Targeted alpha therapy of glioblastoma multiforme: First clinical experience with ²¹³Bi-substance P

Objectives Glioblastoma multiforme (GBM) has a very poor prognosis with a median overall survival of 15 months despite of aggressive therapy including surgery, chemotherapy and radiation therapy. Targeted alpha therapy with the short range, high LET alpha emitter ²¹³Bi offers the potential for selective irradiation of tumors, while minimizing damage to adjacent, functional critical areas of the brain. The peptide carrier substance P is targeting NK 1 receptors, which are consistently over-expressed on GBM cells. We report the first clinical experience with ²¹³Bi-labeled DOTA-Substance P (²¹³Bi-SP) in patients with recurrent GBM.

Methods Patients with histologically confirmed recurrence of GBM after standard therapy (surgery, radio- and chemotherapy) were included. Following intracavitary or intratumoral insertion of 1 or 2 catheter systems, patients were treated with 1 - 6 doses of 2 GBq ²¹³Bi-SP in intervals of 2 months. ⁶⁸Ga-SP was co-injected with the therapeutic doses to assess biodistribution using PET/CT. Therapeutic response was monitored with MRI and FDG-PET.

Results Treatment with up to 11 GBq ²¹³Bi-SP was tolerated well with only mild transient adverse reactions. PET/CT of co-injected ⁶⁸Ga-SP showed high retention of the radiolabeled peptide at the tumor site. Out of 20 evaluable patients, 8 patients are alive, while 12 patients died due to PD (n=11) or non-treatment related causes (n=1) (follow up period up to 20 months). The current median survival of all 20 patients is 18 months (8 patients alive) compared to 15 months after standard therapy alone.

Conclusions Treatment of recurrent GBM with ²¹³Bi-SP is safe with a favorable toxicity profile. Tumor control could be achieved predominantly in patients that received multiple doses of ²¹³Bi-SP. Targeted alpha therapy with ²¹³Bi-SP may evolve as a promising novel option for treatment of GBM.

Research Support The authors are indebted for use of parts of the ²²⁵Ac/²¹³Bi to the U.S. Department of Energy’s, Office of Nuclear Physics, Isotope Development and Production for Research and Applications Program.