Therapeutic efficacy of PD1/PDL1 blockade in B16 melanoma is greatly enhanced by immunization with dendritic cell-targeting lentiviral vector and protein vaccine.

While immune checkpoint inhibition is rapidly becoming standard of care in many solid tumors, immune checkpoint inhibitors (ICIs) fail to induce clinical responses in many patients, presumably due to insufficient numbers of tumor-specific T cells in the tumor milieu. To this end, immunization protocols using viral vectors expressing tumor-associated antigens are being explored to induce T cell responses that synergize with ICIs. However, the optimal combination of vaccine and immune checkpoint regimen remains undefined. Here, a dendritic cell-targeting lentiviral vector (ZVex®) expressing the endogenous murine tyrosinase-related protein 1 (mTRP1), or the human tumor antigen NY-ESO-1, was explored as monotherapy or heterologous prime-boost (HPB) vaccine regimen together with recombinant tumor antigen in the murine B16 melanoma model. PD1/PDL1 blockade significantly enhanced ZVex/mTRP1, but not ZVex/NY-ESO-1, induced immune responses in mice, whereas the opposite effect was observed with anti-CTLA4 antibody. Anti-tumor efficacy of anti-PD1, but not anti-PDL1 or anti-CTLA4, was significantly enhanced by ZVex/mTRP1 and HPB vaccination. These results suggest mechanistic differences in the effect of checkpoint blockade on vaccine-induced immune and anti-tumor responses against self versus non-self tumor antigens, possibly due to tolerance and state of exhaustion of anti-tumor T cells.

LV305, a dendritic cell-targeting integration-deficient ZVex(TM)-based lentiviral vector encoding NY-ESO-1, induces potent anti-tumor immune response.

We have engineered an integration-deficient lentiviral vector, LV305, to deliver the tumor antigen NY-ESO-1 to human dendritic cells in vivo through pseudotyping with a modified Sindbis virus envelop protein. Mice immunized once with LV305 developed strong, dose-dependent, multifunctional, and cytotoxic NY-ESO-1-specific cluster of differentiation 8 (CD8) T cells within 14 days post-immunization and could be boosted with LV305 at least twice to recall peak-level CD8 T-cell responses. Immunization with LV305 protected mice against tumor growth in an NY-ESO-1-expressing CT26 lung metastasis model, with the protective effect abrogated upon depletion of CD8 T cells. Adoptive transfer of CD8 T cells, alone or together with CD4 T cells or natural killer cells, from LV305-immunized donor mice to tumor-bearing recipient mice conferred significant protection against metastatic tumor growth. Biodistribution of injected LV305 in mice was limited to the site of injection and the draining lymph node, and injected LV305 exhibited minimal excretion. Mice injected with LV305 developed little to no adverse effects, as evaluated by toxicology studies adherent to good laboratory practices. Taken together, these data support the development of LV305 as a clinical candidate for treatment against tumors expressing NY-ESO-1.

Fetal blood sampling in labour and the decision to delivery interval.

OBJECTIVE: To determine the time interval from decision to result for fetal blood sampling (FBS) and the time from an abnormal pH result to delivery of the neonate. STUDY DESIGN: A prospective study of 107 consecutive attempts at FBS on 72 out of 1450 patients in labour from 1st April 2006 to 1st August 2006 at St James University Hospital in Leeds, England. Statistical analysis was performed by using nonparametric tests. RESULTS: 107 attempts at FBS on 72 cases were reviewed. Overall the median time from decision to the result of FBS was 17min (interquartile range: 11-22min). 27% (19/70) of fetuses had abnormal results and the median time from result to delivery was 21min (interquartile range: 16-25min) in these cases. The median time from decision to perform FBS to delivery was 37min in cases where acidaemia was present. Body mass index (BMI) cervical dilatation and grade of operator were the factors which affected median time from decision to the result of FBS. CONCLUSION: The time from decision to the result of FBS should be considered in the delivery decision-making process in cases complicated by suspected fetal compromise.