CARTITUDE-1 (NCT03548207) is a phase 1b/2 study of ciltacabtagene autoleucel (cilta-cel; JNJ-68284528), a chimeric antigen receptor T cell (CAR-T) therapy with two B-cell maturation antigen ...(BCMA)–targeting single-domain antibodies, in relapsed/refractory multiple myeloma (RRMM). Updated results from a median 18-month follow-up are reported here.
Eligible patients had MM, received ≥3 prior regimens or were double refractory to a proteasome inhibitor (PI) and immunomodulatory drug (IMiD), and had received a PI, IMiD, and anti-CD38 antibody. After apheresis, bridging therapy was allowed. Patients received a single cilta-cel infusion (target dose: 0.75×106 CAR+ viable T cells/kg; range 0.5-1.0×106) 5–7 days (d) after lymphodepletion (300 mg/m2 cyclophosphamide, 30 mg/m2 fludarabine daily for 3 d). Primary objectives were to characterize cilta-cel safety, confirm the recommended phase 2 dose (phase 1b), and evaluate efficacy (phase 2). Cytokine release syndrome (CRS) was graded by Lee et al (Blood 2014) and neurotoxicity by CTCAE, v5.0 in phase 1b. CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded by American Society for Transplantation and Cellular Therapy (ASTCT) criteria in phase 2. Lee et al and CTCAE v5.0 were mapped to ASTCT for CRS and ICANS, respectively.
As of February 11, 2021, 97 patients (median of 6 prior lines) received cilta-cel. Overall response rate per independent review committee (primary endpoint) was 97.9% (95% CI, 92.7–99.7); 80.4% achieved stringent complete response (sCR) and 94.8% achieved very good partial response or better. Median time to first response was 1 month (mo) (range, 0.9–10.7), and median time to ≥CR was 2.6 mo (range, 0.9–15.2). Median duration of response was 21.8 mo (95% CI, 21.8–NE). Of 61 minimal residual disease (MRD)-evaluable patients, 91.8% were MRD negative at 10−5. The 18-month progression-free survival (PFS) and overall survival rates (95% CI) were 66% (54.9–75.0) and 80.9% (71.4–87.6), respectively; median PFS was 22.8 mo (95% CI, 22.8–NE) for all patients, and not reached for patients with sCR. Grade 3/4 hematologic AEs ≥20% included neutropenia (95%), anemia (68%), leukopenia (61%), thrombocytopenia (60%), and lymphopenia (50%). CRS occurred in 95% of patients (4% grade 3/4); median time to onset was 7 d (range, 1–12) and median duration was 4 d (range, 1–14, excluding 1 patient with 97-d duration). CRS resolved in all but one with grade 5 CRS/hemophagocytic lymphohistiocytosis. 21% of patients had CAR-T neurotoxicity (grade ≥3, 10%). Twenty-one deaths occurred during the study: none ≤30 days; 2 ≤100 days; and 19 >100 days after infusion, among which, 10 were due to disease progression, 6 were treatment-related as assessed by the investigator, and 5 were due to AEs unrelated to treatment.
Cilta-cel is under further investigation in other MM populations in earlier lines of therapy and in outpatient settings.
At a longer median follow-up of 18 mo, a single cilta-cel infusion yielded early, deep, and durable responses with a manageable safety, in heavily pretreated patients with MM.
We are developing a collapsible, percutaneously inserted, axial flow blood pump to support the cavopulmonary circulation in infants with a failing single ventricle physiology. An initial design of ...the impeller for this axial flow blood pump was performed using computational fluid dynamics analysis, including pressure-flow characteristics, scalar stress estimations, blood damage indices, and fluid force predictions. A plastic prototype was constructed for hydraulic performance testing, and these experimental results were compared with the numerical predictions. The numerical predictions and experimental findings of the pump performance demonstrated a pressure generation of 2-16 mm Hg for 50-750 ml/min over 5,500-7,500 RPM with deviation found at lower rotational speeds. The axial fluid forces remained below 0.1 N, and the radial fluid forces were determined to be virtually zero due to the centered impeller case. The scalar stress levels remained below 250 Pa for all operating conditions. Blood damage analysis yielded a mean residence time of the released particles, which was found to be less than 0.4 seconds for both flow rates that were examined, and a maximum residence time was determined to be less than 0.8 seconds. We are in the process of designing a cage with hydrodynamically shaped filament blades to act as a diffuser and optimizing the impeller blade shape to reduce the flow vorticity at the pump outlet. This blood pump will improve the clinical treatment of patients with failing Fontan physiology and provide a unique catheter-based therapeutic approach as a bridge to recovery or transplantation.
Multiple Myeloma (MM) is an incurable malignancy of bone marrow plasma cells characterized by wide molecular diversity and complex clonal and subclonal architecture. Intra-tumor heterogeneity ...reflects the evolution of the disease. Clonal structure may affect response to treatment, which, in turn, may shape tumor evolution and, consequently, contribute to drug resistance. Thus, analysis of tumor clonality has profound implications for personalized medicine.
Using our recently developed network model of newly diagnosed MM from the MMRF CoMMpass study (Lagana et al, Leukemia 2017) , MMNet, we have identified patterns of gene co-expression significantly associated with tumor clonality and showed that clonality is correlated with mutational burden and relapse.
