A Costimulatory CAR Improves TCR-based Cancer Immunotherapy.

T-cell receptors (TCR) recognize intracellular and extracellular cancer antigens, allowing T cells to target many tumor antigens. To sustain proliferation and persistence, T cells require not only signaling through the TCR (signal 1), but also costimulatory (signal 2) and cytokine (signal 3) signaling. Because most cancer cells lack costimulatory molecules, TCR engagement at the tumor site results in incomplete T-cell activation and transient antitumor effects. To overcome this lack of signal 2, we genetically modified tumor-specific T cells with a costimulatory chimeric antigen receptor (CoCAR). Like classical CARs, CoCARs combine the antigen-binding domain of an antibody with costimulatory endodomains to trigger T-cell proliferation, but CoCARs lack the cytotoxic CD3ζ chain to avoid toxicity to normal tissues. We first tested a CD19-targeting CoCAR in combination with an HLA-A*02:01-restricted, survivin-specific transgenic TCR (sTCR) in serial cocultures with leukemia cells coexpressing the cognate peptide-HLA complex (signal 1) and CD19 (signal 2). The CoCAR enabled sTCR+ T cells to kill tumors over a median of four additional tumor challenges. CoCAR activity depended on CD19 but was maintained in tumors with heterogeneous CD19 expression. In a murine tumor model, sTCR+CoCAR+ T cells improved tumor control and prolonged survival compared with sTCR+ T cells. We further evaluated the CoCAR in Epstein-Barr virus-specific T cells (EBVST). CoCAR-expressing EBVSTs expanded more rapidly than nontransduced EBVSTs and delayed tumor progression in an EBV+ murine lymphoma model. Overall, we demonstrated that the CoCAR can increase the activity of T cells expressing both native and transgenic TCRs and enhance antitumor responses.

Epidermin and gallidermin: Staphylococcal lantibiotics.

The Staphylococcus epidermidis derived epidermin was the first lantibiotic that has been shown to be ribosomally synthesized and posttranslationally modified. Together with gallidermin, produced by Staphylococcus gallinarum, they belong to the large class of cationic antimicrobial peptides (CAMPs) that act against a broad spectrum of Gram-positive bacteria. Here we describe the genetic organization, biosynthesis and modification, excretion, extracellular activation of the modified pre-peptide by proteolytic processing, self-protection of the producer, gene regulation, structure, and the mode of action of gallidermin and epidermin. We also address mechanisms of bacterial tolerance to these lantibiotics and other CAMPs. Particularly gallidermin has a high potential for therapeutic application, as it is active against methicillin-resistant Staphylococcus aureus strains (MRSA) and as it is able to prevent biofilm formation at sublethal concentrations.