–9). The primary endpoint was met; detection rates were significantly lower with 18F-fluciclovine PET-CT (13 [26%; 95% CI 15–40] of 50) than with PSMA PET-CT (28 [56%; 41–70] of 50), with an odds ratio (OR) of 4·8 (95% CI 1·6–19·2; p=0·0026) at the patient level; in the subanalysis of the pelvic nodes region (four [8%; 2–19] with 18F-fluciclovine vs 15 [30%; 18–45] with PSMA PET-CT; OR 12·0 [1·8–513·0], p=0·0034); and in the subanalysis of any extrapelvic lesions (none [0%; 0–6] vs eight [16%; 7–29]; OR non-estimable [95% CI non-estimable], p=0·0078). With higher detection rates, PSMA should be the PET tracer of choice when PET-CT imaging is considered for subsequent treatment management decisions in patients with prostate cancer and biochemical recurrence after radical prostatectomy and low PSA concentrations (≤2·0 ng/mL). Further research is needed to investigate whether higher detection rates translate into improved oncological outcomes. None.

β-Thalassemia pathology is due not only to loss of β-globin ( HBB ), but also to erythrotoxic accumulation and aggregation of the β-globin-binding partner, α-globin ( HBA1/2 ). Here we describe a Cas9/AAV6-mediated genome editing strategy that can replace the entire HBA1 gene with a full-length HBB transgene in β-thalassemia-derived hematopoietic stem and progenitor cells (HSPCs), which is sufficient to normalize β-globin:α-globin messenger RNA and protein ratios and restore functional adult hemoglobin tetramers in patient-derived red blood cells. Edited HSPCs were capable of long-term and bilineage hematopoietic reconstitution in mice, establishing proof of concept for replacement of HBA1 with HBB as a novel therapeutic strategy for curing β-thalassemia. A new genome editing strategy can normalize the β-globin:α-globin balance in human hematopoietic stem cells from patients with β-thalassemia and restore functional adult hemoglobin tetramers in patient-derived red blood cells.

Angle-resolved photoemission spectroscopy (ARPES) is the most powerful technique to investigate the electronic band structure of crystalline solids. To completely characterize the electronic structure of topological materials, one needs to go beyond band structure mapping and access information about the momentum-resolved Bloch wave function, namely, orbitals, Berry curvature, and topological invariants. However, because phase information is lost in the process of measuring photoemission intensities, retrieving the complex-valued Bloch wave function from photoemission data has yet remained elusive. We introduce a novel measurement methodology and associated observable in extreme ultraviolet angle-resolved photoemission spectroscopy, based on continuous modulation of the ionizing radiation polarization axis. Tracking the energy- and momentum-resolved amplitude and phase of the photoemission intensity modulation upon polarization axis rotation allows us to retrieve the circular dichroism in photoelectron angular distributions (CDAD) without using circular photons, providing direct insights into the phase of photoemission matrix elements. In the case of two relevant bands, it is possible to reconstruct the orbital pseudospin (and thus the Bloch wave function) with moderate theory input, as demonstrated for the prototypical, layered, semiconducting, transition metal dichalcogenide2H−WSe2. This novel measurement methodology in ARPES, which is articulated around the manipulation of the photoionization transition dipole matrix element, in combination with a simple tight-binding theory, is general and adds a new dimension to obtaining insights into the orbital pseudospin, Berry curvature, and Bloch wave functions of many relevant crystalline solids.

The androgen receptor (AR) signaling inhibitor enzalutamide (enza) is one of the principal treatments for metastatic castration-resistant prostate cancer (CRPC). Several emergent enza clinical resistance mechanisms have been described, including lineage plasticity in which the tumors manifest reduced dependency on the AR. To improve our understanding of enza resistance, herein we analyze the transcriptomes of matched biopsies from men with metastatic CRPC obtained prior to treatment and at progression ( n  = 21). RNA-sequencing analysis demonstrates that enza does not induce marked, sustained changes in the tumor transcriptome in most patients. However, three patients’ progression biopsies show evidence of lineage plasticity. The transcription factor E2F1 and pathways linked to tumor stemness are highly activated in baseline biopsies from patients whose tumors undergo lineage plasticity. We find a gene signature enriched in these baseline biopsies that is strongly associated with poor survival in independent patient cohorts and with risk of castration-induced lineage plasticity in patient-derived xenograft models, suggesting that tumors harboring this gene expression program may be at particular risk for resistance mediated by lineage plasticity and poor outcomes. Lineage plasticity is increasingly recognized as an emergent resistance mechanism after treatment with androgen receptor signalling inhibitors. To understand determinants of resistance, the authors analyzed the transcriptomes of patient tumor biopsies before enzalutamide treatment and at progression and identified a gene expression program associated with lineage plasticity risk and poor outcomes.

