Theranostic Combination of Molecularly Targeted Radiotherapy and Immunotherapy Optimizes Therapeutic Response in a Syngeneic Murine Model of Melanoma

Objectives: In situ vaccination is achievable in GD2+ (disialoganglioside-2) tumor-bearing mice by using a local combination of 12Gy external beam radiation (RT) followed by intratumoral (IT) immunocytokine (IC) [hu14.18-IL2, an anti-GD2 antibody fused to IL2]. It is hypothesized that combining molecularly targeted radiotherapy (MTRT) with RT+IT-IC could improve in situ vaccination. The goals of our study were to determine the administered activity of MTRT that maximizes the therapeutic response of the combination with RT+IT-IC and estimate the corresponding absorbed dose to the tumor. To achieve these goals, our tumor-targeting alkylphosphocholine (NM600) was radiolabeled with the theranostic pair ⁸⁶Y/⁹⁰Y.

Methods: C57BL/6 female mice bearing a syngeneic B78 melanoma flank tumor were administered 9.25 MBq of ⁸⁶Y-NM600 (n=3) IV, and longitudinal microPET/CT scans were acquired at 2, 16, 24, and 48 h post injection (p.i.). CT-based contours of the tumor and organs of interest were overlaid on the PET volumes; tumor selectivity and biodistribution were reported as %ID/g. Using ⁸⁶Y-NM600 PET image volumes and a Monte Carlo based dosimetry platform, the mean Gy/MBq delivered to B78 tumors and normal tissues by the therapeutic analog ⁹⁰Y-NM600 was estimated. For the treatment studies, groups of mice bearing B78 flank tumors (200-300 mm³; n=5) were administered a single IV dose of ⁹⁰Y-NM600 (0.925, 1.85, or 3.7 MBq) one week prior to RT+IT-IC and tumor growth was monitored via caliper measurements. Results: MicroPET/CT imaging confirmed selectivity and retention of ⁸⁶Y-NM600 in B78 tumors (3 %ID/g at 48 h) and hepatobiliary excretion of the tracer (6 %ID/g at 48 h in the liver). Mouse-specific dosimetry estimates show the tumor dose (1.5 Gy/MBq) was higher than all contoured organs except for the liver (2.7 Gy/MBq). Preliminary results suggest that B78 tumor-bearing mice treated with ⁹⁰Y-NM600 combined with RT+IT-IC may elicit enhanced tumor regression compared to RT+IT-IC alone. A dose titration of ⁹⁰Y-NM600 demonstrated that 1.85 MBq, which corresponded to an absorbed dose of approximately 3 Gy, had the largest increase in therapeutic response when combined with RT+IT-IC. However, both 0.925 MBq (1.5 Gy tumor dose) and 3.7 MBq (6 Gy tumor dose) exhibited similar degrees of tumor regression, which may suggest that the major anti-tumor mechanism is the immune response, while the RT and ⁹⁰Y-NM600 are making the tumor microenvironment more responsive to immunotherapy.

Conclusions: Our preliminary results suggest that the synergy between MTRT and RT+IT-IC for the treatment of murine melanoma may be optimized by using theranostic agents and patient-specific prescriptions of MTRT to avoid abrogation of a synergistic therapeutic impact on the anti-tumor immune response.

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