Glioblastoma

Example 1

Three patients with recurrent glioblastoma were treated with L19-TNFα at a dose level of 10 μg/kg. Already twenty-four hours after the infusion, a decrease in overall tumor perfusion and an emerging tumor necrosis was detected, as shown in FIG. 1A. One patient had progressive disease after three months and two patients still have stable disease with an increasing area of necrosis in the tumor region at six months after treatment. This is surprising considering that the Progression Free Survival (PFS) for recurrent glioblastoma is 1.5 months.

The patient with progressive disease underwent re-section and the tissue from this surgery, i.e. after treatment with L19-TNFα, was compared with the tissue obtained during first surgery. By immunohistochemistry, a significant increase in tumor-infiltrating CD4 and CD8 T-cells in the tumor after L19-TNFα treatment was detected. Furthermore, increased levels of cleaved caspase-3 were found suggesting a higher number of dead tumor cells, as shown in FIG. 1B. These data demonstrate the in situ activation due to the targeted delivery of TNF.

Example 7

To perform PLA with PDX samples, the glioblastoma patient derived FFPE samples were used (provided by Samsung Seoul hospital in Seoul, Korea). After FFPE sample were de-paraffinized and performed heat induced antigen retrieval for 15 minutes at 100° C. Slides were blocked with blocking solution provided by Duolink and incubated with rabbit anti-CXCR4 (1:200, Thermoscientific, PA3305), mouse anti-ADRB2 (1:200, Santacruz, Sc-271322), at 37° C. for 1 h in a humidifying chamber. The other process was same as described above (PLA with PDC).

In the FIG. 15A, nuclei were visualized with DAPI staining, and CXCR4-ADRB4 heteromers were stained with PLA as small dots. As shown in FIG. 15B, PLA ratio is different according to the patient and based on this result, indicating that it is possible to perform personalized medicine by the companion diagnostics.

Example 10

Radiation is an effective treatment for glioblastoma. But tumor resistance and recurrence develops in all patients.

A panel of GBM PDCLs, see Example 9, were chosen for evaluation of the combination of TG02 and radiation therapy for the treatment of glioblastoma (FIG. 31). Cells were treated first with TG02 at increasing concentrations. Within 30 minutes, cells were treated with increasing doses of radiation and cell proliferation was measured 72 hours post-treatment. TG02 alone had anti-proliferative activity in these cell lines. The addition of TG02 augmented the effects radiation in a synergistic manner. The combination of TG02 and radiation exceeds the Bliss predicted model (greater than a 10% change from the Bliss predicted model), demonstrating synergy between TG02 and radiation in multiple PDCLs.