23ME-00610, a genetically informed, first-in-class antibody targeting CD200R1 to enhance antitumor T cell function.

Immune checkpoint inhibition (ICI) has revolutionized cancer treatment; however, only a subset of patients benefit long term. Therefore, methods for identification of novel checkpoint targets and development of therapeutic interventions against them remain a critical challenge. Analysis of human genetics has the potential to inform more successful drug target discovery. We used genome-wide association studies of the 23andMe genetic and health survey database to identify an immuno-oncology signature in which genetic variants are associated with opposing effects on risk for cancer and immune diseases. This signature identified multiple pathway genes mapping to the immune checkpoint comprising CD200, its receptor CD200R1, and the downstream adapter protein DOK2. We confirmed that CD200R1 is elevated on tumor-infiltrating immune cells isolated from cancer patients compared to the matching peripheral blood mononuclear cells. We developed a humanized, effectorless IgG1 antibody (23ME-00610) that bound human CD200R1 with high affinity (KD <0.1 nM), blocked CD200 binding, and inhibited recruitment of DOK2. 23ME-00610 induced T-cell cytokine production and enhanced T cell-mediated tumor cell killing in vitro. Blockade of the CD200:CD200R1 immune checkpoint inhibited tumor growth and engaged immune activation pathways in an S91 tumor cell model of melanoma in mice.

Allogeneic CAR T Cells Targeting DLL3 Are Efficacious and Safe in Preclinical Models of Small Cell Lung Cancer.

PURPOSE: Small cell lung cancer (SCLC) is an aggressive disease with limited treatment options. Delta-like ligand 3 (DLL3) is highly expressed on SCLC and several other types of neuroendocrine cancers, with limited normal tissue RNA expression in brain, pituitary, and testis, making it a promising CAR T-cell target for SCLC and other solid tumor indications. EXPERIMENTAL DESIGN: A large panel of anti-DLL3 scFv-based CARs were characterized for both in vitro and in vivo activity. To understand the potential for pituitary and brain toxicity, subcutaneous or intracranial tumors expressing DLL3 were implanted in mice and treated with mouse cross-reactive DLL3 CAR T cells. RESULTS: A subset of CARs demonstrated high sensitivity for targets with low DLL3 density and long-term killing potential in vitro. Infusion of DLL3 CAR T cells led to robust antitumor efficacy, including complete responses, in subcutaneous and systemic SCLC in vivo models. CAR T-cell infiltration into intermediate and posterior pituitary was detected, but no tissue damage in brain or pituitary was observed, and the hormone-secretion function of the pituitary was not ablated. CONCLUSIONS: In summary, the preclinical efficacy and safety data presented here support further evaluation of DLL3 CAR T cells as potential clinical candidates for the treatment of SCLC.

Design and Validation of Inducible TurboCARs with Tunable Induction and Combinatorial Cytokine Signaling.

Although cytokine support can enhance CAR T-cell function, coadministering cytokines or engineering CAR T cells to secrete cytokines can result in toxicities. To mitigate these safety risks, we engineered iTurboCAR T cells that coexpress a novel inducible Turbo (iTurbo) cytokine signaling domain. iTurbo domains consist of modular components that are customizable to a variety of activating inputs, as well as cytokine signaling outputs multiplexable for combinatorial signaling outcomes. Unlike most canonical cytokine receptors that are heterodimeric, iTurbo domains leverage a compact, homodimeric design that minimizes viral vector cargo. Using an iTurbo domain activated by the clinically validated dimerizer, AP1903, homodimeric iTurbo domains instigated signaling that mimicked the endogenous heterodimeric cytokine receptor. Different iTurbo domains programmed iTurboCAR T cells toward divergent phenotypes and resulted in improved antitumor efficacy. iTurbo domains, therefore, offer the flexibility for user-programmable signaling outputs, permitting control over cellular phenotype and function while minimizing viral cargo footprint.

Local and regional variability in utilization and allocation of hepatitis C virus-infected hearts for transplantation.

