MV-NIS is an oncolytic measles virus encoding the human thyroidal sodium iodide symporter (NIS).Here, we report the results of preclinical pharmacology and toxicology studies conducted in support of our clinical protocol "Phase I Trial of Systemic Administration of Edmonston Strain of Measles Virus, Genetically Engineered to Express NIS, with or without Cyclophosphamide, in Patients with Recurrent or Refractory Multiple Myeloma." Dose-response studies in the KAS-6/1 myeloma xenograft model demonstrated a minimum effective dose of 4 × 10 6 TCID 50 (tissue culture infectious dose 50)/kg. Toxicity studies in measles-naive squirrel monkeys and measles-susceptible transgenic mice were negative at intravenous doses up to 10 8 and 4 × 10 8 TCID 50 /kg, respectively. Abundant viral mRNA, maximal on day 8, was detected in cheek swabs of squirrel monkeys, more so after pretreatment with cyclophosphamide. On the basis of these data, the safe starting dose of MV-NIS for our clinical protocol was set at 1 -2 × 10 4 TCID 50 /kg (10 6 TCID 50 per patient).Measles virus (MV, family Paramyxoviridae) was isolated in 1954 from the throat washings of a measles patient, David Edmonston. 1 Tissue culture passage resulted in loss of pathogenicity and attenuation of wild-type MV (Figure 1), giving rise to the Edmonston measles vaccines used worldwide today. 2 We recently discovered that attenuated Edmonston strain MV has potent antitumor activity in vitro and in vivo. 3 Intravenous, intratumoral, or intraperitoneal administration of the virus inhibited tumor growth or induced tumor regression in a variety of human tumor xenograft models. [4][5][6][7] To tailor the virus for cancer therapy, we Correspondence: SJ Russell (sjr@mayo.edu). CONFLICT OF INTERESTThe authors declared no conflict of interest. NIH Public Access Author ManuscriptClin Pharmacol Ther. Author manuscript; available in PMC 2009 October 28. Published in final edited form as:Clin Pharmacol Ther. 2007 December ; 82(6): 700-710. doi:10.1038/sj.clpt.6100409. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscripthave genetically engineered the viral coat protein to display tumor-targeting ligands to enable tumor-specific killing or inserted trackable transgenes into the viral genome to enable noninvasive monitoring of viral gene expression. [8][9][10][11][12] MV-NIS is an Edmonston-lineage MV that expresses the human sodium iodide symporter (hNIS) (Figure 2). 12 The NIS protein is normally expressed in the thyroid, mammary glands, stomach, and salivary tissue. Expression of NIS allows cells to actively transport iodide ions into the cell. Thus, patients with thyroid cancer are typically treated with 131 I to destroy the NIS-expressing thyroid cancer while leaving most normal tissues undamaged. 13 Loss of thyroid function due to the radiotherapy can be treated by replacement therapy with synthetic thyroid hormones. Insertion of NIS into MV facilitates pharmacokinetic evaluation and enhancement of MV oncolytic activity. MV-NIS-infected cells express...

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Chimeric antigen receptor modified (CAR) T cells targeting CD19 have mediated dramatic responses in relapsed or refractory acute lymphoblastic leukemia (ALL), yet a notable number of patients have CD19-positive relapse within one year of treatment. It remains unclear if the long-term response is associated with the characteristics of CAR T cells in infusion products, hindering the identification of biomarkers to predict therapeutic outcomes prior to treatment. Herein we present 101,326 single cell transcriptomes and surface protein landscape from the CAR T infusion products of 12 pediatric ALL patients upon CAR antigen-specific stimulation in comparison with TCR mediated activation and controls. We observed substantial heterogeneity in the antigen-specific activation states, among which a deficiency of Th2 function was associated with CD19 positive relapsed patients (median remission 9.6 months) compared with very durable responders (remission over 54 months). Proteomic profiles also revealed that the frequency of early memory T cell subsets, rather than activation or co-inhibitory signatures could distinguish CD19-positive relapse. Additionally, a deficit of type 1 helper and cytotoxic effector function and an enrichment for terminally differentiated CD8+ T cells exhibiting low cytokine polyfunctionality was associated with initial non-responders. By contrast, the single-cell transcriptomic data of unstimulated or TCR-activated CAR T cells failed to predict clinical responses. In aggregate, our results dissect the landscape of CAR-specific activation states in infusion products that can identify patients who do not develop a durable response to the therapy, and unveil the molecular mechanisms that may inform strategies to boost specific T cell function to maintain long term remission.