In order to characterize the evolution of clonal structure from diagnosis to relapse, we analyzed Whole-Exome data (WES) from 19 patients enrolled in CoMMpass for whom sequencing data for multiple time points was available. The cohort included both male (12; 63%) and female (7; 37%) patients of white/caucasian (14; 73%) and black/african-american (5; 27%) origin. Patients were distributed among five of the ten classes defined by MMNet: CCND1 (4; 21%), MAF (1; 5%), MMSET (2; 10%), HY/NRAS (4; 21%), and IMM (4; 21%) (4 were unassigned). Also, six patients had the t(11;14) and two had the t(4;14) chromosomal translocations. All patients had received induction therapy, consisting of combinations of proteasome inhibitors (PI) (Bortezomib: 19, 100%; Carfilzomib: 3, 16%), immunomodulatory drugs (IMiDs) (Lenalidomide: 13, 68%; Pomalidomide: 2, 10%; Thalidomide: 1, 5%), steroids (18, 95%) and monoclonal antibodies (Daratumumab: 1, 5%). Best responses to therapy were CR/sCR (3; 16%), VGPR (7; 37%) and PR (9; 47%). Fourteen (68%) patients had SD or PD at the second sequencing time point, with a median PFS of 456 days.
Our analysis inferred subclonal tumor composition and evolution based on somatic mutations and copy number alterations (CNA) using PhyloWGS (Deshwar et al, Genome Biol 2015). Patients had one (14; 74%), two (4; 21%) or three (1; 5%) founding clones at baseline, and numerous subclones. Trajectories of cancer cell populations revealed dramatic changes in most patients in terms of clonal and subclonal cell fractions between baseline and relapse. In most patients we observed emergence of new competing clones at relapse, where one or more subclones decreasing in size were replaced by other subclones, indicating selective pressure introduced by therapy (Fig. 1).
Subclones were characterized in terms of mutations and CNA and were labeled as stable/resistant or sensitive based on their trajectories from baseline to relapse. Our analysis revealed significant inter-patient heterogeneity in terms of mutations and clonal composition, with few overlaps. We identified subclonal drivers by screening the observed mutations and CNA against a database of known cancer drivers and analysis of co-occurrence and mutual exclusivity. Our analysis revealed that stable/resistant clones were characterized by concurrent deletion of 17p and 13q, and/or mutations in NRAS. In particular, 7 out of 19 patients had at least one mutation in NRAS, observed at baseline in 5 cases, and with two patients carrying two different mutations in two different clones. Our findings support earlier adoption of targeted therapy against RAS (e.g. Trametinib). Other drivers found exclusively in resistant clones included DIS3, FAM46C, ROBO1 and CCND1.
Overall, our analysis provides genomics characterization of relapsed patients in CoMMpass following induction therapy, reveals heterogeneous clonal and subclonal composition and trajectories from baseline to relapse, and defines specific somatic mutations (e.g. NRAS) and CNA as drivers of resistance to induction therapy.
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Madduri:Foundation Medicine, Inc.: Consultancy. Chari:Janssen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding; Amgen: Honoraria, Research Funding; Celgene Corporation: Consultancy, Research Funding. Cho:Bristol Myers-Squibb: Other: advisory board, Research Funding; Agenus, Inc.: Research Funding; Genentech: Other: advisory board, Research Funding; Ludwig Institute for Cancer Research: Research Funding; Multiple Myeloma Research Foundation: Research Funding. Barlogie:Millenium Pharmaceuticals: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding. Jagannath:Celgene: Consultancy; Bristol-Meyers Squibb: Consultancy; Merck: Consultancy; Medicom: Speakers Bureau; MMRF: Speakers Bureau; Novartis: Consultancy. Dudley:GlaxoSmithKline: Consultancy; Janssen Pharmaceuticals, Inc.: Consultancy; Ayasdi, Inc.: Equity Ownership; Ecoeos, Inc.: Equity Ownership; NuMedii, Inc.: Equity Ownership, Patents & Royalties; Ontomics, Inc.: Equity Ownership; Personalis: Patents & Royalties; AstraZeneca: Consultancy.
Myotonic Dystrophy is an autosomal dominant trinucleotide repeat expansion disorder caused by a CTG repeat in the 3’ untranslated region of the DMPK gene. These repeats become pathogenic when ...transcribed into RNA as they form ribonuclear foci comprised of auto complementary CUG hairpin structures, which in turn bind MBNL1, a key RNA splicing regulator. DM1 patients suffer from multisystemic muscle wasting, or myopathy, in muscled areas like arms, forearms, hands, ankles, jaws, tongue, and neck flexors (Ozimski et al., 2020). Utilizing small molecules to target CUG RNA hairpins is a potential tractable mechanism to prevent downstream mis-splicing thereby improving disease phenotype in patients. No published work, on novel small molecule drug discovery or drug repurposing, has shown potent CUG RNA binding with downstream in-vivo splicing rescue. This study shows early hit finding for small molecule binding to CUG RNA hairpins can be achieved using both biophysical methods and computational screening. Utilizing both approaches in conjunction, a statistically significant number (3.2%) of overlapping hits can be selected for further experimental validation.
Sildenafil (Viagra) is the first on-demand oral medication approved for treatment of male erectile dysfunction (ED). Since the unprecedented release of sildenafil, the initial surge of 'Viagra craze' ...has subsided and there is a considerable decline in world-wide prescriptions. We did a long-term efficacy study of sildenafil in our community practice to assess the discontinuation rate and the etiologic factors causing discontinuation.
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