Seong-Geun Kim

Oncolytic and Immunotherapeutic Vaccinia Induces Antibody-Mediated Complement-Dependent Cancer Cell Lysis in Humans

The oncolytic and immunotherapeutic vaccinia virus Pexa-Vec (JX-594) induces antibody-mediated complement-dependent cancer cell cytolysis in rabbits and cancer patients, prolonging their survival. The Enemy of My Enemy Is My Friend: Virotherapy for Cancer Oncolytic viruses, which can kill cancer cells directly and by stimulating the patient’s immune system, have some clear advantages over other immune approaches to cancer treatment. They do not induce autoimmunity, they do not have to be custom-made for each patient, and they are not specific to tumors that express a particular antigen. Previous works with these viruses have shown promising results, and some of them are now in clinical trials. However, the steps by which these viruses exert their effects against the cancer cells in animals and humans are not yet fully understood. Now, the work by Kim et al. uncovers some of the mechanism for the action of Pexa-Vec, a vaccinia virus–derived oncolytic vaccine, which is already being tested in patients with multiple types of advanced cancers. In a rabbit model of squamous cell carcinoma, the authors demonstrated the induction of antibody-mediated complement-dependent cytotoxicity (CDC) after treatment with Pexa-Vec. The resulting antitumor activity could be transferred from one rabbit to another by transferring serum, even long after the virus was administered and then cleared from the blood, providing additional evidence for the role of antibodies. Serum from human patients treated with Pexa-Vec also induced CDC against cancer cells, primarily against cancer of the same type. For example, serum from a renal cancer patient treated with the virus was most effective at triggering CDC against renal cancer cells, consistent with a specific antibody-mediated process. The ability of each patient’s serum to induce CDC against cultured cancer cells correlated with that patient’s survival. Larger trials in human patients will be required to confirm the pilot study results presented here and build on the current understanding of oncolytic virotherapy and the role of CDC. In addition, further studies will need to investigate the role of other immune mechanisms, such as cell-mediated immunity, in the effects of oncolytic virus vaccines. In the meantime, the current study highlights the role of Pexa-Vec in the induction of antitumor CDC and shows its effects on survival, even in patients with late-stage cancer who have few other options. Oncolytic viruses cause direct cytolysis and cancer-specific immunity in preclinical models. The goal of this study was to demonstrate induction of functional anticancer immunity that can lyse target cancer cells in humans. Pexa-Vec (pexastimogene devacirepvec; JX-594) is a targeted oncolytic and immunotherapeutic vaccinia virus engineered to express human granulocyte-macrophage colony-stimulating factor (GM-CSF). Pexa-Vec demonstrated replication, GM-CSF expression, and tumor responses in previous phase 1 trials. We now evaluated whether Pexa-Vec induced functional anticancer immunity both in the rabbit VX2 tumor model and in patients with diverse solid tumor types in phase 1. Antibody-mediated complement-dependent cancer cell cytotoxicity (CDC) was induced by intravenous Pexa-Vec in rabbits; transfer of serum from Pexa-Vec–treated animals to tumor-bearing animals resulted in tumor necrosis and improved survival. In patients with diverse tumor types treated on a phase 1 trial, CDC developed within 4 to 8 weeks in most patients; normal cells were resistant to the cytotoxic effects. T lymphocyte activation in patients was evidenced by antibody class switching. We determined that patients with the longest survival duration had the highest CDC activity, and identified candidate target tumor cell antigens. Thus, we demonstrated that Pexa-Vec induced polyclonal antibody–mediated CDC against multiple tumor antigens both in rabbits and in patients with diverse solid tumor types.

High total metabolic tumor volume in PET/CT predicts worse prognosis in diffuse large B cell lymphoma patients with bone marrow involvement in rituximab era.

Bone marrow involvement (BMI) in diffuse large B cell lymphoma (DLBCL) was naively regarded as an adverse clinical factor. However, it has been unknown which factor would separate clinical outcomes in DLBCL patients with BMI. Recently, metabolic tumor volume (MTV) on positron emission tomography/computed tomography (PET/CT) was suggested to predict prognosis in several lymphoma types. Therefore, we investigated whether MTV would separate the outcomes in DLBCL patients with BMI. MTV on PET/CT was defined as an initial tumor burden as target lesion ≥ standard uptake value, 2.5 in 107 patients with BMI. Intramedullary (IM) MTV was defined as extent of BMI and total MTV was as whole tumor burden. 260.5 cm(3) and 601.2 cm(3) were ideal cut-off values for dividing high and low MTV status in the IM and total lymphoma lesions in Receiver Operating Curve analysis. High risk NCCN-IPI (p<0.001, p<0.001), bulky disease (p=0.011, p=0.005), concordant subtype (p=0.025, p=0.029), high IM MTV status (p<0.001, p<0.001), high total MTV status (p<0.001, p<0.001), and ≥ 2CAs in BM (p=0.037, p=0.033) were significantly associated with progression-free survival (PFS) and overall survival (OS) than other groups. In multivariate analysis, high risk NCCN-IPI (PFS, p=0.006; OS, p=0.013), concordant subtype (PFS, p=0.005; OS, p=0.007), and high total MTV status (PFS, p<0.001; OS, p<0.001) had independent clinical impacts. MTV had prognostic significances for survivals in DLBCL with BMI.

