CAR-T cell technologies that interact with the tumour microenvironment in solid tumours.

Introduction: Chimeric antigen receptor (CAR) T-cells have emerged as a ground-breaking therapy for the treatment of hematological malignancies due to their capacity for rapid tumor-specific killing and long-lasting tumor immunity. However, the same success has not been observed in patients with solid tumors. Largely, this is due to the additional challenges imposed by safe and uniform target selection, inefficient CAR T-cell access to sites of disease and the presence of a hostile immunosuppressive tumor microenvironment.

Synergistic T cell signaling by 41BB and CD28 is optimally achieved by membrane proximal positioning within parallel chimeric antigen receptors.

Second generation (2G) chimeric antigen receptors (CARs) contain a CD28 or 41BB co-stimulatory endodomain and elicit remarkable efficacy in hematological malignancies. Third generation (3G) CARs extend this linear blueprint by fusing both co-stimulatory units in series. However, clinical impact has been muted despite compelling evidence that co-signaling by CD28 and 41BB can powerfully amplify natural immune responses.

How Can We Engineer CAR T Cells to Overcome Resistance?

Chimeric antigen receptor (CAR) T cell therapy has achieved unrivalled success in the treatment of B cell and plasma cell malignancies, with five CAR T cell products now approved by the US Food and Drug Administration (FDA). However, CAR T cell therapies for solid tumours have not been nearly as successful, owing to several additional challenges. Here, we discuss mechanisms of tumour resistance in CAR T cell therapy and the emerging strategies that are under development to engineer CAR T cells to overcome resistance.

Importance of the Immunodominant CD8 T Cell Epitope of Plasmodium berghei Circumsporozoite Protein in Parasite- and Vaccine-Induced Protection.

The circumsporozoite protein (CSP) builds up the surface coat of sporozoites and is the leading malaria pre-erythrocytic-stage vaccine candidate. CSP has been shown to induce robust CD8 T cell responses that are capable of eliminating developing parasites in hepatocytes, resulting in protective immunity. In this study, we characterized the importance of the immunodominant CSP-derived epitope SYIPSAEKI of in both sporozoite- and vaccine-induced protection in murine infection models.

Trickle infection and immunity to Trichuris muris.

The majority of experiments investigating the immune response to gastrointestinal helminth infection use a single bolus infection. However, in situ individuals are repeatedly infected with low doses. Therefore, to model natural infection, mice were repeatedly infected (trickle infection) with low doses of Trichuris muris.