Targeting the membrane-proximal C2-set domain of CD33 for improved CAR T cell therapy.

Current CD33-targeted immunotherapies typically recognize the membrane-distal V-set domain of CD33. Here, we show that decreasing the distance between T cell and leukemia cell membrane increases the efficacy of CD33 chimeric antigen receptor (CAR) T cells. We therefore generated and optimized second-generation CAR constructs containing single-chain variable fragments from antibodies raised against the membrane-proximal C2-set domain, which bind CD33 regardless of whether the V-set domain is present (CD33 antibodies).

PD-L1 macrophage and tumor cell abundance and proximity to T cells in the pretreatment large B-cell lymphoma microenvironment impact CD19 CAR-T cell immunotherapy efficacy.

CD19-targeted chimeric antigen receptor T-cell (CAR-T) immunotherapy has transformed the management of relapsed/refractory large B-cell lymphoma (LBCL), yet durable remissions are observed in less than half of treated patients. The tumor microenvironment (TME) is a key and understudied factor impacting CD19 CAR-T therapy outcomes. Using NanoString nCounter transcriptome profiling ( = 24) and multiplex immunohistochemistry (mIHC,  = 15), we studied the TME in pretreatment biopsies from patients with LBCL undergoing CD19 CAR-T therapy.

Timing of anti-PD-L1 antibody initiation affects efficacy/toxicity of CD19 CAR T-cell therapy for large B-cell lymphoma.

More than half of the patients treated with CD19-targeted chimeric antigen receptor (CAR) T-cell immunotherapy for large B-cell lymphoma (LBCL) do not achieve durable remission, which may be partly due to PD-1/PD-L1-associated CAR T-cell dysfunction. We report data from a phase 1 clinical trial (NCT02706405), in which adults with LBCL were treated with autologous CD19 CAR T cells (JCAR014) combined with escalating doses of the anti-PD-L1 monoclonal antibody, durvalumab, starting either before or after CAR T-cell infusion. The addition of durvalumab to JCAR014 was safe and not associated with increased autoimmune or immune effector cell-associated toxicities.

Sham-controlled randomized multicentre trial of transcranial direct current stimulation for prolonged disorders of consciousness.

Background And Purpose: Transcranial direct current stimulation (tDCS) has been shown to improve signs of consciousness in a subset of patients with disorders of consciousness (DoC). However, no multicentre study confirmed its efficacy when applied during rehabilitation. In this randomized controlled double-blind study, the effects of tDCS whilst patients were in rehabilitation were tested at the group level and according to their diagnosis and aetiology to better target DoC patients who might repond to tDCS.

A novel polymer-conjugated human IL-15 improves efficacy of CD19-targeted CAR T-cell immunotherapy.

Chimeric antigen receptor (CAR)-modified T-cell therapies targeting CD19 represent a new treatment option for patients with relapsed/refractory (R/R) B-cell malignancies. However, CAR T-cell therapy fails to elicit durable responses in a significant fraction of patients. Limited in vivo proliferation and survival of infused CAR T cells are key causes of failure.

T Cell Fitness and Autologous CAR T Cell Therapy in Haematologic Malignancy.

A range of emerging therapeutic approaches for the treatment of cancer aim to induce or augment endogenous T cell responses. Chimeric antigen receptor (CAR) T cell therapy (CTT) is one such approach that utilises the patient's own T cells, engineered to target cell surface antigens, to eliminate haematological malignancies. Despite mediating high rates of responses in some clinical trials, this approach can be limited by dysfunctional T cells if they are present at high frequencies either in the starting material from the patient or the CAR T cell product.

Risk factors for 2-year mortality in patients with prolonged disorders of consciousness: An international multicentre study.

Background And Purpose: Patients with prolonged disorders of consciousness (pDoC) have a high mortality rate due to medical complications. Because an accurate prognosis is essential for decision-making on patients' management, we analysed data from an international multicentre prospective cohort study to evaluate 2-year mortality rate and bedside predictors of mortality.

Methods: We enrolled adult patients in prolonged vegetative state/unresponsive wakefulness syndrome (VS/UWS) or minimally conscious state (MCS) after traumatic and nontraumatic brain injury within 3 months postinjury.

Therapeutic Targeting of Mesothelin with Chimeric Antigen Receptor T Cells in Acute Myeloid Leukemia.

Purpose: We previously identified mesothelin (MSLN) as highly expressed in a significant fraction of acute myeloid leukemia (AML) but entirely silent in normal hematopoiesis, providing a promising antigen for immunotherapeutic targeting that avoids hematopoietic toxicity. Given that T cells genetically modified to express chimeric antigen receptors (CAR) are effective at eradicating relapsed/refractory acute lymphocytic leukemia, we developed MSLN-directed CAR T cells for preclinical evaluation in AML.

Experimental Design: The variable light (VL) and heavy (VH) sequences from the MSLN-targeting SS1P immunotoxin were used to construct the single-chain variable fragment of the standard CAR containing 41-BB costimulatory and CD3Zeta stimulatory domains.

CAR-T Cell Therapy for Acute Myeloid Leukemia: Preclinical Rationale, Current Clinical Progress, and Barriers to Success.

Chimeric antigen receptor (CAR)-T cell therapy has shown impressive results in chemorefractory B cell malignancies, raising the possibilities of using this immunotherapeutic modality for other devastating hematologic malignancies, such as acute myeloid leukemia (AML). AML is an aggressive hematologic malignancy which, like B cell malignancies, poses several challenges for clinical translation of successful immunotherapy. The antigenic heterogeneity of AML results in a list of potential targets that CAR-T cells could be directed towards, each with advantages and disadvantages.

