Citations

AbstractThe phase 3 FIRST trial demonstrated significant improvement in progression‐free survival (PFS) and overall survival (OS) with an immune‐stimulatory agent, lenalidomide, in combination with low‐dose dexamethasone until disease progression (Rd continuous) vs melphalan +prednisone + thalidomide (MPT) in transplant‐ineligible patients with newly diagnosed multiple myeloma (NDMM). Rd continuous similarly extended PFS vs fixed‐duration Rd for 18 cycles (Rd18). Outcomes in the Canadian/US subgroup (104 patients per arm) are reported in this analysis. Rd continuous demonstrated a significant improvement in PFS vs MPT (median, 29.3 vs 20.2 months; HR, 0.69 [95% CI, 0.49‐0.97]; p = 0.03326) and an improvement vs Rd18 (median, 21.9 months). Median OS was 56.9 vs 46.8 months with Rd continuous vs MPT (p = 0.15346) and 59.5 months with Rd18. The overall response rate was higher with Rd continuous and Rd18 (78.8% and 79.8%) vs MPT (65.4%). In the 49.0%, 52.9%, and 29.8% of patients with at least very good partial response in the Rd continuous, Rd18, and MPT arms, respectively, the median PFS was 56.0, 30.9, and 40.2 months, respectively. The most common grade 3/4 treatment‐emergent adverse events were neutropenia (28.4%, 30.1%, and 52.0%), anemia (23.5%, 21.4%, and 23.5%), and infections (37.3%, 30.1%, and 24.5%) with Rd continuous, Rd18, and MPT, respectively. These results were consistent with those in the intent‐to‐treat population, confirming the benefit of Rd continuous vs MPT in the Canadian/US subgroup and supporting the role of Rd continuous as a standard of care for transplant‐ineligible patients with NDMM.

AbstractCancer treatment has been transformed by checkpoint blockade therapies, with the highest anti-tumor activity of anti-programmed death 1 (PD-1) antibody therapy seen in Hodgkin lymphoma. Disappointingly, response rates have been low in the non-Hodgkin lymphomas, with no activity seen in relapsed/refractory chronic lymphocytic leukemia (CLL) with PD-1 blockade. Thus, identifying more powerful combination therapy is required for these patients. Here, we preclinically demonstrate enhanced anti-CLL activity following combinational therapy with anti-PD-1 or anti-PD-1 ligand (PD-L1) and avadomide, a cereblon E3 ligase modulator (CELMoD). Avadomide induced type I and II interferon (IFN) signaling in patient T cells, triggering a feedforward cascade of reinvigorated T-cell responses. Immune modeling assays demonstrated that avadomide stimulated T-cell activation, chemokine expression, motility and lytic synapses with CLL cells, as well as IFN-inducible feedback inhibition through upregulation of PD-L1. Patient-derived xenograft tumors treated with avadomide were converted to CD8+ T cell-inflamed tumor microenvironments that responded to anti-PD-L1/PD-1-based combination therapy. Notably, clinical analyses showed increased PD-L1 expression on T cells, as well as intratumoral expression of chemokine signaling genes in B-cell malignancy patients receiving avadomide-based therapy. These data illustrate the importance of overcoming a low inflammatory T-cell state to successfully sensitize CLL to checkpoint blockade-based combination therapy.

ObjectiveDeficiency of adenosine deaminase 2 (DADA2) is a monogenic form of vasculitis that can resemble polyarteritis nodosa (PAN). This study was undertaken to identify potential disease‐causing sequence variants in ADA2 in patients with idiopathic PAN, granulomatosis with polyangiitis (GPA), or microscopic polyangiitis (MPA).MethodsPatients with idiopathic PAN (n = 118) and patients with GPA or MPA (n = 1,107) were screened for rare nonsynonymous variants in ADA2 using DNA sequencing methods. ADA‐2 enzyme activity was assessed in selected serum samples.ResultsNine of 118 patients with PAN (7.6%) were identified as having rare nonsynonymous variants in ADA2. Four patients (3.4%) were biallelic for pathogenic or likely pathogenic variants, and 5 patients (4.2%) were monoallelic carriers for 3 variants of uncertain significance and 2 likely pathogenic variants. Serum samples from 2 patients with PAN with biallelic variants were available and showed markedly reduced ADA‐2 enzyme activity. ADA‐2 enzyme testing of 86 additional patients revealed 1 individual with strongly reduced ADA‐2 activity without detectable pathogenic variants. Patients with PAN and biallelic variants in ADA2 were younger at diagnosis than patients with 1 or no variant in ADA2, with no other clinical differences noted. None of the patients with GPA or MPA carried biallelic variants in ADA2.ConclusionA subset of patients with idiopathic PAN meet genetic criteria for DADA2. Given that tumor necrosis factor inhibition is efficacious in DADA2 but is not conventional therapy for PAN, these findings suggest that ADA‐2 testing should strongly be considered in patients with hepatitis B virus–negative idiopathic PAN.

