Zachary S. Morris MD, PhD, Presenter: Nothing to Disclose

David Francis, Abstract Co-Author: Nothing to Disclose

Emily Guy, Abstract Co-Author: Nothing to Disclose

Monica Gressett, Abstract Co-Author: Nothing to Disclose

Emma Strode, Abstract Co-Author: Nothing to Disclose

Jacquelyn A. Hank, Abstract Co-Author: Nothing to Disclose

Alexander Rakhmilevich, Abstract Co-Author: Nothing to Disclose

Paul M. Harari MD, Abstract Co-Author: Nothing to Disclose

Paul Sondel, Abstract Co-Author: Nothing to Disclose

Tumor-specific monoclonal antibodies (mAb) are a common type of immunotherapy capable of engaging innate immune cells to elicit antibody-dependent cell-mediated cytotoxicity (ADCC). Mounting evidence suggests radiation therapy (RT) may complement immunotherapies by enhancing tumor immune susceptibility. The interaction of RT and ADCC has not been extensively investigated.

C57BL/6 and NCr nude mice were engrafted with GD2-positive B78 melanoma, and A/J mice with GD2-positive NXS2 neuroblastoma. Macroscopic tumors (~ 200 mm3) were treated with sham or single fraction 12 Gy RT. Mice were then treated with 5 daily intra-tumor injections of 50-µg human IgG, anti-GD2 hu14.18 mAb, or hu14.18-IL2 immunocytokine (IC). NK cell depletion was achieved by IP injection of 0.5 mg NK1.1 mAb every 5 days beginning the day of RT. For clonogenic assays, drug was maintained in culture from 1 hr prior to RT until fixation. Expression of immune susceptibility markers was measured by flow cytometry.

In vitro clonogenic assays demonstrate no effect of hu14.18 or hu14.18-IL2 on the intrinsic radiosensitivity of B78 or NXS2 cells. In tumor-bearing mice we observe synergy between RT and anti-GD2 mAb resulting in tumor regression and improved animal survival. This interaction is not observed following depletion of NK cells or substitution of mAb with hu14.18 that lacks the Fc portion. Synergy is enhanced by substituting mAb with hu14.18-IL2, resulting in complete resolution of most tumors. In contrast to mAb, the synergy of RT and IC is minimally affected by NK cell depletion but is diminished in nude mice. Timing of IC delivery following RT influences this synergy; IC treatment on days 1-5 or 11-15 shows less tumor regression than treatment on days 6-10. This timing coincides with an increase in expression of Fas/CD95 on tumor cells following RT. Intriguingly, during this interval we observe increased tumor cell expression of the T-cell checkpoint inhibitor ligand, PD-L1.

We present preliminary evidence of synergy between RT and ADCC. Our findings suggest a therapeutic opportunity for combining RT with immunotherapies that simultaneously target innate immune response and T-cell activation.

Radiation can synergize with ADCC in murine models and this warrants clinical investigation of strategies for exploiting this cooperative interaction between radiation and tumor-specific antibodies.

Morris, Z, Francis, D, Guy, E, Gressett, M, Strode, E, Hank, J, Rakhmilevich, A, Harari, P, Sondel, P, In Vivo Synergy of Radiation and Antibody-Dependent Cell-Mediated Cytotoxicity.  Radiological Society of North America 2014 Scientific Assembly and Annual Meeting, - ,Chicago IL. http://archive.rsna.org/2014/14002557.html