Whole-cell cancer vaccination: from autologous to allogeneic tumor- and dendritic cell-based vaccines

The field of tumor vaccination is currently undergoing a shift in focus, from individualized tailor-made vaccines to more generally applicable vaccine formulations. Although primarily predicated by financial and logistic considerations, stemming from a growing awareness that clinical development for wide-scale application can only be achieved through backing from major pharmaceutical companies, these new approaches are also supported by a growing knowledge of the intricacies and minutiae of antigen presentation and effector T-cell activation. Here, the development of whole-cell tumor and dendritic cell (DC)-based vaccines from an individualized autologous set-up to a more widely applicable allogeneic approach will be discussed as reflected by translational studies carried out over the past two decades at our laboratories and clinics in the vrije universiteit medical center (VUmc) in Amsterdam, The Netherlands

Nuclear receptor NR2F6 inhibition potentiates responses to PD-L1/PD-1 cancer immune checkpoint blockade

Immune checkpoints blockade (ICB) is a viable anti-cancer strategy. Here the authors show that nuclear receptor NR2F6 acts as an immune checkpoint in T cells and, using mouse models and human T cells, they show NR2F6 inhibition might improve current ICB therapy or work as an alternative therapeutic strategy

Peripheral blood IFN-gamma-secreting V alpha 24(+)V beta 11(+) NKT cell numbers are decreased in cancer patients independent of tumor type or tumor load

Natural killer T (NKT) cells are CDld-restricted lvmphoid cells and are characterized by an invariant T-cell receptor, which in humans consists of a V alpha 24 chain paired with a V beta 11 chain. These cells are known for their rapid production of large amounts of cytokines (e.g., IFN-gamma and IL-4), thereby modulating other cells of the immune system such as T cells, Nk cells and dendritic cells. NKT cells have been reported to play important regulatory roles in many immune responses, including antitumor immune responses. Here, we demonstrate an age-dependent decrease in circulating V alpha 24(+)V beta 11(+) NKT cell numbers in both healthy controls and cancer patients and demonstrate that in both groups females have higher NKT cell levels compared to males. In a large group of 120 cancer patients, we show that circulating V alpha 24(+)V beta 11(+) NKT cell numbers are about 50% lower than in age-and gender-matched healthy controls and that this decrease is independent of tumor type or tumor load. This decrease was not restored upon tumor removal by means of surgery or radiotherapy. Even though the percentage of NKT cells that secrete IFN-gamma, as detected by ELISPOT, is normal in cancer patients, the absolute number of circulating IFN-gamma-secreting NKT cells is reduced. Together, our results suggest that the reduced circulating V alpha 24(+)V beta 11(+) NKT cell numbers in cancer patients are not affected by tumor load, but might actually reflect a risk factor for tumor development, e.g., by hampering efficient tumor immunosurveillance. (c) 2005 Wiley-Liss. Inc

Tumor uptake and biodistribution of 89Zirconium-labeled ipilimumab in patients with metastatic melanoma during ipilimumab treatment

Introduction Ipilimumab, a monoclonal antibody targeting CTLA-4, is approved for the treatment of metastatic melanoma and significantly improves overall survival. Because of the high costs and the potential serious toxicity of ipilimumab, it is of great importance to identify biomarkers that correlate with clinical activity and that can be used to select patients who will benefit from CTLA-4 blockade therapy. We hypothesize that patients who do not respond to treatment with ipilimumab have lower drug levels in tumor tissues as compared to patients with a good response to therapy. In addition, we hypothesize that immune related adverse events (irAEs) are associated with high drug levels in the affected tissue. As irAEs usually occur approximately 6-8 weeks after the first injection of ipilimumab, we hypothesize that the drug levels in potentially affected tissues will increase at the second injection. Experimental procedures To visualize in vivo localization of ipilimumab in patients diagnosed with metastatic melanoma, 37 MBq, 10 mg 89Zr-labeled ipilimumab was injected within 2 hours after their first ipilimumab dose (3 mg/kg). Whole body PET/CT scans were obtained at 2h, 72h and 144h post injection and this procedure was repeated three weeks later at the second ipilimumab cycle. Biodistribution and tumor uptake were assessed visually by a nuclear physician. Focal uptake in tumor lesions exceeding local background was determined in volumes of interest (VOI) and SUVpeak values were obtained. Biodistribution was quantified by defining vital organs (i.e. lungs, kidneys, spleen, liver) and calculating mean %ID/kg. Blood was drawn for dosimetry and immunophenotyping at several time points during the trial. Presented here are initial results of the first three patients, up to 29 patients are planned to be included. Results Biodistribution of 89Zr-labeled ipilimumab showed a pattern distinctive for 89Zr-labeled antibodies with uptake in liver and spleen, as well as prolonged circulating antibody in the bloodstream corresponding to the pharmacokinetics of ipilimumab. Visual evaluation confirmed uptake of 89Zr-labeled ipilimumab in 5/12 evaluable tumor lesions, visible at both first and second injection of ipilimumab. Tumor uptake was comparable for 72h and 144h post injection with a mean of 6.9 %ID/kg (range 3.3-10.1) and a SUVpeak of 4.4 (range 2.3-8.9). There were no significant differences in tumor uptake between first and second dose of ipilimumab (mean 7.31 and 6.54 %ID/kg respectively). Conclusions Preliminary data of this ongoing study showed that the tracer is able to visualize and quantify uptake of ipilimumab in tumors. Correlations between tumor uptake and response to treatment will be presented. Furthermore, special interest will be given to uptake in lymphoid organs and locations for irAEs