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D. Lakhiani



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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 - 16:30  |  Author(s): D. Lakhiani

      • 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.