Synergistic antitumor effect of chemotherapy and immunotherapy in syngeneic brain tumor models in mice

MARIA G CASTRO; MARIANELA CANDOLFI; KADER YAGIZ; KURT M KROEGER; DAVID FOULAD; GABRIELLE E ALZADEH; MATTHEW TESARFREUND; PEDRO R LOWENSTEIN

Washington DC, EEUU

Congreso; American Association for Cancer Research 101 Annual Meeting; 2010

Glioblastoma multiforme (GBM), the most common primary brain cancer in adults, carries a dismal prognosis, in spite of the most advanced standard of care. This tumor constitute a therapeutic challenge due to its invasive nature, which makes complete surgical resection virtually impossible, its intrinsic radio- and chemotherapy resistance, and its high rate of mutation. Lately, treatment with temozolomide (TMZ) in addition to surgery and radiotherapy increased median survival from ~6 to ~20 months. Nevertheless, the three year survival is ~5%. Alternative experimental approaches appear as useful adjuvants to be used in the treatment for GBM. Our previous results show that intatumoral administration of an adenoviral vector expressing Flt3L recruits antigen presenting cells to intracranial GBM. However, this is not enough to induce anti-tumor immunity, and tumor cell death seems to be required to release tumor antigen and intracellular inflammatory molecules. Considering that TMZ constitutes the latest care of treatment for glioma patients, in the present work to aimed to combine intratumoral administration of Ad-Flt3L with systemic TMZ in order to increase the efficacy of both approaches and lead to increased survival of syngenic intracranial GBM models. Although treatment with TMZ alone led to a discreet improved in survival (~40% increase in median survival compared to saline controls), combined chemo-immunotherapy significantly increased the survival of mice bearing intracranial gliomas (GL26: 40% long term survival; GL261: 20% long term survival) or metastatic melanoma (B16-F10: median survival saline: 27 d; TMZ: 41 d; TMZ+Ad-Flt3L: 48 d), when compared to single therapies. The anti-tumor effect was further enhanced when intratumoral administration of conditionally cytotoxic Ad-TK+GCV was added to the chemo-immunotheraputic approach, leading to 50-70% long term survival in all three tumor models. The efficacy of this treatment was dependent on the release of the pro-inflammatory nuclear protein HMGB1 from dying tumor cells, induced by TMZ and Ad-TK treatment. In addition, the anti-tumor effect of this combined approach required an intact immune system, since the treatment failed when administered to KO mice that lack lymphocytes (CD4+, CD8+ T cells, and B cells) or dendritic cells. Our results contradict the traditional dogma that chemotherapy invariably leads to a state of immune-suppression that impairs the ability of the immune system to mount an anti-tumor response. Here we show that combination of chemotherapy and other cytotoxic agents with immunotherapy leads to synergistic antitumor efficacy and supports its clinical implementation in patients with GBM.