Black men have a 2-fold increased risk of dying from prostate cancer compared with White men. However, race-specific differences in response to initial treatment remain unknown. To compare overall and treatment-specific outcomes of Black and White men with localized prostate cancer receiving definitive radiotherapy (RT). A systematic search was performed of relevant published randomized clinical trials conducted by the NRG Oncology/Radiation Therapy Oncology Group between January 1, 1990, and December 31, 2010. This meta-analysis was performed from July 1, 2019, to July 1, 2021. Randomized clinical trials of definitive RT for patients with localized prostate cancer comprising a substantial number of Black men (self-identified race) enrolled that reported on treatment-specific and overall outcomes. Individual patient data were obtained from 7 NRG Oncology/Radiation Therapy Oncology Group randomized clinical trials evaluating definitive RT with or without short- or long-term androgen deprivation therapy. Unadjusted Fine-Gray competing risk models, with death as a competing risk, were developed to evaluate the cumulative incidences of end points. Cox proportional hazards models were used to evaluate differences in all-cause mortality and the composite outcome of distant metastasis (DM) or death. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was followed. Subdistribution hazard ratios (sHRs) of biochemical recurrence (BCR), DM, and prostate cancer-specific mortality (PCSM). A total of 8814 patients (1630 [18.5%] Black and 7184 [81.5%] White) were included; mean (SD) age was 69.1 (6.8) years. Median follow-up was 10.6 (IQR, 8.0-17.8) years for surviving patients. At enrollment, Black men were more likely to have high-risk disease features. However, even without adjustment, Black men were less likely to experience BCR (sHR, 0.88; 95% CI, 0.58-0.91), DM (sHR, 0.72; 95% CI, 0.58-0.91), or PCSM (sHR, 0.72; 95% CI, 0.54-0.97). No significant differences in all-cause mortality were identified (HR, 0.99; 95% CI, 0.92-1.07). Upon adjustment, Black race remained significantly associated with improved BCR (adjusted sHR, 0.79; 95% CI, 0.72-0.88; P < .001), DM (adjusted sHR, 0.69; 95% CI, 0.55-0.87; P = .002), and PCSM (adjusted sHR, 0.68; 95% CI, 0.50-0.93; P = .01). The findings of this meta-analysis suggest that Black men enrolled in randomized clinical trials present with more aggressive disease but have better BCR, DM, and PCSM with definitive RT compared with White men, suggesting that other determinants of outcome, such as access to care, are important factors of achieving racial equity.

National guidelines recommend next generation sequencing (NGS) of tumors in patients diagnosed with metastatic prostate cancer (mPCa) to identify potential actionable alterations. We sought to describe the spectrum and frequency of alterations in PCa-related genes and pathways, as well as associations with self-identified race/ethnicity, and overall survival in US Veterans. This retrospective cohort study included Non-Hispanic Black (NHB) and Non-Hispanic white (NHW) Veterans with mPCa who obtained NGS through the Veterans Affairs National Precision Oncology Program. 45 genes in seven canonical or targetable mPCa pathways were evaluated in addition to TMB and MSI status. Multivariable logistic regression evaluated associations between race/ethnicity and genomic alteration frequencies. Cox proportional hazards models were used to determine associations between race/ethnicity, specific gene/pathway alteration, and overall survival. 5,015 Veterans with mPCa who had NGS conducted were included (1,784 NHB, 3,231 NHW). NHB Veterans were younger, had higher PSA at diagnosis, were less likely to report Agent Orange exposure, and resided in more deprived neighborhoods compared to NHW Veterans. Nine of the top ten most commonly altered genes were the same in NHB v NHW Veterans; however, the frequencies of alterations varied by race/ethnicity. NHB race/ethnicity was associated with higher odds of genomic alterations in (OR 1.7 [1.2-2.6]) as well as immunotherapy targets (OR 1.7 [1.1-2.7]) including MSI high status (OR 3.1 [1.1-9.4]). Furthermore, NHB race/ethnicity was significantly associated with lower odds of genomic alterations in the AKT/PI3K pathway (OR 0.6 [0.4-0.7]), AR axis (OR 0.7 [0.5-0.9]), and tumor suppressor genes (OR 0.7 [0.5-0.8]). Cox proportional hazards modelling stratified by race/ethnicity demonstrated alterations in tumor suppressor genes including were associated with shorter OS in both NHB (HR 1.54 [1.13-2.11] and NHW individuals (HR 1.52 [1.25-1.85]). In the equal access VA healthcare setting, Veterans undergoing NGS for mPCa exhibited differences in alteration frequencies in both actionable and non-actionable pathways that may be associated with survival. This analysis affirms the utility of genomic testing for identifying candidates irrespective of race/ethnicity for precision oncology treatments, which could contribute to equitable outcomes in patients with mPCa.