Targeting the membrane-proximal C2-set domain of CD33 for improved CD33-directed immunotherapy.

There is increasing interest in targeting CD33 in malignant and non-malignant disorders. In acute myeloid leukemia, longer survival with the CD33 antibody-drug conjugate gemtuzumab ozogamicin (GO) validates this strategy. Still, GO benefits only some patients, prompting efforts to develop more potent CD33-directed therapeutics.

Associations between the Gut Microbiota, Immune Reconstitution, and Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation.

Immune reconstitution following allogeneic hematopoietic stem cell transplantation (allo-HSCT) sets the stage for the goal of a successful transplant-the prevention of disease relapse without graft versus host disease (GVHD) and opportunistic infection. In both epidemiologic studies and in controlled animal studies, it is known that the gut microbiome (GM) can profoundly influence normal innate and adaptive immune development and can be altered by microbial transfer and antibiotics. Following allo-HSCT the GM has been shown to influence clinical outcomes but published associations between the GM and immune reconstitution post-allo-HSCT are lacking.

Eye blink rate increases as a function of cognitive load during an auditory oddball paradigm.

Previous evidence suggests that changes in spontaneous eye blink rate (EBR) in human adults might reflect the amount of attentional demand (i.e. cognitive load) during cognitive tasks.

Multicenter prospective study on predictors of short-term outcome in disorders of consciousness.

Objective: This international multicenter, prospective, observational study aimed at identifying predictors of short-term clinical outcome in patients with prolonged disorders of consciousness (DoC) due to acquired severe brain injury.

Methods: Patients in vegetative state/unresponsive wakefulness syndrome (VS/UWS) or in minimally conscious state (MCS) were enrolled within 3 months from their brain injury in 12 specialized medical institutions. Demographic, anamnestic, clinical, and neurophysiologic data were collected at study entry.

Value and affordability of CAR T-cell therapy in the United States.

In the United States the increasing number of Food and Drug Administration (FDA)-approved, innovative, and potentially effective commercial cancer therapies pose a significant financial burden on public and private payers. Chimeric antigen receptor (CAR) T cells are prototypical of this challenge. In 2017 and 2018, tisagenlecleucel (Kymriah, Novartis) and axicabtagene ciloleucel (Yescarta, Kite) were approved by the FDA for use after showing groundbreaking results in relapsed/refractory B-cell malignancies.

Consciousness and the Dimensionality of DOC Patients via the Generalized Ising Model.

The data from patients with severe brain injuries show complex brain functions. Due to the difficulties associated with these complex data, computational modeling is an especially useful tool to examine the structure-function relationship in these populations. By using computational modeling for patients with a disorder of consciousness (DoC), not only we can understand the changes of information transfer, but we also can test changes to different states of consciousness by hypothetically changing the anatomical structure.

Multimodal Neuroimaging Approach to Variability of Functional Connectivity in Disorders of Consciousness: A PET/MRI Pilot Study.

Behavioral assessments could not suffice to provide accurate diagnostic information in individuals with disorders of consciousness (DoC). Multimodal neuroimaging markers have been developed to support clinical assessments of these patients. Here we present findings obtained by hybrid fludeoxyglucose (FDG-)PET/MR imaging in three severely brain-injured patients, one in an unresponsive wakefulness syndrome (UWS), one in a minimally conscious state (MCS), and one patient emerged from MCS (EMCS).

Repeated transcranial direct current stimulation in prolonged disorders of consciousness: A double-blind cross-over study.

Objective: To evaluate effects of 5 sessions of transcranial direct current stimulation (tDCS) over the left dorsolateral prefrontal cortex in patients with prolonged disorders of consciousness (DOC).

Methods: Seven patients in vegetative state (VS) and 6 in minimally conscious state (MCS), at ≥3months after brain injury, were randomized into two groups: group 1 received one week of active tDCS and 1week of sham stimulation, separated by 1 resting week; group 2 received active and sham stimulation in reverse order. We performed clinical and EEG evaluations before and after the first stimulation session, two hours after the last weekly stimulation, twice during the resting week, and during a 3-month follow-up.

A combination of local inflammation and central memory T cells potentiates immunotherapy in the skin.

Adoptive T cell therapy uses the specificity of the adaptive immune system to target cancer and virally infected cells. Yet the mechanism and means by which to enhance T cell function are incompletely described, especially in the skin. In this study, we use a murine model of immunotherapy to optimize cell-mediated immunity in the skin.

The metalloendopeptidase gene Pitrm1 is regulated by hedgehog signaling in the developing mouse limb and is expressed in muscle progenitors.

Pitrm1 is a zinc metalloendopeptidase that has been implicated in Alzheimer's disease and mitochondrial peptide degradation, but to date no major role in embryonic development has been documented. In a screen for genes regulated by hedgehog signaling in the mouse limb, we showed that expression of Pitrm1 is upregulated in response to loss of the Gli3 transcription factor. Here we confirm spatial changes in Pitrm1 expression in the Gli3 mutant mouse limb and examine Pitrm1 expression in Shh null and Ptch1 conditional deletion mouse mutants.

Pax9 and Jagged1 act downstream of Gli3 in vertebrate limb development.

From early in limb development the transcription factor Gli3 acts to define boundaries of gene expression along the anterior-posterior (AP) axis, establishing asymmetric patterns required to provide positional information. As limb development proceeds, posterior mesenchyme expression of Sonic hedgehog (Shh) regulates Gli3 transcription and post-translational processing to specify digit number and identity. The molecular cascades dependent on Gli3 at later stages of limb development, which link early patterning events with final digit morphogenesis, remain poorly characterised.