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E. Rozali

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    P1.05 - Poster Session 1 - Preclinical Models of Therapeutics/Imaging (ID 156)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.05-021 - Dual checkpoint blockade using anti-PD-1 and anti-CTLA4 combined with cisplatin chemotherapy is effective in a murine mesothelioma model (ID 3214)

      09:30 - 16:30  |  Author(s): E. Rozali

      • Abstract

      Chemotherapy (cisplatin, pemetrexed) remains is the standard of care for mesothelioma (MM) in Australia, however novel immunotherapies are now emerging in clinical trial. Anti-PD-1 (MDX-1106) and anti-CTLA4 (tremelimumab) block different aspects of negative T cell regulation to prolong the activation and survival of anti-tumour cytotoxic T lymphocytes (CTL). While anti-CTLA4 is being tested in Phase II clinical trial, the efficacy of anti-PD-1 in MM patients is yet to be determined. The notion of combining chemo-immunotherapy has gained ground in recent years with the discovery that chemotherapy-induced tumour cell death can be immunogenic, and thus exploited with the right immunotherapy drug.

      The murine mesothelioma line generated in our lab, AB1-HA, was inoculated subcutaneously into the flanks of Balb/c mice. Tumour growth and survival following treatment with anti-PD-1 and/or anti-CTLA4, plus chemotherapy (gemcitabine, cisplatin) was monitored. Tissues (spleen, lymph nodes) were harvested at various time-points for flow cytometric analaysis to investigate immune correlates of response.

      Dual checkpoint blockade (anti-CTLA4 + anti-PD-1) was effective at delaying tumour outgrowth and improving survival, over either treatment alone (anti-PD-1 had negligible effect on AB1-HA growth). Combining this with cisplatin chemotherapy achieved an even greater effect, however this was not the case with gemcitabine.

      The effect of dual checkpoint blockade mirrors that which has recently been discovered in mouse models of melanoma [1]and colon cancer [2]. The ability to combine this with chemotherapy to our knowledge has not been previously identified. Furthermore, it is interesting that the triple combination was only successful with cisplatin rather than gemcitabine, which in our hands has been shown to be immunogenic and works synergistically with other immunotherapies, such as anti-CD40. Not only can this finding be directly translated to the clinic, it also prompts future investigation into how best to combine different therapies to tackle malignancies that may be refractory to standard monotherapy treatments. 1. Curran, M.A., et al., PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A, 2010. 107(9): p. 4275-80. 2. Duraiswamy, J., et al., Dual Blockade of PD-1 and CTLA-4 Combined with Tumor Vaccine Effectively Restores T-Cell Rejection Function in Tumors. Cancer Res, 2013. 73(12): p. 3591-603.