Author of

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

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

  • 11733

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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): A. McDonnell
    • 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.