Volume 3 Supplement 2
Immunocytokine augments local and abscopal response and animal survival when added to radiation and CTLA-4 checkpoint inhibition in a murine melanoma model
© Morris et al. 2015
Published: 4 November 2015
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.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.