Research Donovan Flumens

Abstract

Acute myeloid leukemia (AML) is one of the most common leukemias in adults with a 5‐year overall survival rate of only 30%. Despite therapeutic advances in the last decade, novel adoptive T-cell immunotherapies using anti-tumor chimeric antigen receptors (CARs) and T-cell receptors (TCRs) are not fully developed for AML. Moreover, expression of immunosuppressive immune checkpoints (IICPs) hinder the success of these T-cell therapies. To address this issue, the aim of this project is to develop an innovative multi-epitope Wilms' tumor 1 (WT1)-specific TCR, CD200-specific non-signaling chimeric antigen receptor (NSCAR) and IICP-disrupted (mulTplex)-engineered adoptive T-cell therapy for AML. We will combine TCRs with different human leukocyte antigen (HLA) restrictions and specificities against diverse epitopes of WT1, a key intracellular antigen, in a multi-epitope strategy. To avoid the interaction between native and introduced TCRs, native TCRs will be disrupted by CRISPR-Cas9 technology. The NSCAR, which lacks the typical CAR's signaling domain, will act as an "anchor" for the T cells by locking onto AML cells through CD200, a novel extracellular AML antigen, and without triggering T-cell activation. By doing so, we expect to improve TCR-mediated anti-AML cytotoxic capacity of mulTplex-engineered T cells. To further harness the anti-leukemic activity of engineered T cells, AML-associated IICPs will also be disrupted using CRISPR-Cas9 methods. Both in vitro and in vivo evaluation of mulTplex-engineered T cells will ensure translation of our innovative combinatorial approach into clinical studies.

Researcher(s)

• Promoter: Lion Eva
• Fellow: Flumens Donovan

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Genetic engineering of lymphocytes for adoptive cell transfer has marked a turning point in personalized immunotherapy, especially in the treatment of cancer. Adoptive T-cell immunotherapies using antitumor chimeric antigen receptors (CARs) and T-cell receptors (TCRs) have, however, not met expectations yet for the majority of malignancies, including acute myeloid leukemia (AML). Moreover, expression of immunosuppressive immune checkpoints (IICPs) hinders the success of these therapies. To address the shortcomings of current T-cell therapies, the aim of this research project is to develop an innovative combinatorial and genetically engineered adoptive T-cell therapy focusing on AML as a disease model. In this project four important issues will be covered. First, cancer cells capitalize on processes such as downregulating peptide-major histocompatibility complex (pMHC) ligands to lower their immunogenicity and, by doing so, evade immune detection. Second, TCRs that target tumor self-antigens are scarce and usually have low affinities, having difficulties in binding target tumor antigens. Finding ways to improve interaction between pMHC ligands and low affinity TCRs, such as those that target self-antigens, would improve the chance of success in TCR-engineered T-cell therapies. Third, adoptive T-cell therapies are confronted with immunosuppressive environments that hinder their efficacy via engagement of IICPs, such as PD-1, TIM-3, or LAG-3. Determining the most relevant IICPs is key for developing effective adoptive T-cell therapies. Fourth, these therapies must be tumor-specific and efficacious once translated into a clinical setting. Taken together, combinatorial and flexible approaches for TCR-engineering will mark the next-generation of T-cell immunotherapies, by addressing (a) improved interaction between T cells and cancer cells, (b) immune evasion through IICPs, (c) cost-effectiveness of an all-in-one therapy, and (d) safety using RNA-based methods. In summary, improved adoptive T-cell therapies that overcome CAR and TCR challenges as well as the immunosuppressive environment that hinders antileukemic T-cell action will facilitate innovative solutions for cancer treatment.

Researcher(s)

• Promoter: Lion Eva
• Co-promoter: Anguille Sébastien
• Fellow: Flumens Donovan

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project website

Project type(s)

• Research Project