Engineering Solutions for Mitigation of Chimeric Antigen Receptor T-Cell Dysfunction

The clinical successes of chimeric antigen receptor (CAR)-T-cell therapy targeting cell surface antigens in B cell leukaemias and lymphomas has demonstrated the proof of concept that appropriately engineered T-cells have the capacity to destroy advanced cancer with long term remissions ensuing. Nevertheless, it has been significantly more problematic to effect long term clinical benefit in a solid tumour context. A major contributing factor to the clinical failure of CAR-T-cells in solid tumours has been named, almost interchangeably, as T-cell "dysfunction" or "exhaustion". While unhelpful ambiguity surrounds the term "dysfunction", "exhaustion" is canonically regarded as a pejorative term for T-cells. Recent understanding of T-cell developmental biology now identifies exhausted cells as vital for effective immune responses in the context of ongoing antigenic challenge. The purpose of this review is to explore the critical stages in the CAR-T-cell life-cycle and their various contributions to T-cell exhaustion. Through an appreciation of the predominant mechanisms of CAR-T-cell exhaustion and resultant dysfunction, we describe a range of engineering approaches to improve CAR-T-cell function

First recorded breeding of Clarke’s Weaver Ploceus golandi

The breeding site and nest of the Kenyan-endemic Clarke’s Weaver had remained a mystery for 100 years. The species was described in 1913 from the north Kenya Coast, but the first breeding colony was found in March 2013 in the northern section of the Dakatcha Woodlands, northwest of Malindi. An estimated 400–500 nests were concentrated in a small area of a tiny wetland. Adults were displaying and nest-building on 23 March, and when next visited on 7 April, adults were feeding young in the nest. Nests were coarsely woven with a low side entrance, placed in the tops of tall sedges, standing in water. Both males and females contributed to nest building and to feeding the young on insects, and breeding appeared to be closely synchronized, so that by 19 April the colony had been abandoned

Integrative analysis of neuroblastoma by single-cell RNA sequencing identifies the NECTIN2-TIGIT axis as a target for immunotherapy

Pediatric patients with high-risk neuroblastoma have poor survival rates and urgently need more effective treatment options with less side effects. As novel and improved immunotherapies may fill this need, we dissected the immunoregulatory interactions in neuroblastoma by single-cell RNA-sequencing of 25 tumors (10 pre- and 15 post-chemotherapy, including 5 pairs) to identify strategies for optimizing immunotherapy efficacy. Neuroblastomas were infiltrated by NK, T and B cells, and immunosuppressive myeloid populations. NK cells showed reduced cytotoxicity and T cells had a dysfunctional profile. Interaction analysis revealed a vast immunoregulatory network and identified NECTIN2-TIGIT as a crucial immune checkpoint. Combined blockade of TIGIT and PD-L1 significantly reduced neuroblastoma growth, with complete responses in vivo. Moreover, addition of TIGIT blockade to standard relapse treatment in a chemotherapy-resistant Th-ALKF1174L/MYCN 129/SvJ syngeneic model significantly improved survival. Concluding, our integrative analysis of neuroblastoma’s vast immunoregulatory network provides novel targets and a rationale for immunotherapeutic combination strategies

Antigen-specific B-cell receptor sensitizes B cells to infection by influenza virus

Influenza A virus-specific B lymphocytes and the antibodies they produce protect against infection. However, the outcome of interactions between an influenza haemagglutinin-specific B cell via its receptor (BCR) and virus is unclear. Through somatic cell nuclear transfer we generated mice that harbour B cells with a BCR specific for the haemagglutinin of influenza A/WSN/33 virus (FluBI mice). Their B cells secrete an immunoglobulin gamma 2b that neutralizes infectious virus. Whereas B cells from FluBI and control mice bind equivalent amounts of virus through interaction of haemagglutinin with surface-disposed sialic acids, the A/WSN/33 virus infects only the haemagglutinin-specific B cells. Mere binding of virus is not sufficient for infection of B cells: this requires interactions of the BCR with haemagglutinin, causing both disruption of antibody secretion and FluBI B-cell death within 18 h. In mice infected with A/WSN/33, lung-resident FluBI B cells are infected by the virus, thus delaying the onset of protective antibody release into the lungs, whereas FluBI cells in the draining lymph node are not infected and proliferate. We propose that influenza targets and kills influenza-specific B cells in the lung, thus allowing the virus to gain purchase before the initiation of an effective adaptive response.National Institutes of Health (U.S.