Mean cell volume can be an early predictor for the cytogenetic response of chronic myeloid leukemia patients treated with imatinib

Imatinib-induced macrocytic anemia was known to result from c-kit inhibition in chronic myeloid leukemia (CML). However, recent studies showed that the prevalence of anemia is increased with high trough imatinib level and increased doses of imatinib influence decreased proliferation of burst forming units-erythroids (BFU-Es). The aim of this study was to evaluate the continuously increased mean cell volume (MCV) levels correlation with cytogenetic response and the favorable outcome in early chronic phase (CP)-CML patients. Clinical importance of MCV level was evaluated to correlate with cytogenetic response and compared with Sokal score, a known excellent prognostic parameter of cytogenetic response (CCR) in 84 early CP-CML patients. The patients with early and continuously increased MCV level irrespective of anemia achieved higher CCR after 12 months of imatinib therapy than patients with non-CCR (p=0.011). When the value was compared with low Sokal score, elevated MCV was independent predictor of CCR (RR=12.925, p=0.002 vs. RR=35.445, p<0.001). Furthermore, the patients with early and continuously increased MCV level had a higher probability of maintaining CCR than non-increased level (p=0.019). Increased MCV level was surrogate marker of achievement and durability to CCR for early CP-CML patients in the present study.

Effects of low level laser therapy (LLLT) on pressured human osteoblasts: A histomorphologic and quantitative study

Previous research has investigated the effects of LLLT during titanium implantation, tooth movement and bone graft using deproteinized bovine bone and recognized that these circumstances were nothing more than intentional controlled overpressure against static cells since this controlled trauma could affect cell function/malfunction, or cell recovery/apoptosis. The present preliminary study was conducted to prove if LLL would influence cell viability and cell function after excessive damage, which is enough to diminish cell numbers and distort the features of cells. Our aim is to evaluate whether low level laser irradiation (LLLi) could be helpful in the recovery of traumatized osteoblasts (pressure damaged cells) by observing the morphology and the survival rate of those cells. This model used bone cell cultures which were traumatized by a pressure with 250 G of centripetal force and observed their response to such trauma and low level laser irradiation. In this experiment, a Ga-Al-As diode LLL (IMPRA-ORT, NDLux, Seoul, KOREA) was used with a wavelength of 808 nm, a focus of 14 × 24 mm, which was wide enough to cover the whole dish surface or well within at least 2 times radiation, and an output of 100 mW. Statistical analysis showed a higher recovery rate of damaged osteoblasts in the radiation group than the non-radiation group (p < 0.05). The nonradiation group had a very poor proliferation rate in comparison to the control group (p < 0.05) in every time period. In the control group, actin filaments showed a random orientation and cell process branched variously around each cell. In contrast, compressed cells, these patterns were turned into thicker and shorter cytoskeletons. As time progressed, every living cell recovered from the severe stress and recovered both form and function. In summary, the present study showed the capacity of LLLT to aid the recovery of the cell skeleton and affect cell viability on overpressured osteoblasts. These results may contribute toward a better understanding of the effect of LLLT on the recovery of cells after trauma. In addition, our results demonstrated that LLLT could be used in the field of bone tissue engineering to traumatized bone conditions and repair large bone defects such as bone graft and implant installation.

Reversible Cerebellar Ataxia Related to Extrapontine Myelinolysis without Hyponatremia after Cisplatin-Based Chemotherapy for Cholangiocarcinoma

A 60-year-old woman presented with cerebellar signs including dysarthria and ataxia, after intravenous infusion of cisplatin-based chemotherapy. Several blood tests showed mild neutropenia, normocytic normochromic anemia, but no evidence of a marked hyponatremia. Brain magnetic resonance imaging with diffusion-weighted sequences showed hyper-intense signal abnormalities in the extrapontine region, sparing the basis pontis. Here, we report on the case of a patient with reversible cerebellar ataxia related to extrapontine myelinolysis without hyponatremia after treatment with cisplatin-based chemotherapy for cholangiocarcinoma and discuss the literature on cerebellar ataxia in patients who underwent recent chemotherapy for malignancy.