Mediation of antitumor activity by AZD4820 oncolytic vaccinia virus encoding IL-12.

Oncolytic viruses are engineered to selectively kill tumor cells and have demonstrated promising results in early-phase clinical trials. To further modulate the innate and adaptive immune system, we generated AZD4820, a vaccinia virus engineered to express interleukin-12 (IL-12), a potent cytokine involved in the activation of natural killer (NK) and T cells and the reprogramming of the tumor immune microenvironment. Testing in cultured human tumor cell lines demonstrated broad oncolytic activity and IL-12 transgene expression.

Activity of murine surrogate antibodies for durvalumab and tremelimumab lacking effector function and the ability to deplete regulatory T cells in mouse models of cancer.

Preclinical studies of PD-L1 and CTLA-4 blockade have relied heavily on mouse syngeneic tumor models with intact immune systems, which facilitate dissection of immunosuppressive mechanisms in the tumor microenvironment. Commercially developed monoclonal antibodies (mAbs) targeting human PD-L1, PD-1, and CTLA-4 may not demonstrate cross-reactive binding to their mouse orthologs, and surrogate anti-mouse antibodies are often used in their place to inhibit these immune checkpoints. In each case, multiple choices exist for surrogate antibodies, which differ with respect to species of origin, affinity, and effector function.

Antibody-Drug Conjugates Bearing Pyrrolobenzodiazepine or Tubulysin Payloads Are Immunomodulatory and Synergize with Multiple Immunotherapies.

Immunogenic cell death (ICD) is the process by which certain cytotoxic drugs induce apoptosis of tumor cells in a manner that stimulates the immune system. In this study, we investigated whether antibody-drug conjugates (ADCS) conjugated with pyrrolobenzodiazepine dimer (PBD) or tubulysin payloads induce ICD, modulate the immune microenvironment, and could combine with immuno-oncology drugs to enhance antitumor activity. We show that these payloads on their own induced an immune response that prevented the growth of tumors following subsequent tumor cell challenge.

Targeting CD73 in the tumor microenvironment with MEDI9447.

MEDI9447 is a human monoclonal antibody that is specific for the ectoenzyme CD73 and currently undergoing Phase I clinical trials. Here we show that MEDI9447 is a potent inhibitor of CD73 ectonucleotidase activity, with wide ranging immune regulatory consequences. MEDI9447 results in relief from adenosine monophosphate (AMP)-mediated lymphocyte suppression in vitro and inhibition of mouse syngeneic tumor growth in vivo.

Doxil synergizes with cancer immunotherapies to enhance antitumor responses in syngeneic mouse models.

Based on the previously described roles of doxorubicin in immunogenic cell death, both doxorubicin and liposomal doxorubicin (Doxil) were evaluated for their ability to boost the antitumor response of different cancer immunotherapies including checkpoint blockers (anti-PD-L1, PD-1, and CTLA-4 mAbs) and TNF receptor agonists (OX40 and GITR ligand fusion proteins) in syngeneic mouse models. In a preventative CT26 mouse tumor model, both doxorubicin and Doxil synergized with anti-PD-1 and CTLA-4 mAbs. Doxil was active when CT26 tumors were grown in immunocompetent mice but not immunocompromised mice, demonstrating that Doxil activity is increased in the presence of a functional immune system.

Neural stem/progenitor cells participate in the regenerative response to perinatal hypoxia/ischemia.

Perinatal hypoxia/ischemia (H/I) is the leading cause of neurologic injury resulting from birth complications. Recent advances in critical care have dramatically improved the survival rate of infants suffering this insult, but approximately 50% of survivors will develop neurologic sequelae such as cerebral palsy, epilepsy or cognitive deficits. Here we demonstrate that tripotential neural stem/progenitor cells (NSPs) participate in the regenerative response to perinatal H/I as their numbers increase 100% by 3 d and that they alter their intrinsic properties to divide using expansive symmetrical cell divisions.

Neuroinflammation and both cytotoxic and vasogenic edema are reduced in interleukin-1 type 1 receptor-deficient mice conferring neuroprotection.

