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Immunocytokine augments local and abscopal response and animal survival when added to radiation and CTLA-4 checkpoint inhibition in a murine melanoma model
  1. Zachary S Morris1,
  2. Emily I Guy1,
  3. David M Francis1,
  4. Monica M Gressett1,
  5. Eric A Armstrong1,
  6. Shyhmin Huang1,
  7. Stephen D Gillies2,
  8. Alan J Korman3,
  9. Jacquelyn A Hank4,
  10. Alexander L Rakhmilevich1,
  11. Paul M Harari1 and
  12. Paul M Sondel5
  1. Aff1 grid.14003.360000000099041312Dept. of Human OncologyUniversity of Wisconsin School of Medicine and Public Health Madison WI USA
  2. Aff2 Provenance Biopharmaceuticals Carlisle MA USA
  3. Aff3 grid.419971.3Bristol-Myers Squibb Company Redwood City CA USA
  4. Aff4 grid.14003.360000000099041312Department of Human OncologyUniversity of Wisconsin-Madison Madison WI USA
  5. Aff5 grid.14003.360000000099041312Department of Human OncologyDepartment of Pediatrics, University of Wisconsin-Madison Madison WI USA

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Meeting abstracts

We have identified a cooperative interaction between radiation and intratumoral injection of anti-GD2 immunocytokine (hu14.18-IL2) in murine tumor models. In a moderate size (~200mm3), single tumor, B78 melanoma model this combination results in complete tumor regression in 71% of animals and a memory T cell response. We hypothesized that intratumoral immunocytokine would improve local and abscopal response to combined radiation and anti-CTLA-4 antibody.

Mice bearing large B78 tumors (~500mm3) were treated with single fraction (12Gy) or sham radiation, intratumoral immunocytokine or control IgG (50μg days 6-10 after radiation), and intraperitoneal IgG2a anti-CTLA-4 or control IgG (100μg days 3, 6, and 9 after radiation). In this large tumor model the effect of combined radiation and immunocytokine was reduced (27% complete response) and addition of immunocytokine to radiation and anti-CTLA-4 improved tumor response (73% complete response) and animal survival compared to doublet combinations of these agents. In a model of microscopic metastatic disease generated by IV injection of animals bearing large primary B78 tumors (~500mm3) with 4x105 GD2-deficient B16 melanoma cells (parental to B78) on the day of radiation, we observed improved survival with the addition of immunocytokine to combined radiation and anti-CTLA-4.

However, in a model of established metastatic disease with a moderate size (~200mm3) primary B78 melanoma and a palpable (~50mm3) distant B78 tumor we did not observe an abscopal response when treating the primary tumor with radiation and intratumoral immunocytokine. Strikingly, when compared to animals with a single tumor we observed a profound inhibitory effect of the non-radiated second tumor such that primary tumor response to radiation and immunocytokine was indistinct from radiation alone in this two-tumor model. Delivering radiation to both the primary and secondary tumors eliminated this inhibitory effect of the secondary tumor. In this two-tumor model we combined primary tumor radiation and intratumoral immunocytokine with intraperitoneal IgG2b or IgG2a anti-CTLA-4. Both isotypes inhibit CTLA-4 activity but the latter has a reportedly greater ability to deplete intratumoral regulatory T cells (Tregs). While IgG2b anti-CTLA-4 had minimal effect on primary tumor response to radiation and immunocytokine, IgG2a anti-CTLA-4 rendered 80% of animals disease-free when given with radiation and immunocytokine, implicating Tregs in the suppressive effect of the second tumor on primary tumor response. In this two-tumor model, combination of radiation, immunocytokine, and IgG2a anti-CTLA-4 enhanced primary tumor and abscopal response as well as survival compared to doublet combinations. Clinical trial designs to explore these findings will be presented.