Abstract CD40 is a co-stimulatory receptor of the TNF receptor superfamily expressed on antigen presenting cells (APCs). Antibodies targeting CD40 may have therapeutic benefit via multiple mechanisms including innate immune activation that can support generation of antigen-specific, antitumor T cell responses, and binding to CD40-expressing cancer cells leading to antibody-mediated target cell killing. Multiple CD40-directed antibodies are in clinical development and differ by immunoglobulin isotype, affinity to CD40, and selectivity for FcγR-binding. These alterations could lead to differences in pharmacodynamic and antitumor activity. SEA-CD40 is an agonistic non-fucosylated, humanized IgG1 monoclonal antibody directed against CD40. SEA-CD40 has enhanced FcγRIIIa binding (~10x greater than parent IgG1 antibody) that drives increased effector function, resulting in more potent immune stimulatory activity than antibodies with muted or selective FcγR binding. The enhanced effector function of SEA-CD40 may confer greater immune stimulation and antitumor activity relative to other CD40-directed therapeutics. Preclinically, SEA-CD40 exposure results in a distinct signature of responses including activation of APCs, CD8+ and CD4+ T cells and NK cells, and targeted depletion of CD40+ B cells. SEA-CD40 demonstrates superior activity compared to other CD40-targeted antibodies in vitro and in vivo, suggesting that the enhanced effector function is critical for optimal immune cell agonism. For example, SEA-CD40 drove in vitro ADCC activity 100-fold above the parent antibody and exhibited robust ADCC with the low and high affinity FcγRIIIA genotype. At matched dose levels in cynomolgus monkeys, SEA-CD40 induced circulating cytokines and sustained B cell depletion that were up to 50-fold above that induced with the parent antibody. The SEA-CD40 signature of activation translates to increased antitumor activity as a single agent and in combination with standard of care treatments in preclinical models, suggesting the potential for beneficial combination therapy in the clinic. The SEA-CD40 immune signature was confirmed by pharmacodynamic changes in an ongoing phase 1 clinical trial in patients with relapsed/refractory metastatic solid tumors (NCT02376699). SEA-CD40 treatment induced dose-dependent increases in circulating cytokines and chemokines associated with myeloid and lymphoid immune activation and trafficking. SEA-CD40 treatment also resulted in activation of CD4+ and CD8+ T cells and CD40-targeted B cell depletion in the periphery. These findings support continued clinical evaluation of SEA-CD40. The ongoing phase 1 clinical trial is actively enrolling and includes a cohort in pancreatic cancer assessing the combination of SEA-CD40, gemcitabine, nab-paclitaxel, and pembrolizumab. Citation Format: Haley Neff-LaFord, Juneko E. Grilley-Olson, David C. Smith, Brendan Curti, Sanjay Goel, Timothy M. Kuzel, Svetomir N. Markovic, Olivier Rixe, David L. Bajor, Thomas F. Gajewski, Martin Gutierrez, Elisabeth I. Heath, John Thompson, Sahar Ansari, Shyra Gardai, Celine Jacquemont, Michael Schmitt, Andrew L. Coveler. SEA-CD40 is a non-fucosylated anti-CD40 antibody with potent pharmacodynamic activity in preclinical models and patients with advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5535.

Abstract Nivolumab, an anti–programmed death-1 (PD-1) monoclonal antibody, showed promising activity in relapsed or refractory (R/R) follicular lymphoma (FL) in a phase 1 study. We conducted a phase 2 trial to further evaluate its efficacy and safety in patients with R/R FL and to explore biomarkers of response. Patients with R/R FL and at least 2 prior lines of therapy, each containing a CD20 antibody or an alkylating agent, were treated with nivolumab 3 mg/kg every 2 weeks. The primary end point was objective response rate (ORR) assessed by an independent radiologic review committee. Biomarker analyses included gene expression profiling and multiplex immunofluorescence studies of pretreatment tumor samples. A total of 92 patients were treated. After a minimum follow-up of 12 months, ORR was 4% (4 of 92 patients). Median progression-free survival (PFS) was 2.2 months (95% confidence interval [CI], 1.9-3.6 months). Median duration of response was 11 months (95% CI, 8-14 months). Exploratory analyses suggested that responders had significantly higher proportion of CD3+ T cells in the tumor microenvironment than nonresponders, but no significant differences in PD-1 or programmed death-ligand 1 expression were observed. High expression of a set of tumor-associated macrophage genes was associated with reduced PFS (hazard ratio, 3.28; 95% CI, 1.76-6.11; P = .001). The safety profile was consistent with previous reports of nivolumab. In conclusion, nivolumab monotherapy was associated with very limited activity in patients with R/R FL. Better understanding of the immune biology of this disease may facilitate the development of effective checkpoint-based strategies. This trial was registered at www.clinicaltrials.gov as #NCT02038946.

