Author of

• 10557

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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
  • Moderators:
  • Coordinates: 10/28/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 10578

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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 - 09:30  |  Author(s): A. Khong
    • Abstract

    Background
    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.

    Methods
    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.

    Results
    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.

    Conclusion
    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.

• 11515

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  P2.05 - Poster Session 2 - Preclinical Models of Therapeutics/Imaging (ID 158)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/29/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 11535

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    P2.05-020 - Combined gemcitabine and anti-CTLA4 therapy to target residual tumour following partial debulking surgery in a mouse mesothelioma model (ID 3206)

    09:30 - 09:30  |  Author(s): A. Khong
    • Abstract

    Background
    Complete surgical resection of solid malignancies is often not achieved due to growth of occult tumour cells, distant metastases, or the invasiveness of the tumour mass. Hence there is a need for adjuvant therapies that may be administered following surgery to target residual tumour. Using a murine mesothelioma model we have previously shown that combining gemcitabine with anti-CTLA4 is effective at generating an anti-tumour immune response, leading to tumour regression and improved survival. We sought to use this treatment regimen to improve the post-surgical outcome of debulking surgery.

    Methods
    The murine mesothelioma line generated in our lab, AB1-HA, was inoculated subcutaneously into the flanks of Balb/c mice. Established tumours (<50mm[2]) were debulked by surgical removal of 75% of the tumour mass. Treatment with gemcitabine and anti-CTLA4 were commenced on the day of surgery, and mice were monitored for residual tumour outgrowth and survival. Size-matched controls were treated in parallel.

    Results
    Dual administration of gemcitabine with anti-CTLA4 was effective at causing regression of remaining tumour and improving survival following partial debulking surgery, over either therapy alone. The outcome of this treatment when administered to debulked tumours was comparable to that achieved against smaller, size-matched tumours.

    Conclusion
    We have shown that larger tumours can be successfully partially debulked and the remaining tumour treated using a combination of gemcitabine and anti-CLTA4. Thus, combined chemo-immunotherapy is a feasible option for post-surgical treatment option to remove residual tumours.