Oncolytic viruses exert an anti-tumour effect through two mechanisms: direct oncolytic and indirect immune-mediated mechanisms. Although oncolytic herpes simplex virus type 1 (HSV-1) has been approved for melanoma treatment and is being examined for its applicability to a broad spectrum of malignancies, it is not known whether it has an anti-myeloma effect. In the present study, we show that the third-generation oncolytic HSV-1, T-01, had a direct oncolytic effect on five of six human myeloma cell lines in vitro. The anti-tumour effect was enhanced in the presence of peripheral blood mononuclear cells (PBMCs) from healthy individuals and, to a lesser extent, from patients with myeloma. The enhancing effect of PBMCs was abrogated by blocking type I interferons (IFNs) or by depleting plasmacytoid dendritic cells (pDCs) or natural killer (NK) cells, suggesting that pDC-derived type I IFNs and NK cells dominated the anti-tumour effect. Furthermore, the combination of T-01 and lenalidomide exhibited enhanced cytotoxicity, and the triple combination of T-01, lenalidomide and IFN-a had a maximal effect. These data indicate that oncolytic HSV-1 represents a viable therapy for plasma cell neoplasms through direct oncolysis and immune activation governed by pDCs and NK cells. Lenalidomide is likely to augment the anti-myeloma effect of HSV-1.
Background: Comorbidity may influence the treatment and long-term quality of life of chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs). The Charlson Comorbidity Index (CCI) assesses comorbidity by taking into account the severity of 19 precedent comorbid conditions [J Chron Dis 1987; 40: 373]. The CCI was originally introduced as a measure of the mortality risk of general hospitalized patients, and it can estimate the risk of morbidity in a patient with any medical background. The CCI has been validated to predict patients' life expectancy in various underlying diseases, and it is widely used for both hospitalized patients and outpatients. We evaluated the risk of comorbidity at the diagnosis of CML to determine whether treatment with tyrosine kinase inhibitors (TKIs) results in longer survival in a cohort of Japanese patients. Patients and method: We used a chart review to survey CML patients diagnosed between November 2001 and December 2012 in Kagawa, Japan, where we collected all of the patients based on their registration in another population-based study. Inclusion criteria were (1) diagnosis of CML in the chronic phase during the study period and (2) treatment by TKIs at any point of the study period. Patients of all ages were included. The available TKIs were imatinib, nilotinib and dasatinib. We did not exclude patients treated with two or more TKIs. We used the CCI to evaluate concomitant underlying disease at diagnosis, and we calculated the Sokal and Hasford scores to compare the predictability of prognosis with the CCI at diagnosis. We used the Sokal and Hasford scores as the standard reference. Results: Eighty (47 male, 33 female) cases were enrolled (median age 56 yrs, range 6-89 yrs). The distribution of CCI scores at diagnosis were 2-11 (median 2). The initial treatment was started in 73 cases by imatinib, two cases by nilotinib, and four by dasatinib (one is unknown). Only one patient underwent stem cell transplantation after 2-yr treatment by imatinib, because of the development of myelodysplastic syndrome (this case was not censored.) As of the last follow-up, the treatment responses were 46 major molecular responses (MMRs), 12 complete cytogenetic responses (CCyRs) and 14 complete hematological responses (CHRs). Seventy-five percent of the cases (60/80) achieved CCyR at 12 mos after TKI administration. We observed only five deaths during the 55.5-mos median follow-up period (0.3-217 mos; 3 pneumonia, 1 cancer and 1 unknown cause). The number of patients according to the given CCI comorbidity risk categories are presented in Table 1. The patient numbers in the risk categories (low/intermediate/high) per the Sokal and Hasford scores were 33/27/7 and 21/43/3, respectively. The CCI scores were significantly correlated with the Sokal and Hasford scores (R >0.5). Twenty-seven cases with a CCI score ≥3 (52 cases had CCI <2) had significantly poor survival both from diagnosis (log rank, P=0.0136) and from TKI treatment (P =0.0025). The most common CCI comorbidity factor was 'diabetes without organ failure.' The most serious comorbidity was 'metastatic cancer,' seen in four cases. CCI scores were inversely associated with overall survival (R = −0.11). Discussion: In CML, concomitant comorbidity at diagnosis is more strongly associated with survival, especially after TKI treatment compared to after diagnosis. This suggests that TKI treatment may influence patients' health conditions by contributing to the induction of adverse events. Thus, the clinical impact of CCI for CML patients treated with TKIs is supplemental, but CCI is useful to take care of the patient. Table 1. Numbers of patients according to the given comorbidity risk categories of CCI A. Myocardial Infarction (1 point) 1 B. Congestive Heart Failure (1 point) 3 C. Peripheral Vascular Disease (1 point) 1 D. Cerebrovascular Disease (1 point) 1 E. Dementia (1 point) 5 F. COPD (1 point) 4 G. Connective Tissue Disease (1 point) 1 H. Peptic Ulcer Disease (1 point) 2 I. Diabetes Mellitus (1 point uncomplicated, 2 points if end-organ damage) 7 and 2 J. Moderate to Severe Chronic Kidney Disease (2 points) 2 K. Hemiplegia (2 points) 1 L. Leukemia (2 points) 80 M. Malignant Lymphoma (2 points) 0 N. Solid Tumor (2 points, 6 points if metastatic) 2 and 3 O. Liver Disease (1 point mild, 3 points if moderate to severe) 3 and 0 P. AIDS (6 points) 0 Disclosures No relevant conflicts of interest to declare.
