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<jats:title>Abstract</jats:title><jats:p>CRISPR systems are widespread in the prokaryotic world, providing adaptive immunity against mobile genetic elements<jats:sup>1,2</jats:sup>. Type III CRISPR systems, with the signature gene <jats:italic>cas10</jats:italic>, use CRISPR RNA to detect non-self RNA, activating the enzymatic Cas10 subunit to defend the cell against mobile genetic elements either directly, via the integral histidine–aspartate (HD) nuclease domain<jats:sup>3–5</jats:sup> or indirectly, via synthesis of cyclic oligoadenylate second messengers to activate diverse ancillary effectors<jats:sup>6–9</jats:sup>. A subset of type III CRISPR systems encode an uncharacterized CorA-family membrane protein and an associated NrN family phosphodiesterase that are predicted to function in antiviral defence. Here we demonstrate that the CorA-associated type III-B (Cmr) CRISPR system from <jats:italic>Bacteroides fragilis</jats:italic> provides immunity against mobile genetic elements when expressed in <jats:italic>Escherichia coli</jats:italic>. However, <jats:italic>B. fragilis</jats:italic> Cmr does not synthesize cyclic oligoadenylate species on activation, instead generating <jats:italic>S</jats:italic>-adenosyl methionine (SAM)-AMP (SAM is also known as AdoMet) by conjugating ATP to SAM via a phosphodiester bond. Once synthesized, SAM-AMP binds to the CorA effector, presumably leading to cell dormancy or death by disruption of the membrane integrity. SAM-AMP is degraded by CRISPR-associated phosphodiesterases or a SAM-AMP lyase, potentially providing an ‘off switch’ analogous to cyclic oligoadenylate-specific ring nucleases<jats:sup>10</jats:sup>. SAM-AMP thus represents a new class of second messenger for antiviral signalling, which may function in different roles in diverse cellular contexts.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Immunotherapy failures can result from the highly suppressive tumour microenvironment that characterizes aggressive forms of cancer such as recurrent glioblastoma (rGBM)<jats:sup>1,2</jats:sup>. Here we report the results of a first-in-human phase I trial in 41 patients with rGBM who were injected with CAN-3110—an oncolytic herpes virus (oHSV)<jats:sup>3</jats:sup>. In contrast to other clinical oHSVs, CAN-3110 retains the viral neurovirulence <jats:italic>ICP34.5 </jats:italic>gene transcribed by a nestin promoter; nestin is overexpressed in GBM and other invasive tumours, but not in the adult brain or healthy differentiated tissue<jats:sup>4</jats:sup>. These modifications confer CAN-3110 with preferential tumour replication. No dose-limiting toxicities were encountered. Positive HSV1 serology was significantly associated with both improved survival and clearance of CAN-3110 from injected tumours. Survival after treatment, particularly in individuals seropositive for HSV1, was significantly associated with (1) changes in tumour/PBMC T cell counts and clonal diversity, (2) peripheral expansion/contraction of specific T cell clonotypes; and (3) tumour transcriptomic signatures of immune activation. These results provide human validation that intralesional oHSV treatment enhances anticancer immune responses even in immunosuppressive tumour microenvironments, particularly in individuals with cognate serology to the injected virus. This provides a biological rationale for use of this oncolytic modality in cancers that are otherwise unresponsive to immunotherapy (ClinicalTrials.gov: <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT03152318">NCT03152318</jats:ext-link>).</jats:p>