Immune Response in Patients With Newly Diagnosed Glioblastoma Multiforme Treated With Intranodal Autologous Tumor Lysate-dendritic Cell Vaccination After Radiation Chemotherapy

Survival

Survival

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Summary

The study investigates how patients with GBM responded to cervical intranodal immunization with autologous tumour lysate-loaded dendritic cells (DCs) after radiation treatment and TMZ. The findings imply that DC immunization in patients with GBM in conjunction with radiation and chemotherapy is possible, safe, and may trigger tumour-specific immune responses.

Patients characteristics

Patients with newly diagnosed GBM confirmed by neuropathology review and have a resected tumour yield ≥8×107 tumour cells, after mechanical and enzymatic digestion of tumour tissue. Patients with a Karnofsky Performance Scale Index of ≥60, and adequate hematologic, hepatic, and renal function.

Methodology

Vaccine preparation
Elutriated monocytes were cultured in AIM-V serum–free media for 9 days with 500 IU/mL granulocyte macrophage colony-stimulating factor and 20 ng/mL IL-4 (day 0, 3, and 6), tumor lysate (1-3 tumor cell equivalents per DC; day 5), and 50 ng/mL tumor necrosis factor α (day 6). Enriched monocytes were cultured in X-Vivo 15 media with 1% heat in- activated autologous serum for 8 days with 1,000 IU/mL granulocyte macrophage colony-stimulating factor and 40 ng/mL IL-4 (day 0, 3, and 6), tumor lysate (1-3 tumor cell equivalents per DC; day 5), and 50 ng/mL tumor necrosis factorα and 1 μg/mL PGE2 (day 7). Freeze-fractured and irradiated tumor lysate was obtained from mechanically and enzymatically treated fresh tissue. Frozen DCs from preparation of vaccine #1, stored in 90% autologous serum and 10% DMSO, were thawed and used for vaccine #2.

Treatment

The total dose of 1×107 DC cells was injected in equal aliquots into 2 bilateral cervical lymph nodes using ultrasound guidance. Evaluable patients received 1 vaccination every 2 weeks on 3 occasions.

Results

Clinical outcomes
The median progression-free survival for the 10 patients was 9.5 months and the median OS was 28 months. All 7 patients with evidence of tumour progression received second-line therapy with a bevacizumab-based regimen. The only adverse event attributed to DC vaccine was grade 2 unilateral neck pain after 1 cervical lymph node vaccine administration in 1 patient that persisted for several weeks.
There were no serious adverse events related to DC vaccination. All patients were alive at 6 months after diagnosis and the 6-month PFS was 90%.
Immunologic response
There was no DTH skin reactivity to autologous tumour pre-vaccination or postvaccination in any patient. Before the treatment no skin reactivity was detected for the control anergy panel in any patient, but after vaccination 2 patients developed a positive skin reaction to Candida.Two weeks after vaccination, an increase in the proportion of CD8+ T memory cells (CD45RO+CCR7−) and in naive B cells (CD19+CD27−). In addition, posttreatment increases in the percent of circulating CD4+TREG cells (CD25 +FoxP3+) but not in the absolute numbers of CD4+TREG cells.

Conclusion

In patients with GBM, immune therapy with DC vaccination after radiation and TMZ resulted in tumour- specific immune responses that were associated with prolonged survival. Our data suggest that DC vaccination in combination with radiation and chemotherapy in patients with GBM is feasible, safe, and may induce tumour-specific immune responses.

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Scientific article publishing date: 9/7/2016

Immucura identifier BSC22_386EN

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