Developpement de nouvelles biothérapies
Persons in charges: E. Tartour, S. Oudard, F. Goldwasser, F. Batteux, J.L. Theillaud
Development of innovative biotherapies based on a better understanding between tumor-host interaction and the sharing of original preclinical models :
- Therapeutic cancer vaccines combined with antagonist molecules to overcome immunosuppression or anergy present in the tumor microenvironement of head and neck cancer
- How to exploit immunomodulation mediated by antiangiogenic molecules in clinical trials?
- Modulation of endogenous oxidative stress or expression of mutated CYP450 to increase the potency of chemotherapy
- Improving antibody therapy by the recruitment of adaptative immunity
Therapeutic cancer vaccines combined with antagonist molecules to overcome immunosuppression or anergy present in the tumor microenvironement of head and neck cancer
Oncogenic papillomavirus, good target for immunotherapy, could be found within 30-35% of oropharynx cancer (N. Tran et al., Head Neck 2007). HPV 16 is the dominant serotype expressed in head and neck cancers. In preclinical models, these tumors are sensitive to immunotherapy. Currently, a preventive vaccine, providing protection against HPV16 and HPV18, has been registered. This vaccine is fully protective against the occurrence of persistent infection and the associated development of high-grade genital lesions (J. Paavonen et al., Lancet 2007; S. M. Garland et al., N Engl J Med 2007). Notably, these prophylactic vaccines showed no benefit in women (500 millions) who were already infected with the HPV types covered by this vaccine (C. M. Wheeler Nat Clin Pract Oncol 2007). A recent approach validated the proof of concept of therapeutic cancer vaccine against HPV in vulvar dysplasia associated with HPV (G. G. Kenter et al., N Engl J Med 2009). To develop a therapeutic cancer vaccine against established head and neck tumor expressing HPV, the E Tartour group will select the E6-E7 antigens derived from HPV, as their expression are required to maintain the tumor phenotype and thus classical escape mechanisms such as downregulation of their expression could not occur. These antigens will be vectorized by the B subunit of Shiga toxin, a vector for antigen which targets dendritic cells and elicits robust humoral and CTL response in many model antigens including self antigens (Vingert et al., Eur J Immunol 2006; O. Adotevi et al., J Immunol 2007). The complete homology of the Gb3 receptor between various species may allow a better extrapolation of our results. At last based on previous analysis of head and neck tumor microenvironment (C. Badoual et al., Clin Cancer Res 2006; C. Badoual et al., Head Neck 2010), showing high levels of infiltration of these tumors by regulatory T cells and PD1 T cells, these vaccines will be combined with molecules able to alleviate this immunosuppression (anti-PD1, inhibitors of regulatory T cells…). All these strategies will be tested in E6-E7 transgenic mice which develop spontaneous tumors of the tongue after treatment with a chemical carcinogen, 4-nitroquinoline-N-oxide (4-NQO), These tumors mimicked the phenotype similar of human tumors (K. Strati et al., Cancer Res 2007).
How to exploit immunomodulation mediated by antiangiogenic molecules in clinical trials?
In recent years, many anti-angiogenic (Avastin, Sutent, Nevaxar…) have been approved for clinical use in patients with cancers. However, after a first phase of clinical response, most patients will develop resistance to this treatment by the end of the first year (E. Barrascout et al., Bull Cancer 2010). It is thus urgent to identify and optimize clinical new drug combinations with these molecules. Recently, various studies in mice and humans have shown that the anti-angiogenic molecule, sunitinib, was capable of inhibiting various immunosuppressive mechanisms associated with cancer progression (J. H. Finke et al., Clin Cancer Res 2008; J. Ozao-Choy et al., Cancer Res 2009; H. Xin et al., Cancer Res 2009). We showed that the decrease in regulatory T lymphocytes in patients with metastatic renal cancer treated with sunitinib was correlated with better clinical outcome (O. Adotevi et al., J Immunother 2010). Because of this body of evidence showing that sunitinib could improve the immune status of patients with cancer, this project conducted by S. Oudard (Oncology-HEGP) and P. Loulergue (CIC-BT Cochin) in collaboration with F. Goldwasser (Oncology-Cochin) O. Launay (CIC-BT-Cochin) and E. Tartour/H. Fridman (Immunology HEGP and CIC-BT) will seek to show that the administration of this molecule can increase a vaccine response in these patients. Two vaccines (anti-tetanus toxin and anti-VZV) will be selected for this study because of their ability to activate differently the immune system and thus to better analyze the impact of sunitinib on the immune response. The success of this study will form the rational development of clinical protocols combining sunitinib – or other anti-angiogenic molecules with immunostimulatory properties – to immunotherapy in patients with cancer. The design of this study will also define the sequence of optimal therapeutic combination of anti-angiogenic therapy with immunotherapy.
