This program is developed in an animated context associated with the very promising results obtained with antibodies directed against the immune “checkpoints” (CTLA-4, PD-1 and PDL-1 in particular) in melanoma, colon and lung cancer, the recent development of CARs : chimeric antigen receptors, bi-specific antibodies or anti-cancer vaccines.
New approaches to treatment and clinical trials in immunology
1) Using the Shiga toxin
Project coordinated by Dr Ludger Johannes (Inserm / IC) and Dr Jean-Claude Florent (CNRS / IC)
Pathogens are systems that exploit the biological functions of their hosts. The Shiga bacterium, an example on the subject, is able to route the catalytic subunit of its toxin from the intestine of the host to their kidneys. The Shiga toxin is capable of crossing tissue barriers and escaping from both the extra and intra cellular immune system. It’s very low immunogenicity is attributed to the fact that it is protected in the serum of patients by chaperone cells allowing it to escape antibodies. Intracellular stability is linked to its ability to manage its own absorption itself by using unconventional signalling pathways.
The Shiga toxin receptor, the glycolipid Gb3, is expressed in millions of copies on different types of cancer cells and is internalised upon activation by its ligand. Experiments indicate that the non-toxic receptor-binding B sub-unit (called STxB) can deliver medication like chemotherapy to in vitro and in vivo cancer cells. The STxB also binds efficiently to dendritic cells.
The objective of this project is to build on these findings by synthesising and evaluating the immunogenicity of conjugated toxins / tumour antigens.
2) Vaccines directed against tumour antigens
Project coordinated by Dr Olivier Lantz (IC) and Dr Clotilde Thery (Inserm / IC)
Using the immune system to treat diseases (disseminated or not) is a very attractive prospect as the targets of this approach are tumour specific antigens and the incidence of side effects should, as such, be low.
T cells (CD4 or CD8) and antibodies, two effectors of the immune response, have been successfully adapted to treat tumours in patients showing the benefit of immunotherapy against cancer. The results obtained with the two therapeutic antibodies Herceptin for carcinomas expressing Her2/Neu or Rituximab for B cell lymphomas expressing the CD20 antigen illustrate the validity of this method.
The amplification of T cells (CD4 or CD8) is still a costly patient specific process difficult to undertake in good manufacturing practice (GMP) conditions.
Inducing immune responses to tumour specific antigens by a conventional process of vaccination with these antigens should theoretically be a cheaper and easier approach for anti-cancer immunotherapy. But the successful induction of an active anti-cancer immune response after vaccination with antigens (such as proteins with conventional adjuvants) still remains a challenge.
This project aims at evaluating two complementary therapeutic vaccination approaches :
- Chemical coupling between long peptides (30-40 amino acids) and various types of adjuvants
- Generating an anti-tumour therapeutic DNA vaccination antigen combining a secretion of antigen particles (naked plasmid DNA encoding tumour DNA) and pro immune treatment (induction of the immune response via T-cells and antibodies via electroporation)
3) Towards the development of therapeutic antibodies
Project coordinated by Dr Sebastian Amigorena (CNRS / IC) and Dr Franck Perez (CNRS / IC)
The third component of the immunotherapy program includes several sub-projects around the theme of therapeutic antibodies against cancer. The most characteristic is based on a monoclonal TN specific antibody, a glycolic antigen expressed specifically by tumour cells. This antibody induces toxicity mediated by the antibody dependant cells (ADCC) and includes the rejection of the tumour in a mouse model of breast carcinoma.
- Johannes L. et al. (2012). Conjugates of the B subunit of Shiga toxin for use as contrasting agents for imaging and therapy. Patent PCT/EP2013/075712.
- Schmidt F. et al. (2012). Conjugates of the B subunit of Shiga toxin for anticancer therapies. Patent PCT/EP2013/075731.
- Tartour, E., and L. Johannes. (2011). Compositions having means for targeting at least one antigen to dendritic cells. Patent P11305959.6.
Featured bibliography :
- Renard, H.-F et al. (2015). Endophilin-A2 functions in membrane scission in clathrin-independent endocytosis. Nature 517, 493–496.
- Stimmer, L., et al (2014). Human breast cancer and lymph node metastases express Gb3 and can be targeted by STxB-vectorized chemotherapeutic compounds. BMC Cancer 14, 916.
- Lakshminarayan, R et al. (2014). Galectin-3 drives glycosphingolipid-dependent biogenesis of clathrin-independent carriers. Nat Cell Biol 16, 592–603.
- Djender, S et al (2014). Bacterial cytoplasm as an effective cell compartment for producing functional VHH-based affinity reagents and Camelidae IgG-like recombinant antibodies. Microbial Cell Factories 13, 140.
- Olichon, A., and de Marco, A. (2012). Preparation of a naïve library of camelid single domain antibodies. Methods Mol. Biol. 911, 65–78.
- Hubert, P., and Amigorena, S. (2012). Antibody-dependent cell cytotoxicity in monoclonal antibody-mediated tumor immunotherapy. Oncoimmunology 1, 103–105.