Varicella Zoster Meningitis, Optic Neuritis Preceding the Development of Posterior Outer Retinal Necrosis, and Central Retinal Artery Occlusion in a HIV Patient

Varicella-zoster virus (VZV) has been known to cause various eye disorders in both immunocompetent and immunocompromised patients. We present a case of a forty-nine-year-old female patient with acquired immunodeficiency syndrome (AIDS) who presented with headache, fever, and blurred vision. Cerebrospinal fluid (CSF) analysis was consistent with VZV meningitis. Magnetic resonance imaging (MRI) of the brain showed enhancement of the right optic nerve indicative of optic neuritis. She responded well to acyclovir and steroids and discharged on the same. Four weeks after discharge, she presented with sudden onset blindness in the left eye. A cerebral angiogram revealed left retinal artery occlusion and was treated with tissue plasminogen activator (tPA). Funduscopic examination showed patchy areas of necrosis in the periphery which were rapidly progressive, diagnostic of posterior outer retinal necrosis (PORN). She was started on ganciclovir and cidofovir and experienced significant improvement in her visual acuity

Non-viral precision T cell receptor replacement for personalized cell therapy.

The T cell receptor (TCR) provides the fine specificity of T cells to recognize mutations in cancer cells 1-3. We developed a clinical-grade approach based on CRISPR/Cas9 non-viral precision genome editing to simultaneously knock-out the two endogenous TCR genes, TCRα (TRAC) and TCRβ (TRBC), and insert in the TRAC locus the two chains of a neoantigen-specific TCR (neoTCR), isolated from the patient\u27s own circulating T cells using a personalized library of soluble predicted neoantigen-HLA capture reagents. Sixteen patients with refractory solid cancers received up to three distinct neoTCR-transgenic cell products, each expressing a patient-specific neoTCR, in a cell dose-escalation, first-in-human phase 1 clinical trial (NCT03970382). One patient had grade 1 cytokine release syndrome, and one grade 3 encephalitis. All had the expected side effects from the lymphodepleting chemotherapy. Five patients had stable disease, and the other 11 had disease progression as best response on therapy. NeoTCR-transgenic T cells were detected in tumour biopsies post-infusion at frequencies higher than the native TCRs pre-infusion. This study demonstrates the feasibility of isolating and cloning multiple TCRs recognizing mutational neoantigens, the simultaneous knock-out of the endogenous TCR and knock-in of the neoTCRs using single-step, non-viral precision genome editing, the manufacturing of neoTCR engineered T cells at clinical grade, the safety of infusing up to three gene edited neoTCR T cell products, and the ability of the transgenic T cells to traffic to the patients\u27 tumours