Publications by authors named "Alison Crawford"

Ubamatamab, a Mucin 16 (MUC16) × cluster of differentiation 3 (CD3) bispecific antibody that promotes T-cell-mediated cytotoxicity of MUC16-expressing cells, is being investigated for the treatment of ovarian cancer. Intravenous administration of ubamatamab, with or without the anti-programmed cell death-1 inhibitor cemiplimab, is being evaluated in a first-in-human study in patients with recurrent ovarian cancer. In vitro cytotoxicity and cytokine data and projected ubamatamab human pharmacokinetic (PK) profiles scaled with monkey PK parameters enabled starting-dose selection in humans.

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The clinical use of interleukin-2 (IL-2) for cancer immunotherapy is limited by severe toxicity. Emerging IL-2 therapies with reduced IL-2 receptor alpha (IL-2Rα) binding aim to mitigate toxicity and regulatory T cell (Treg) expansion but have had limited clinical success. Here, we show that IL-2Rα engagement is critical for the anti-tumor activity of systemic IL-2 therapy.

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Background: Nurse scientists have significantly contributed to health equity and ensuring cultural tailoring of interventions to meet unique needs of individuals. Methodologies for cultural tailoring of self-mangament interventions among marginalized populations have limitedly accommodated intersectionality and group heterogeneity when addressing health needs.

Purpose: Identify methodological limitations in cultural tailoring of interventions among priority populations and issue recommendations on cultural elements that researchers can target to ensure valid cultural tailoring approaches.

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T-cell-redirecting bispecific antibodies have emerged as a new class of therapeutic agents designed to simultaneously bind to T cells via CD3 and to tumor cells via tumor-cell-specific antigens (TSA), inducing T-cell-mediated killing of tumor cells. The promising preclinical and clinical efficacy of TSAxCD3 antibodies is often accompanied by toxicities such as cytokine release syndrome due to T-cell activation. How the efficacy and toxicity profile of the TSAxCD3 bispecific antibodies depends on the binding affinity to CD3 remains unclear.

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Objective: To investigate whether pre-season self-reported mental toughness and self-regulation strategies predicts post-season stress, mental health, group cohesion, and satisfaction in varsity athletes.

Participants: Sixty-seven varsity athletes from a U-Sport Canadian university.

Methods: Athletes completed pre- and post-season measures of mental toughness, emotion regulation, self-control, group cohesion, and satisfaction.

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Immunotherapies to treat cancer have made tremendous progress over the past decade. In particular, T cell-directed therapies have gained considerable attention with CD3 bispecific antibodies and CAR T cells showing potent responses against hematologic tumors. At present, the ability to adapt these therapeutics to treat solid tumors is less established.

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Introduction: Evidence-based psychological strategies are being used as clinicians look for helpful interventions for patients diagnosed with the enigmatic chronic urological pelvic pain condition of interstitial cystitis/bladder pain syndrome (IC/BPS). Pain and pain catastrophizing are associated with chronic pelvic pain outcomes but the longitudinal role of catastrophizing on patient pain in IC/BPS remains unknown.

Methods: Women with IC/BPS were recruited from tertiary care clinics across North America and completed a battery of questionnaires, including demographics, pain, depression, catastrophizing at baseline, six months, and one year.

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Patients with hematologic cancers have improved outcomes after treatment with bispecific antibodies that bind to CD3 on T cells and that redirect T cells toward cancer cells. However, clinical benefit against solid tumors remains to be shown. We made a bispecific antibody that targets both the common prostate tumor-specific antigen PSMA and CD3 (PMSAxCD3) and provide evidence for tumor inhibition in several preclinical solid tumor models.

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T cell activation is initiated upon binding of the T cell receptor (TCR)/CD3 complex to peptide-major histocompatibility complexes ("signal 1"); activation is enhanced by engagement of a second "costimulatory" receptor, such as the CD28 receptor on T cells binding to its cognate ligand(s) on the target cell ("signal 2"). CD3-based bispecific antibodies act by replacing conventional signal 1, linking T cells to tumor cells by binding a tumor-specific antigen (TSA) with one arm of the bispecific and bridging to TCR/CD3 with the other. Although some of these so-called TSAxCD3 bispecifics have demonstrated promising antitumor efficacy in patients with cancer, their activity remains to be optimized.

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Introduction: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a devastating urological chronic pelvic pain condition with an unknown etiology. Evidence-based psychological strategies are becoming more successful for symptom management as we learn more about the targets for intervention. Previous research has established an indirect relationship between depression and pain through catastrophizing, but there have yet to be studies examining the emerging role of emotion regulation in this relationship.

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Advanced ovarian cancer is frequently treated with combination chemotherapy, but high recurrence rates show the need for therapies that can produce durable responses and extend overall survival. Bispecific antibodies that interact with tumor antigens on cancer cells and activating receptors on immune cells offer an innovative immunotherapy approach. Here, we describe a human bispecific antibody (REGN4018) that binds both Mucin 16 (MUC16), a glycoprotein that is highly expressed on ovarian cancer cells, and CD3, thus bridging MUC16-expressing cells with CD3 T cells.

