Team:Evry/Description

   

Project overview

Cancer cases could rise by 50 % by 2020, with 15 million new cases every year in the world (1). Surgical operation is not a sufficient solution for long-term remission and many cancers are not operable. For example, only 20% of patients with pancreatic cancer have surgically resectable tumors at the time of diagnosis. Among these 20% patients, the vast majority will experience recurrence within the first 2 years (2).

Cytotoxic chemotherapy is the the most available treatment for cancer. Unfortunately, the efficacy of chemotherapy is limited and cures are rarely achieved, in particular for solid tumors (3). Little improvement has been made for overall survival with chemotherapy alone. In particular, most chemotherapies kill target cells by triggering a process of programmed cell death and this mode of cell death can be tolerogenic for cancer (3). Second, lymphocyte depletion (lymphopenia) is a common side effect of many anti-cancer drugs.

In 2013, immunotherapy was awarded « breakthrough of the year » by Science (4). Immunotherapy consists of inducing the immune system against cancer cells. It is now administered in first line or combined to chemotherapy to overcome its potential immunosuppressive effect. On the contrary of chemotherapy, it can provide a durable effect with improved survival (5).

Two strategies are employed in immunotherapies : active and passive therapies.Passive immunotherapy is based on external immunity effectors delivered to the patient, like monoclonal antibodies or cytokines delivery. The main advantage of these therapies is that they do not rely on the immune system, for immunocompromised patients for example. In addition, they offer an immediate protection. However, this first generation of immunotherapies do not provide a long-lasting protection and their efficiency is limited by a lack of specificity toward the patient tumor antigen.

The objective of active immunotherapy is to break this tolerance by eliciting a CD8+ response against specific TAAs. Advantages of active immunotherapy include the induction of a long immune response with an immunological memory, and many any vectors available for induction according to the cell type targeted. Active Immunotherapies are essentially targeted therapies, but they are not personalized to the patient tumor antigen. The main limitation for personalized active immunotherapy are development costs. One of the first immunotherapy approved against melanoma, Yervoy, cost in average 40,000$ a month and is not specific (6). Immunotherapies more specific and based on DCs, like Provenge®, are even more expensive with 93,000$ for each treatment (7), because DCs induction is an ex vivo labor-intensive process. In the case of Provenge®, patients must match the prostate tumor antigen PAP in order to qualify for this therapy.

High production costs prevent these active immunotherapies to be adapted to the patient features, limiting the therapeutic outcome. To cut down costs and production time while improving efficiency, we created a yeast targeting DC in vivo, based on the non-pathogenic baker yeast S. cerevisiae. Synthetic biology transforms living organisms into engineerable chassis with a bottom-up strategy. The bottom-up approach allows sub-parts assembling to create complex systems with new features. Our living chassis takes advantage of this approach to make personalized medicine a reality, with a scalable cancer therapy. The standardized chassis targeting DC is personalized to the patient tumor antigen introduced in the form of plasmid in the chassis.

Our project is divided in 4 main wet lab sub-projects:

Project 1

We first developed a software to predict the most specific and immunogenic antigen from patient tumor sequencing data

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Project 2

Next, we designed S. cerevisiae to surface display the antigen predicted by our software to trigger the immune system against it.

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Project 3

We tested our system against a model antigen for melanoma derived from ovalbumin. In vitro and in vivo assays on melanoma bearing mice confirmed the ability of our recombinant yeast to induce a potent CD8+ response against our targeted antigen.

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Project 4

Tumor environment is highly immunosuppressive and can lead to T-cell anergy despite their activation by our chassis. To break this local immune tolerance, we designed S. cerevisiae to secrete the cytokine interferon gamma directly inside the tumor. Then, we encapsulated these yeasts in porous alginate beads in order to protect them from the immune system inside the tumor, while preserving their secretion ability. Here, we made a proof of concept with GFP producing yeasts encapsulated in beads.

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Project 3

Hypoxic resistant cancer cells are still able to evade the immune response. To detect these hypoxic cancer cells that can resist both chemotherapy and radiotherapy, we created a yeast bio-sensor for hypoxia. Upon detection of hypoxic tumor environment, S. cerevisiae releases perforin and granzyme B to trigger cell apoptosis. The proof of concept was established with RFP production under control of our bio-sensor and a hypoxic gradient.

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