Modulation of endogenous oxidative stress or expression of mutated CYP450 to increase the potency of chemotherapy
Two innovatives approaches to increase the therapeutic index of chemotherapy will be optimized:
(1) Isabelle de Waziers from the research team of P. Laurent-Puig developed a project of Virus-directed enzyme prodrug therapy (VDEPT). This is an emerging strategy against cancer. This approach consists of expressing in human lung and head and neck cancer cell lines, the cytochrome P4502B6/NADPH cytochrome P450 reductase fusion gene (CYP2B6/RED) able to activate, in situ, a prodrug, the cyclophosphamide (CPA), into cytotoxic metabolites. By directed mutagenesis on CYP2B6 and modification of the linker size between CYP2B6 and RED, the efficiency of their mutated gene fusion to metabolize CPA was increased by 10-fold. This group intends to pursue this work improving the infection protocol of tumoral cells using recombinant lentivirus (instead of adenovirus) expressing their new efficient mutated fusion gene and testing CPA cytotoxicity in several human pulmonary and head and neck cancer cell lines. Given that other prodrugs can be activated into cytotoxic metabolites by the RED (mytomycine C, tyrapazamine), their association with CPA will be studied. At last, the strategy will be tested in vivo using models of nude mice xenografted with the various head and neck and lung tumor cell lines (collaboration with UPRS EA3585 (IGR, Villejuif) and mice developing spontaneous head and neck and lung tumors in collaboration with C. Fridman and E. Tartour’s group. According to the results obtained in these in vivo models, this strategy could be extrapolated in human therapy.
(2) The team of F.Batteux, J.Alexandre, F Goldwasser and B.Weill develops new anti-tumoral treatments based on the modulation of the endogenous oxidative stress. This group has demonstrated that ROS act as second messenger of the tumor cell proliferation (A. Laurent et al., Cancer Res 2005) and that modulation of ROS can be used to improve the therapeutic index of some chemotherapeutic drugs (D. Trachootham et al., Nat Rev Drug Discov 2009). In line with those observations, this group has recently reported the improvement of the therapeutic index of anticancer drugs by the superoxide dismutase mimic Mangafodipir (J. Alexandre et al., J Natl Cancer Inst 2006). Patents granted to Paris Descartes University). Mangafodipir increases oxaliplatin efficacy on two animal models of liver and colon cancer while decreasing its side effects especially leukopenia and neurotoxicity (J. Alexandre et al., J Natl Cancer Inst 2006). PROTEXEL®, a Biotech company has obtained the exclusive rights of the patents and promotes three ongoing clinical trials in the Department of Clinical Oncology (Pr F. Goldwasser & Dr J. Alexandre) at Cochin / Hôtel Dieu hospital. Moreover, the group is a founding partner of the REDCAT consortium that associates ten labs and two pharmaceutical companies from five different European countries. This consortium develops “from bench to bedside” the therapeutic potential of fourty new and original anti-tumoral redox modulating molecules synthesized by organic chemistry lab, partner of the REDCAT consortium.
Improving antibody therapy by the recruitment of adaptative immunity
Activity of therapeutic antibodies is mainly believed to occur via direct action on tumor cells (blockade of growth factor receptors or induction of tumor cell apoptosis) or by indirect tumor cell cytotoxicity via antibody-dependent cell cytotoxicity (ADCC) or complement-dependent cytotoxicity. In contrast, the long-term effects of antibody on the host adapative response have received little attention. Teillaud’s group recently showed that an initial treatment with anti-CD20 induces protection against human CD20-expressing tumor cells and allows immunocompetent mice to survive tumor challenge. This long-lasting protection requires the presence of the Fc portion of the anti-CD20 mAb and is achieved through the induction of a cellular immune response. CD4+ cells were needed at the beginning of the treatment, but both CD4+ and CD8+ cells were required after tumor challenge to achieve protection (R. Abes, et al., Blood 2010). These findings demonstrate that anti-CD20 mAbs exert therapeutic effects through the induction of an adaptive cellular immune response. These results are in line with recent data showing the requirement of adaptative immunity for the activity of anti-Her2/neu mAb (S. Park et al., Cancer Cell 2010; S. Kim et al., J Clin Invest 2008). Our project will aim i) to determine which Fc receptors are involved in the priming of T cell response ii) to identify and perform a phenotypic characterization of the CD4+T cells required for the generation of CD8+T cell response iii) to assess the induction of endogenous anti-tumor T cell response in patients treated by anti-CD20 mAb.
Four tumors will be selected for this program (colon carcinoma, lung cancer renal cell carcinoma and head and neck cancer). The analysis of their microenvironment with the same approaches and tools will allow us to determine if the same levels of effector, regulatory, inflammatory and immunosuppressive cells are present in these tumor or if difference exist between them. This will lead to common strategies or personalized treatment to reverse the tumor promoting role of this microenvironment.