gms | German Medical Science

Objective: Mesenchymal stem cells (MSC) show an inherent brain tumor cell tropism that can be exploited for targeted delivery of therapeutic genes to invasive glioma. We assessed whether a motile stem cell-based local immunmodulation is able to overcome the immunosuppressive GBM microenvironment and to induce an antitumor immune response.

Methods: MSC from C57BL6 mice were genetically modified to stably co-express murine IL-12 and IL-7 (MSC-IL12/7). Therapeutic effects of intratumoral application (4x105 cells) were tested in the syngeneic orthotopic GL261/C57BL6 mouse model for glioblastoma at day 5 (d5) or day 10 (d10) after GL261 injection. Control groups received either PBS or MSC-GFP. Therapeutic efficiency was determined by survival and assessment of tumor size by 7T MRI at day 18 and during follow-up (n=40). In order to confirm tumor immunity, survivors were re-challenged by an additional intracerebral GL261 injection. Immunmodulatory effects were assessed in a separate experiment by immunhistology and flow-cytometry at different time points to comprehensively profile immune activation of tumor-infiltrating lymphocytes and peripheral blood lymphocytes (n=40).

Results: Intratumoral administration of MSC-IL12/7 at day 5 or day 10 induced a significant tumor growth inhibition with median tumor volumes of 5.1 (d5) and 5.0 mm3 (d10) at day 20 compared to controls with 52.2 (MSC-GFP) and 37.5 mm3 (PBS). Treated tumors displayed more intratumoral T2-hypointensities, suspicious for necrotic tumor destruction (p<0.05). MSC-IL12/7 treatment led to prolongation of median survival (p<0.001, d5: 40.5, d10: 75, PBS: 22, MSC-GFP: 22 days) with 30% (d5) and 50% (d10) long-term survivors (>100 days). MRI in long-term survivors did not reveal any tumor mass and demonstrated a clear tumor regression when compared with the initial MRI. Tumor immunity was confirmed by re-challenging survivors with intracerebral injection of GL261. Whereas new control animals died as expected, re-challenged animals survived without any signs of tumor growth on MRI. Local treatment with MSC-IL12/7 was well tolerated and led to a predominantly CD8+ T-cell mediated anti-tumor response.

Conclusion: The MSC-based delivery of immunmodulatory cytokines is able to efficiently alter the immunosupressive microenvironment in an orthototopic glioblastoma model. The significant and long lasting therapeutic effects warrant a rapid clinical translation of this concept.