Recruiting Natural Killer T Cells to Improve Vaccination: Lessons from Preclinical and Clinical Studies.

The capacity of type I natural killer T (NKT) cells to provide stimulatory signals to antigen-presenting cells has prompted preclinical research into the use of agonists as immune adjuvants, with much of this work focussed on stimulating T cell responses to cancer. In attempting to evaluate this approach in the clinic, our recent dendritic-cell based study failed to show an advantage to adding an agonist to the vaccine. Here we present potential limitations of the study, and suggest why other simpler strategies may be more effective.

Intratumoural administration of an NKT cell agonist with CpG promotes NKT cell infiltration associated with an enhanced antitumour response and abscopal effect.

Intratumoural administration of unmethylated cytosine-phosphate-guanine motifs (CpG) to stimulate toll-like receptor (TLR)-9 has been shown to induce tumour regression in preclinical studies and some efficacy in the clinic. Because activated natural killer T (NKT) cells can cooperate with pattern-recognition via TLRs to improve adaptive immune responses, we assessed the impact of combining a repeated dosing regimen of intratumoural CpG with a single intratumoural dose of the NKT cell agonist α-galactosylceramide (α-GalCer). The combination was superior to CpG alone at inducing regression of established tumours in several murine tumour models, primarily mediated by CD8 T cells.

Mucosal-Associated Invariant T (MAIT) Cell Dysfunction and PD-1 Expression in Prostate Cancer: Implications for Immunotherapy.

Prostate cancer is the second most common cancer in men worldwide. Despite an abundance of prostate-specific antigens, immunotherapies have yet to become a standard of care, potentially limited by T-cell dysfunction. Up to 10% of human circulating T-cells, and a significant fraction in the urogenital tract, are mucosal-associated invariant T (MAIT) cells.

Chimeric antigen receptor T-cell therapies: Optimising the dose.

Lymphocytes such as T-cells can be genetically transduced to express a synthetic chimeric antigen receptor (CAR) that re-directs their cytotoxic activity against a tumour-expressed antigen of choice. Autologous (patient-derived) CAR T-cells have been licensed to treat certain relapsed and refractory B-cell malignancies, and numerous CAR T-cell products are in clinical development. As living gene-modified cells, CAR T-cells exhibit unique pharmacokinetics, typically proliferating within the recipient during the first 14 days after administration before contracting in number, and sometimes exhibiting long-term persistence.

Third-generation anti-CD19 chimeric antigen receptor T-cells incorporating a TLR2 domain for relapsed or refractory B-cell lymphoma: a phase I clinical trial protocol (ENABLE).

Introduction: Autologous T-cells transduced to express a chimeric antigen receptor (CAR) directed against CD19 elicit high response rates in relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL). However, r/r B-NHL remissions are durable in fewer than half of recipients of second-generation CAR T-cells. Third-generation (3G) CARs employ two costimulatory domains, resulting in improved CAR T-cell efficacy in vitro and in animal models in vivo.

Selecting costimulatory domains for chimeric antigen receptors: functional and clinical considerations.

Costimulatory signals are required to achieve robust chimeric antigen receptor (CAR) T cell expansion, function, persistence and antitumor activity. These can be provided by incorporating intracellular signalling domains from one or more T cell costimulatory molecules, such as CD28 or 4-1BB, into the CAR. The selection and positioning of costimulatory domains within a CAR construct influence CAR T cell function and fate, and clinical experience of autologous anti-CD19 CAR T cell therapies suggests that costimulatory domains have differential impacts on CAR T cell kinetics, cytotoxic function and potentially safety profile.

Synthesis of mycothiol conjugate analogues and evaluation of their antimycobacterial activity.

Drug-resistant Mycobacterium tuberculosis is a growing health problem. As proof of principle that the bacterial-specific metabolite mycothiol could be used as a delivery agent for antimycobacterial agents, simplified analogues of mycothiol were synthesised containing an S-trichloroethenyl substituted cysteine residue. It was envisaged that uptake of the mycothiol analogue would be followed by release of the known cytotoxin S-trichloroethenyl cysteine by the action of mycothiol S-conjugate amidase or its paralog, mycothiol deacetylase MshB.

Identification and bioactivity of 3-epi-xestoaminol C isolated from the New Zealand brown alga Xiphophora chondrophylla.

We report here the bioassay-guided isolation of a new 1-deoxysphingoid, 3-epi-xestoaminol C (1), isolated from the New Zealand brown alga Xiphophora chondrophylla. This is the first report of a 1-deoxysphingoid from a brown alga. We describe the isolation and full structure elucidation of this compound, including its absolute configuration, along with its bioactivity against mycobacteria and mammalian cell lines and preliminary mechanism of action studies using yeast chemical genomics.