Background: Oncolytic virus (OV) is an attractive and rapidly developing antitumor therapy. OVs preferentially replicate in tumor cells and exhibit a tumoricidal activity without damaging normal cells. G47Δ is a herpes simplex virus (HSV)-1 genetically engineered to enhance tumor selectivity and immunogenicity. Clinical trials of G47Δ have been conducted for brain and prostate cancers. Anecdotal reports that leukemia and lymphoma shrink following viral infection imply effectiveness of OV therapy against hematological malignancies. Aim: We examined whether G47Δ has the potential for treatment of hematological malignancies. Methods: T-01, an HSV-1 containing modification in the same genes as G47Δ, was used in this study. To assess T-01 infectivity and cytotoxicity for hematological tumor cells, cell lines and clinical samples were incubated with the virus. T-GFP, T-01 containing the GFP gene, was used to quantify the viral infectivity. To examine antitumor activity in vivo, we injected T-01 into subcutaneously inoculated tumors in immunodeficient SCID-Beige mice. To identify the differences between T-01-susceptible and resistant cells, we examined the involvement of HSV entry receptors (nectin-1, HVEM, PILRα, non-muscle myosin IIA and IIB) and antiviral molecules (cGAS-STING and PKR-eIF2α pathways). Jurkat and THP-1 cell lines were infected with the lentivirus vector expressing shRNA against nectin-1. Ramos and RL-male-1 (murine leukemia) cell lines were infected with the lentivirus vector expressing human nectin-1. Results: 15 of 21 cell lines from T-, B-, and myeloid-derived hematological malignancies were infected and killed by T-01. 8 of 15 clinical samples were also killed by T-01, and all the susceptible samples were from relapsed patients. Growth of the subcutaneous GRANTA-519 and ED-40515 (ATL cell line) tumors was significantly suppressed by intratumor injection of T-01. The expression level of nectin-1, the amount of viral entry, and the cytotoxicity were positively correlated in cell lines and clinical samples (Figure 1). In agreement with this, knockdown of nectin-1 decreased the amount of viral entry, and overexpression of nectin-1 induced cytotoxicity by T-01 (Figure 2). In contrast, there was no correlation between the expression levels of the antiviral molecules and the cytotoxicity. Conclusion: Oncolytic HSV-1 has the potential for treatment of relapsed hematological malignancies. Entry via nectin-1 is a determining factor of susceptibility to oncolytic HSV-1 for hematological malignancies. Nectin-1 may be useful as a biomarker for efficacy of G47Δ. Disclosures Takaori-Kondo: Bristol-Myers Squibb: Honoraria, Research Funding; Ono: Research Funding; Takeda: Research Funding; Kyowa Kirin: Research Funding; Chugai: Research Funding; Janssen: Honoraria; Pfizer: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Honoraria. Kadowaki:Takeda Pharmaceutical Company Ltd.: Honoraria, Research Funding; Taiho Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria, Research Funding; Bristol-Myers Squibb Company: Honoraria, Research Funding; Asahi Kasei Pharma Corporation: Honoraria, Research Funding; Astellas Pharma Inc.: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Daiichi Sankyo Company Ltd.: Honoraria, Research Funding; Eisai Co., Ltd.: Honoraria, Research Funding; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding; Merck & Co., Inc.: Honoraria, Research Funding; Ono Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Novartis AG: Honoraria, Research Funding; Pfizer Japan Inc.: Honoraria, Research Funding.
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