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You are here: Home / Teams / Genestier L/Bachy E - LIB / Projets / Anti-tumoral immunity

Anti-tumoral immunity

Understanding the immune exhaustion mechanisms in Hodgkin lymphoma (HL) patients.

The team has dedicated some specific efforts to understand the clinical and biological features of Hodgkin lymphoma especially the cross-talk between tumor cells (Hodgkin and Reed-Sternberg cells) and the immune microenvironment.

We focused our research on highlighting immune signatures of responsiveness to therapeutics that target the T cell inhibitory checkpoint proteins such as PD1. We firstly studied elderly HL patients who presented a particular poor prognosis as compared to young patients and a national prospective cohort of R/R HL patients treated by monoclonal anti-PD1.

We especially used Digital Spatial Profiling technology (NanoString ® ) available on site, for analyzing the role of the topology of immune cells in relation with the tumor Hodgkin and Reed Sternberg cells in the microenvironment. These researches will be secondly extended on patients included in clinical trials that we conducted in LYSA network with PVAB trial (NCT02414568) in first line therapy for elderly patients and the TIRHOL trial (NCT04318080) for R/R patients treated with anti-PD1 monoclonal antibody.


Understanding efficacy and toxicity of CAR-T cells

Chimeric antigen receptor (CAR) T cells have been granted marketing authorization by the European Medicine Agency (EMA) for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) in adults in 2018. Impressive response rates and duration have been observed with CAR T, paving the way for a broad use in hematology but also in solid tumors, autoimmune disorders and other diseases.

Besides efficacy, two main life-threatening complications associated to CAR T cells have been well identified. First, cytokine release syndrome (CRS) usually occurs during the 7 first days after the product infusion, mimicking severe sepsis sometimes leading to fatal hemophagocytic lymphohistiocytosis (HLH). Second, neurotoxicity (or ICANS for Immune effector cell-Associated Neurotoxicity Syndrome) sometimes follows CRS and patients may present with a broad landscape of neurological or psychiatric-like disorders.

Regarding biology, uncovering the interplay between CAR T, innate immune cells and cytokines released by those different players has provided more insights into the understanding of toxicity associated to this immune therapy. Data from mouse models recapitulating key features of CRS and neurotoxicity pointed out human monocytes as the major source of IL-1 and IL-6 during CRS and monocyte depletion prevented the development of CRS. In humans, few studies have reported encouraging results by combining levels of IL-6 and MCP-1, or IFNg and MIP-1a, or sgp130, MCP- 1 and Eotaxin.

A large effort has been undertaken to identify prognostic markers for response and toxicity but no real clinico-biological signature has emerged to date. Altogether, it is therefore almost impossible for now to predict in which of the 4 following boxes patient will fall following CAR T infusion:

  1. clinical response with no or mild toxicity;
  2. response associated with severe side effects;
  3. no response but severe side effects and
  4. no severe toxicity but no response at all.

During the last 2 years, 130 patients have been treated with CAR T cells for R/R DLBCL at our clinical department, constituting the largest cohort in Europe. Data of 61 patients treated outside clinical trials and with at least 3 months of follow-up (FU) have been analyzed and recently published by our team (Sesques et al, Am J Hematol 2020). Apart from a fully clinically annotated database, a large-scale biological samples collection repository has been collected for virtually all patients treated with CAR T cells.

In collaboration with F. Venet and T. Walzer (CIRI), we are currently setting up an integrative biological approach to identify potential new markers predictive for efficacy and toxicity after CAR T cells treatment based on T-cell immunophenotyping, cytokine production and epigenetic studies using ATAC-seq.