The aldosterone renin ratio based on the plasma renin activity and the direct renin assay for diagnosing aldosterone-producing adenoma.

Abstract BACKGROUND: The screening for primary aldosteronism is based on the aldosterone-renin ratio calculated with the plasma renin activity (PRA) value as denominator. A direct measurement of active renin (DRA) is being used as an alternative to PRA, but its diagnostic performance remains unclear. METHOD: We, therefore compared, head-to-head, the aldosterone-renin ratio based on PRA with that based on DRA, at baseline and after captopril administration, for identifying aldosterone-producing adenoma (APA) in 251 patients of the Primary Aldosteronism Prevalence in hYpertension Study (PAPY). The area under the receiver operator characteristics curves was used for estimating the accuracy of the aldosterone-renin ratio based on either renin assay for identifying APA and for the comparison between tests. RESULTS: The rate of primary aldosteronism was 13.2%; 6.4% of the patients had an APA and 6.8% idiopathic hyperaldosteronism; 218 (86.8%) had primary hypertension. The area under the receiver operator characteristics curve for identifying APA was higher than 0.50 for the aldosterone-renin ratio based on both renin values (0.870 +/- 0.058 for DRA and 0.973 +/- 0.028 for PRA) (P < 0.0001 for both) and did not differ significantly between the aldosterone-renin ratios calculated with either renin assay. For the aldosterone-renin ratio based on DRA, the optimal cutoff value for identifying APA was 27.3 ng/mIU, remarkably similar to that previously determined for the aldosterone-renin ratio based on PRA. CONCLUSION: Thus, the aldosterone-renin ratio based on DRA is a valuable alternative to that based on PRA for detecting APA

The aldosterone\u2013renin ratio based on the plasma renin activity and the direct renin assay for diagnosing aldosterone-producing adenoma

Background The screening for primary aldosteronism is based on the aldosterone\u2013renin ratio calculated with the plasma renin activity (PRA) value as denominator. A direct measurement of active renin (DRA) is being used as an alternative to PRA, but its diagnostic performance remains unclear. Method We, therefore compared, head-to-head, the aldosterone\u2013renin ratio based on PRA with that based on DRA, at baseline and after captopril administration, for identifying aldosterone-producing adenoma (APA) in 251 patients of the Primary Aldosteronism Prevalence in hYpertension Study (PAPY). The area under the receiver operator characteristics curves was used for estimating the accuracy of the aldosterone\u2013renin ratio based on either renin assay for identifying APA and for the comparison between tests. Results The rate of primary aldosteronism was 13.2%; 6.4% of the patients had an APA and 6.8% idiopathic hyperaldosteronism; 218 (86.8%) had primary hypertension. The area under the receiver operator characteristics curve for identifying APA was higher than 0.50 for the aldosterone\u2013renin ratio based on both renin values (0.870W0.058 for DRA and 0.973W0.028 for PRA) (P<0.0001 for both) and did not differ significantly between the aldosterone\u2013renin ratios calculated with either renin assay. For the aldosterone\u2013renin ratio based on DRA, the optimal cutoff value for identifying APA was 27.3 ng/mIU, remarkably similar to that previously determined for the aldosterone\u2013renin ratio based on PRA. Conclusion Thus, the aldosterone\u2013renin ratio based on DRA is a valuable alternative to that based on PRA for detecting APA