With the advent of direct-acting antiviral agents, there has been a rapid rise in hepatitis C virus-infected (HCV+) heart transplantation. We aimed to understand local and regional differences in utilization and allocation of HCV+ hearts. Using United Network for Organ Sharing (UNOS) de-identified data from January 1, 2016 to September 30, 2019 we compared trends in the utilization rates (hearts transplanted/donors recovered) of HCV-uninfected (HCV-) to those of HCV+ nonviremic (HCV-NV) and viremic (HCV-V) hearts nationally and by UNOS region. We also evaluated allocation rates (hearts successfully allocated/donors recovered) by organ procurement organization (OPO). We found that (1) in 2019, national utilization rates for HCV-NV and HCV-V hearts were the same as HCV- hearts (27.6% for HCV-NV, 30.9 for HCV-V, and 31.7% for HCV-, P = .277); (2) utilization rates of HCV-NV hearts were low in regions 3 and 4 and of HCV-V hearts in regions 3, 4, and 8 even in the contemporary period since 2018; and (3) there was marked variability in allocation of HCV+ hearts at the OPO level even within the same UNOS region. We conclude that despite national strides in the utilization of HCV+ hearts for transplantation, more aggressive allocation of HCV+ hearts at the OPO level may still significantly affect the organ shortage.

Outcomes in cystic fibrosis lung transplant recipients infected with organisms labeled as pan-resistant: An ISHLT Registry‒based analysis.

BACKGROUND: The presence of pan-resistant organisms in patients with cystic fibrosis (CF) potentially impacts mortality after lung transplant (LT). In this study we aimed to study LT mortality in CF patients with and without pan-resistant infection. METHODS: The International Society for Heart and Lung Transplantation (ISHLT) Thoracic Transplant Registry was used to identify adults with CF, first-time, bilateral LT from 1991 to 2015. Extracted data included demographics, clinical characteristics, post-transplant outcomes, and mortality (infection-related, overall). Multivariate binary logistic regression models were created with 90-day and 1-year mortality as primary outcomes. RESULTS: Among 3,256 LT recipients with CF, 697 were labeled as having pan-resistant infection, the others were included as controls (n = 2,649). Pre-transplant, those labeled as pan-resistant were more likely to require ventilator support, have an infection requiring intravenous antibiotics, and have had ≥2 pneumonia episodes within 1 year. Ninety-day and 1-year mortality was similar between groups, but infection-related mortality at 90days (3.3% vs 1.88%, p = 0.01) and 1 year (6.6% vs 4.6%, p < 0.001) was higher in those labeled as pan-resistant. In multivariate analysis, presence of organisms labeled as pan-resistant was not associated with 90-day (odds ratio [OR] 1.5, 95% confidence interval [CI] 0.93 to 2.42, p = 0.09) or 1-year mortality (OR 1.32, 95% CI 0.95 to 1.83, p = 0.097). CONCLUSIONS: CF patients with pre-transplant infection from organisms labeled as pan-resistant had similar 90-day and 1-year mortality as those without. Despite increased infection-related mortality in these patients, it was not predictive of mortality in multivariate analysis. The higher occurrence of post-transplant infections in these patients warrants diligent follow-up. A multicenter cohort study will be required to validate the findings of our study.

Structure-guided combination therapy to potently improve the function of mutant CFTRs.

Available corrector drugs are unable to effectively rescue the folding defects of CFTR-ΔF508 (or CFTR-F508del), the most common disease-causing mutation of the cystic fibrosis transmembrane conductance regulator, a plasma membrane (PM) anion channel, and thus to substantially ameliorate clinical phenotypes of cystic fibrosis (CF). To overcome the corrector efficacy ceiling, here we show that compounds targeting distinct structural defects of CFTR can synergistically rescue mutant expression and function at the PM. High-throughput cell-based screens and mechanistic analysis identified three small-molecule series that target defects at nucleotide-binding domain (NBD1), NBD2 and their membrane-spanning domain (MSD) interfaces. Although individually these compounds marginally improve ΔF508-CFTR folding efficiency, function and stability, their combinations lead to ~50-100% of wild-type-level correction in immortalized and primary human airway epithelia and in mouse nasal epithelia. Likewise, corrector combinations were effective against rare missense mutations in various CFTR domains, probably acting via structural allostery, suggesting a mechanistic framework for their broad application.