AbstractIntroductionAbnormal gene expression patterns may contribute to the onset and progression of late‐onset Alzheimer's disease (LOAD).MethodsWe performed transcriptome‐wide meta‐analysis (N = 1440) of blood‐based microarray gene expression profiles as well as neuroimaging and cerebrospinal fluid (CSF) endophenotype analysis.ResultsWe identified and replicated five genes (CREB5, CD46, TMBIM6, IRAK3, and RPAIN) as significantly dysregulated in LOAD. The most significantly altered gene, CREB5, was also associated with brain atrophy and increased amyloid beta (Aβ) accumulation, especially in the entorhinal cortex region. cis‐expression quantitative trait loci mapping analysis of CREB5 detected five significant associations (P < 5 × 10−8), where rs56388170 (most significant) was also significantly associated with global cortical Aβ deposition measured by [18F]Florbetapir positron emission tomography and CSF Aβ1‐42.DiscussionRNA from peripheral blood indicated a differential gene expression pattern in LOAD. Genes identified have been implicated in biological processes relevant to Alzheimer's disease. CREB, in particular, plays a key role in nervous system development, cell survival, plasticity, and learning and memory.

Abstract Rationale Usual interstitial pneumonia (UIP) is the defining morphology of idiopathic pulmonary fibrosis (IPF). Guidelines for IPF diagnosis conditionally recommend surgical lung biopsy for histopathology diagnosis of UIP when radiology and clinical context are not definitive. A “molecular diagnosis of UIP” in transbronchial lung biopsy, the Envisia Genomic Classifier, accurately predicted histopathologic UIP. Objectives We evaluated the combined accuracy of the Envisia Genomic Classifier and local radiology in the detection of UIP pattern. Methods Ninety-six patients who had diagnostic lung pathology as well as a transbronchial lung biopsy for molecular testing with Envisia Genomic Classifier were included in this analysis. The classifier results were scored against reference pathology. UIP identified on high-resolution computed tomography (HRCT) as documented by features in local radiologists’ reports was compared with histopathology. Measurements and Main Results In 96 patients, the Envisia Classifier achieved a specificity of 92.1% (confidence interval [CI],78.6–98.3%) and a sensitivity of 60.3% (CI, 46.6–73.0%) for histology-proven UIP pattern. Local radiologists identified UIP in 18 of 53 patients with UIP histopathology, with a sensitivity of 34.0% (CI, 21.5–48.3%) and a specificity of 96.9% (CI, 83.8–100%). In conjunction with HRCT patterns of UIP, the Envisia Classifier results identified 24 additional patients with UIP (sensitivity 79.2%; specificity 90.6%). Conclusions In 96 patients with suspected interstitial lung disease, the Envisia Genomic Classifier identified UIP regardless of HRCT pattern. These results suggest that recognition of a UIP pattern by the Envisia Genomic Classifier combined with HRCT and clinical factors in a multidisciplinary discussion may assist clinicians in making an interstitial lung disease (especially IPF) diagnosis without the need for a surgical lung biopsy.

AbstractHealth‐related quality of life (HRQoL) in patients with chronic lymphocytic leukemia (CLL) is important in guiding treatment decisions. However, the impact of CLL treatment initiation on HRQoL is unclear. We assessed HRQoL using the FACT‐Leu and EQ‐5D‐3L questionnaires in the Connect® CLL Registry, a large, US‐based, multicenter, prospective observational study of CLL patients enrolled between 2010 and 2014, prior to the introduction of novel therapies. Among 889 patients initiating first‐line therapy with chemoimmunotherapy or rituximab monotherapy, questionnaire completion rates were 95.7% and 95.8% at enrollment, and 70.8% and 69.4% at 12 months, for FACT‐Leu Total and EQ‐5D‐3L, respectively. For 849 patients completing all five FACT‐Leu components, average total scores were 135.7 at enrollment and 141.6 at 12 months. Among 526 patients with FACT‐Leu Total scores at enrollment and 12 months, clinically meaningful (≥11‐point) improvements or reductions were observed in 179 (34.0%) and 88 (16.7%) patients, respectively. Mean EQ‐5D‐3L index scores were 0.87 at enrollment and 12 months. Among 513 patients completing EQ‐5D‐3L at enrollment and 12 months, clinically meaningful (≥0.06‐point) improvements or reductions were observed in 125 (24.4%) and 116 (22.6%) patients, respectively. In the Connect® CLL Registry, HRQoL remained stable or slightly improved after 12 months of follow‐up.