M. Tsutsui1, Z. Sun1, P. Speicher1, P. Dolber1,2,3, J. Dannull1, S. Nair1, D. Tyler1,2 1Duke University Medical Center,Surgery,Durham, NC, USA 2Durham VA Medical Center,Durham, NC, USA 3Duke University Medical Center,Pathology,Durham, NC, USA
Introduction:
The effectiveness of regional therapeutics may be related to the degree of local and systemic anti-tumor immune response generated. We utilized an immunocompetent mouse model of advanced extremity melanoma to define the immune aspects of regional chemotherapy infusion.
Methods:
B16F10.9OVA melanoma cells were inoculated subcutaneously in one or both hindlimbs of C57BL/6 mice. After tumor diameter reached 5 mm, isolated limb infusion (ILI) was performed using melphalan or vehicle in one hindlimb with or without anti-CTLA-4. Mice experiencing a complete response were rechallenged with a second tumor inoculation.
Results:
Tumor doubling and quadrupling time were significantly longer using melphalan ILI with systemic anti-CTLA-4 than without (P = 0.005, Hazard Ratio: HR 1.96 and P = 0.02, HR 1.72, respectively); no anti-CTLA-4 effect was observed on tumors that received vehicle ILI. Of the mice rechallenged with a second tumor inoculation, inhibition of tumor growth at the second inoculation site was only observed in mice treated with melphalan ILI and systemic anti-CTLA-4. In animals carrying tumors on both hindlimbs, tumor doubling and quadrupling times on the non-ILI-treated side were significantly longer in animals whose contralateral hindlimb was treated with melphalan ILI and systemic anti-CTLA-4 than with melphalan ILI alone (P = 0.011, HR 5.05 and P = 0.004, HR 9.1, respectively). Systemic tumor specific immune responses were detectable in the regional draining lymph nodes only in animals treated with both melphalan ILI and systemic anti-CTLA-4.
Conclusion:
Optimizing immunologic aspects of regional melanoma therapy may significantly complement systemic immunotherapy strategies.