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B. Robinson



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    P1.04 - Poster Session 1 - Tumor Immunology (ID 153)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.04-001 - Combining Prime-Boost Anti-tumour Vaccination with Debulking Surgery for the Treatment of Malignant Mesothelioma (ID 3143)

      09:30 - 09:30  |  Author(s): B. Robinson

      • Abstract

      Background
      Malignant mesothelioma (MM) is a highly aggressive cancer with a very poor prognosis. Debulking surgery is often used as the principal therapy but is seldom curative. Adjuvant chemotherapy or radiotherapy can be used as to target residual disease, but these too are largely ineffective, while some early post-surgery immunotherapy strategies had limited clinical success. However, there is renewed interest in the use of immunotherapy to treat MM as new modalities have been developed. Recent work form our laboratory and others, has demonstrated that specific immunotherapies can alert the immune system to the presence of tumour. These therapies are particularly useful when used in conjunction with standard treatment protocols such as surgery or chemotherapy. Here we describe the development of a Prime Boost (P/B) anti-tumour vaccination protocol that when combined with debulking surgery and removal of CD4 T cells improved survival outcome of AB1-HA tumour bearing mice.

      Methods
      Using our established mouse model of mesothelioma, AB1-HA tumour bearing BALB/c mice received influenza A PR/8/34/H1N1 (PR8; Prime) and HA expressing recombinant modified Vaccinia Ankara (rMVA‑HA; Boost) anti‑tumour vaccinations before (neoadjuvant) or after (adjuvant) 75% debulking surgery. Diphtheria toxin (DTX) was administered to tumour bearing BALB/c FoxP3.dtr mice to specifically deplete CD4+ FoxP3+ regulatory T cells (Treg). In both models, tumour growth and overall survival was monitored and immunological parameters assessed by multicolour FACS.

      Results
      Neoadjuvant P/B vaccination alone or in combination with 75% debulking surgery induced a significant increase in splenic tumour‑specific CD8 T cells as well as significant increases in the proportion, activation and proliferation status of peripheral CD8 T cells relative to other treatment groups. However, a significant delay in tumour growth was only observed when neoadjuvant P/B vaccination was combined with debulking surgery. Specific depletion of CD8 T cells demonstrated that they were essential for the delay in tumour growth, although their presence was not sufficient to eliminate the tumour outright. Depletion of CD4 T cells during P/B vaccination enhanced the survival outcome of the surgery + vaccination group with 60% of these mice remaining tumour free for > 60 days post-surgery. Data from preliminary experiments in which Treg in tumour bearing FoxP3.dtr mice resulted in complete tumour regression in 20% of DTX treated mice. Tumour specific immunological memory was confirmed as all surviving mice remained tumour free for at least 60 days post rechallenge with the parental AB1 tumour.

      Conclusion
      Anti-tumour P/B vaccination induced tumour‑specific immunity resulting in delayed tumour growth when combined with debulking surgery. Depletion of CD4 T cells during neoadjuvant P/B vaccination enhanced P/B vaccine efficacy leading to cures in 60% of treated mice. Transient depletion of CD4+ FoxP3+ Treg suggesting that vaccine induced anti‑tumour immunity is “restrained”, possibly by regulatory T cells. Based on these findings we are investigating whether combining novel immunotherapies with conventional treatments in the absence of “immunological restrainers” may generate effective therapy for MM. Financial disclosure: This research was funded by a research grant from the Workers’ Compensation Dust Diseases Board, an agency of the New South Wales Government.

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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 - 09:30  |  Author(s): B. Robinson

      • 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.

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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
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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): B. Robinson

      • 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.

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    P2.10 - Poster Session 2 - Chemotherapy (ID 207)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.10-041 - Optimising regulatory T cell (Treg) depletion in combination with chemotherapy for enhanced anti-tumour immunity (ID 2576)

      09:30 - 09:30  |  Author(s): B. Robinson

      • Abstract

      Background
      Cytotoxic chemotherapy is widely used to palliate malignant pleural mesothelioma (MM) and non small cell lung cancer (NSCLC). While originally considered detrimental to the immune system, there is now abundant preclinical data showing that chemotherapy can enhance anti-cancer immunotherapy. Tregs are immunosuppressive CD4[+] T cells thought to inhibit anti-tumour immune responses; murine data suggests that Treg eradication may augment existing anti-tumour immunity. Cyclophosphamide (CTX) is immunostimulatory and at low doses selectively depletes Tregs in mice and humans. The primary objective of this study is to identify an optimum dose and schedule of iterative low dose oral CTX for Treg depletion in the context of pemetrexed-based chemotherapy, and to determine how treatment affects the function and phenotype of the cellular immune response.

      Methods
      In this single centre phase 1b study we investigate an optimum dose and schedule of iterative low dose oral CTX for Treg depletion, in the context of pemetrexed-based chemotherapy, and how treatment affects the function and phenotype of the cellular immune response. Thirty-one patients with advanced malignant pleural mesothelioma (MM) or non-small cell lung cancer (NSCLC) received standard doses of pemetrexed ± cisplatin or carboplatin on a 21 day schedule (6 cycles max.). From the second cycle, escalating doses of oral CTX were administered, initially with 50 mg daily. Weekly peripheral blood samples were collected, and the proportion of Tregs within the CD4[+] population (Treg%) determined by flow cytometry, amongst other immunological parameters.

      Results
      31 participants enrolled on the study (27 MM, 4 NSCLC). The mean number of treatment cycles completed was 4.2 from a potential total of 6 cycles, with 20 participants on-study for at least 4 cycles, and the combination was safe and feasible. Contrary to our initial hypothesis, CTX treatment did not reduce the Treg proportion of CD4[+] T cells in peripheral blood, with baseline Treg (CD127[lo]CD25[+]Foxp3[+]) proportion of CD4+ T cells at 4.44±1.56% and no significant change observed when comparing values from the end of each treatment cycle. Doses above 50/100 mg did not improve depletion. However, analysis of the T-effector cell population has demonstrated an increased frequency of CD38[hi]HLA-DR[hi] cells within the total CD8[+] T cell pool. From the perspective of biological relevance, the ratio of activated T-effector cells to Tregs changes minimally during the first cycle of standard care chemotherapy (baseline = 0.21±0.15 T-effectors per Treg); however, from mid-way through cycle 2 (when CTX treatment begins) onward a notable and variable increase in the proportion of activated T-effector cells is observed (end of cycle 3 = 2.21±3.83 T-effectors per Treg). Detailed immunological data will be presented.

      Conclusion
      These data suggests that CTX with chemotherapy can increase the proportion of activated T-effector cells, an observation that has the potential to improve anti-tumour immunity or chemo-immunotherapy efficacy. We postulate that CTX may affect the function rather than numbers of Treg cells, decreasing their ability to suppress the proliferation of CD8+ effector T cells.