IMMUABLE: Prediction of response to immunotherapy in oncology by ImmunoPET using innovative immune biomarkers and adapted protein formats.
Open position for a PhD student
PhD supervisor: Charles TRUILLET
Graduate school: ITFA (University of Paris Saclay, GS HEADS)
Charles Truillet and Vincent Lebon (BioMaps, Multimodal Imaging Laboratory)
Hervé Nozach and Bernard Maillère (SIMoS, Laboratory of Cellular Immunology and Biotechnology) Eric Tartour and Corinne Tanchot (UMR S970, Georges Pompidou Hospital)
State of the art
A physiological function of the immune system is to recognize and destroy cancer cells. However, despite this control by the immune system, some tumor cells manage to escape this immunosurveillance. The continuous selection pressure of the immune system would induce physiological changes in the tumor cells. In particular, it is now clear that tumor cells modulate certain proteins, called immune checkpoints, mainly to decrease the activity of T cells. Therefore, the overexpression of these proteins in cancer and immune cells makes them a potential therapeutic target. Therefore, immune checkpoints such as CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4), PD-1 (Programmed Death-1) and its ligand PD-L1 are interesting targets for therapy mainly in the form of monoclonal antibodies. These immunotherapies is a real revolution in the fight against cancer, showing efficacy on a wide spectrum of tumors. However, despite remarkable clinical responses in some patients, these immunotherapies remain ineffective for a large majority of patients. Only 12.5% of patients in the United States with advanced cancers treated with immunotherapy showed an objective response.1 This high inter-individual heterogeneity of response to immunotherapies underlines the major need to identify and develop predictive biomarkers of their clinical efficacy.
The objective would be to move towards a more personalized medicine, by delivering the right therapeutic strategy to the right patient at the right time.
Preclinical and clinical studies of PD-1 and PD-L1 blockade suggest that analysis of the tumor microenvironment, notably via PD-L1 expression and CD8+ lymphocyte infiltration in the tumor, are the most sensitive parameters for predicting patient response to treatment.2 However, despite progress in patient selection, the efficacy of PD-L1/PD-1 immunotherapies remains heterogeneous among patients. Two main causes may explain this failure:
- The choice of method. Immunohistochemistry on biopsy sections is the conventional technique in the clinic. However, biopsies do not allow to take into account tumor heterogeneity nor the temporal evolution of tumors over time and treatments. ImmunoPET, combining positron emission tomography (PET) with the specificity and affinity of ligands based on monoclonal antibodies, could address this issue. Recently, we, CEA/SIMoS and CEA/SHFJ have developed and validated in a preclinical model a first ligand adapted for PET immunoassay specifically targeting the PD-L1 biomarker in vivo. We have been able to quantify and map the distribution of PD-L1 in vivo (pending publication in Journal of Nuclear Medicine).4
- The choice of biomarkers, especially those of the immune system. A better understanding of anti-tumor immunity would increase the specificity of therapies. In collaboration with a team from Georges Pompidou Hospital, UMR_S970 of Eric Tartour, we have identified a subpopulation of CD8+T cells called T cells that are more specific to the immune response. This subpopulation of lymphocytes is considered as a predictive biomarker of clinical response to anti-PD-1/PD-L1.
We propose in IMMUABLE to evaluate the efficacy of anti-PD-L1/anti-PD-1 immunotherapies by imaging the evolution of the tumor microenvironment, via three biomarkers: PD-L1, CD8 and the new biomarker. The objective is to propose an immunoPET methodology to personalize the treatment to individual patients.
The ability of PET immunoassays to support the stratification and therapeutic follow-up of patients undergoing anti-PD-1 / anti-PD-L1 immunotherapy relies on the choice of radioligands with the appropriate pharmacokinetics and tissue distribution to effectively visualize the biomarkers of interest. Ideally, these radioligands must penetrate and diffuse rapidly into tumors while being rapidly cleared from the bloodstream, in order to obtain PET images with high tumor-to-noise contrast at short post- injection times.
Thesis project is based on three axes:
- – The evaluation of two new ligands: an anti-CD8 and an anti-biomarker of interest. Different ligand formats will be evaluated in terms of pharmacokinetics in specific tumor models. Ligand selection will be determined based on specific accumulation in the tumor.
- – Monitoring the therapeutic efficacy of anti-PD-1 immunotherapy in a preclinical model via imaging of the three biomarkers (PD-L1, CD8+ and the new biomarker) via the selected ligand.
- – Evaluation and prediction of the efficacy of a new therapeutic axis: the combination of immunotherapy, anti-PD-1 and a targeted therapy, a BRD4 inhibitor impacting the PD-L1 signaling pathway. The three biomarkers will be evaluated by immunoPET and correlated with
ex vivo and survival data.
This project will allow to propose new tools and methodology in immunoPET while studying new biomarkers of interest.
1) Haslam, A. and Prasad, V. (2019), JAMA network open, 2(5), p. e192535. 2) de Vries, E.G.E. et al. (2019), Nature Reviews Clinical Oncology, 16(4), pp. 241–255. 3) andoval, F. et al. Sci. Transl. Med. 5, 172ra20 (2013). 4) Bouleau et al, JNM, doi:10.2967/jnumed.121.262967.
This subject is addressed to a student with a training (university or engineering school) in biology, pharmacology or from a course of study at the interface between biology and biochemistry. We are looking for a candidate with a master’s degree in pharmacology, biochemistry, immunology or with a background in pharmacy.
CEA/Service Hospitalier Frédéric Joliot/BioMaps
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