Background And Purpose: Interleukin-1 (IL-1) is a proinflammatory cytokine implicated in multiple neurodegenerative diseases, including stroke. However, to date, there is no consensus regarding which receptor(s) mediates the detrimental effects of IL-1. We hypothesized that abrogating IL-1 type 1 receptor (IL-1R1) signaling would reduce edema, chemokine expression, and leukocyte infiltration; lower levels of iNOS; and, consequently, decrease free radical damage after mild hypoxia/ischemia (H/I), thus preserving brain cells.

Gray matter oligodendrocyte progenitors and neurons die caspase-3 mediated deaths subsequent to mild perinatal hypoxic/ischemic insults.

With significant improvements in neonatal care, fewer infants sustain severe injury as a consequence of hypoxia/ischemia (H/I). However, the majority of experimental studies have inflicted moderate to severe injuries, or they have assessed damage to the caudal forebrain; therefore, to better understand how a mild H/I episode affects the structures and cells of the rostral forebrain, we assessed the relative vulnerabilities of cells in the neocortex, striatum, corpus callosum, choroid plexus and subventricular zone (SVZ). To inflict mild H/I injury, the right common carotid artery was ligated followed by 1 h of hypoxia (8% O(2)) at 37 degrees C.

Perinatal hypoxia/ischemia damages and depletes progenitors from the mouse subventricular zone.

Hypoxia-ischemia (H/I) as a result of asphyxia at term remains a major cause of neurologic disability. Our previous studies in the P7 rat model of perinatal H/I have shown that progenitors within the subventricular zone (SVZ) are vulnerable to this insult. Since many investigators are using transgenic and knockout mice to determine the importance of specific molecules in the evolution of damage after a stroke, there is a need to perform comparative studies on the relative vulnerability of the mouse SVZ.

Interleukin-1 and the interleukin-1 type 1 receptor are essential for the progressive neurodegeneration that ensues subsequent to a mild hypoxic/ischemic injury.

Excessive inflammation has been implicated in the progressive neurodegeneration that occurs in multiple neurological diseases, including cerebral ischemia, and elevated levels of the proinflammatory cytokine interleukin-1 (IL-1) have been shown to exacerbate brain damage, whereas diminishing IL-1 levels limits the extent of injury. However, to date there is no consensus regarding which receptor(s) mediates the detrimental effects of IL-1. Because we have previously demonstrated that signaling through the IL-1 type 1 receptor (IL-1R1) is necessary for microglial activation and because results from other studies have implicated microglia as effectors of neurodegeneration, we hypothesized that inactivating the IL-1R1 would decrease the extent of damage caused by a hypoxic-ischemic (H/I) insult.

Neural stem cells in the subventricular zone are resilient to hypoxia/ischemia whereas progenitors are vulnerable.

Perinatal hypoxic-ischemic (H/I) brain injury remains a major cause of neurologic disability. Because we have previously demonstrated that this insult depletes cells from the subventricular zone (SVZ), the goal of the present investigation was to compare the relative vulnerability to H/I of neural stem cells versus progenitors. The dorsolateral SVZs of P6 rats were examined at 2 to 48 hours of recovery from H/I using hematoxylin and eosin, in situ end labeling (ISEL), terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling (TUNEL), electron microscopy, and immunofluorescence.

Damage to the choroid plexus, ependyma and subependyma as a consequence of perinatal hypoxia/ischemia.

Cerebral hypoxia/ischemia (H/I) of the premature infant is a major cause of cerebral palsy and mental retardation. An important determinant of the ultimate outcome from this insult is the extent to which the stem cells and progenitors in the brain are affected. Irreversible injury to these cells will impair normal development of the infant's brain and, hence, its function.

Roles of the mammalian subventricular zone in brain development.

There has been enormous progress in uncovering the contributions of the subventricular zone (SVZ) to the developing brain. Here, we review the roles of four anatomically defined embryologic divisions of the SVZ of the mammalian brain: the lateral ganglionic eminence (LGE), the medial ganglionic eminence (MGE), the caudal ganglionic eminence (CGE), and the fetal neocortical SVZ (SVZn), as well as the roles of the two major anatomically defined regions of the postnatal SVZ, the anterior SVZ (SVZa) and the dorsolateral SVZ (SVZdl). We describe the types of cells within each subdivision of the SVZ, the types of brain cells that they generate during embryonic, fetal, and perinatal development, and when known the mechanisms that regulate their differentiation.