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Objectives: To detail a diagnostic dilemma of intentional hand amputation in a man with a history of substance misuse and associated psychosis, depression and traumatic brain injury and to highlight issues in joint psychiatric and surgical management of such a complex patient in a general hospital setting.

Conclusions: Deliberate limb self-amputation is a rare event with the majority of reported cases occurring during an episode of psychosis. This case illustrates the diagnostic utility of the literature supporting that a person who has self-inflicted amputation of a limb should be treated as psychotic until proven otherwise.

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Recent advances in cancer immunotherapy suggest that manipulation of the immune system to enhance the antitumor response may be a highly effective treatment modality. One understudied aspect of immunosurveillance is antiangiogenic surveillance, the regulation of tumor angiogenesis by the immune system, independent of tumor cell lysis. CD4(+) T cells can negatively regulate angiogenesis by secreting antiangiogenic factors such as thrombospondin-1 (TSP-1).

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T cell exhaustion is common during chronic infections. Although CD4(+) T cells are critical for controlling viral load during chronic viral infections, less is known about their differentiation and transcriptional program. We defined the phenotypic, functional, and molecular profiles of exhausted CD4(+) T cells.

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Apolipoprotein F (ApoF) is a sialoglycoprotein that is a component of the HDL and LDL fractions of human serum. We sought to test the hypothesis that ApoF plays an important role in atherosclerosis in mice by modulating lipoprotein function. Atherosclerosis was assessed in male low density lipoprotein receptor knockout (Ldlr KO) and ApoF/Ldlr double knockout (DKO) mice fed a Western diet for 16 weeks.

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Following gene transfer of adeno-associated virus 2/8 (AAV2/8) to the muscle, C57BL/6 mice show long-term expression of a nuclear-targeted LacZ (nLacZ) transgene with minimal immune activation. Here, we show that pre-exposure to AAV2/8 can also induce tolerance to the more immunogenic AAV2/rh32.33 vector, preventing otherwise robust T-cell activation and allowing stable transgene expression.

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Article Synopsis
  • Innate lymphoid cells (ILCs) play a vital role in maintaining the integrity of the intestinal barrier and are linked to chronic diseases like inflammatory bowel disease.
  • Research on ILCs has mainly occurred in mice without adaptive immune cells, leading to uncertainty about their function in the presence of an active immune system.
  • The study found that RORγt(+) ILCs help regulate adaptive immune responses to bacteria without promoting inflammation, indicating their crucial role in maintaining intestinal health through interactions with CD4(+) T cells.
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Exhausted CD8(+) T cells function poorly and are negatively regulated by inhibitory receptors. Transcriptional profiling has identified gene expression changes associated with exhaustion. However, the transcriptional pathways critical to the differences between exhausted and functional memory CD8(+) T cells are unclear.

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T cell exhaustion and loss of memory potential occur during many chronic viral infections and cancer. We investigated when during chronic viral infection virus-specific CD8 T cells lose the potential to form memory. Virus-specific CD8 T cells from established chronic infection were unable to become memory CD8 T cells if removed from infection.

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RANTES (CCL5) is a chemokine expressed by many hematopoietic and non-hematopoietic cell types that plays an important role in homing and migration of effector and memory T cells during acute infections. The RANTES receptor, CCR5, is a major target of anti-HIV drugs based on blocking viral entry. However, defects in RANTES or RANTES receptors including CCR5 can compromise immunity to acute infections in animal models and lead to more severe disease in humans infected with west Nile virus (WNV).

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T cell exhaustion has a major role in failure to control chronic infection. High expression of inhibitory receptors, including PD-1, and the inability to sustain functional T cell responses contribute to exhaustion. However, the transcriptional control of these processes remains unclear.

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CD8(+) T cells in chronic viral infections such as HIV develop functional defects including loss of interleukin-2 (IL-2) secretion and decreased proliferative potential that are collectively termed 'exhaustion'. Exhausted T cells express increased amounts of multiple inhibitory receptors, such as programmed death-1 (PD-1), that contribute to impaired virus-specific T cell function. Although reversing PD-1 inhibition is therefore an attractive therapeutic strategy, the cellular mechanisms by which PD-1 ligation results in T cell inhibition are not fully understood.

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The PD-1/PD-L pathway plays a major role in regulating T-cell exhaustion during chronic viral infections in animal models, as well as in humans, and blockade of this pathway can revive exhausted CD8(+) T cells. We examined the expression of PD-1 and its ligands, PD-L1 and PD-L2, in multiple tissues during the course of chronic viral infection and determined how the amount of PD-1 expressed, as well as the anatomical location, influenced the function of exhausted CD8 T cells. The amount of PD-1 on exhausted CD8 T cells from different anatomical locations did not always correlate with infectious virus but did reflect viral antigen in some tissues.

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