2021-09-002 - EPICART - Development of a DNA methylation kit for predicting the response to chimeric antigen receptor (CAR)-T cell therapy

EPICART

2021-09-002

In vitro diagnostic kit to predict clinical response and prognosis in patients with B-cell malignancies undergoing CAR-T therapy. Epigenetic dysregulation plays an important role in pathologic processes such as diseases initiation and progression, regulating immune related-genes expression and affecting treatment response.

The vision of the Josep Carreras Leukaemia Research Institute is to be a world-class reference and excellent research center that contributes to the improvement of results, and the cure of patients affected by leukemia and other malignant hemopathies, through innovation, sustainability, social responsibility, talent, and professional experience. Our values at IJC are: - Scientific and Social Ethics - Interdisciplinarity - Equality and diversity - Creativity - Perseverance and continuous improvement - Sustainability

EPICART's disruptive in vitro diagnostic method will predict clinical response in patients treated with CART cells. This type of therapy is associated with high toxicity, expensiveness of the treatment and not all patients respond to treatment. As a matter of fact, our findings support that intrinsic molecular features of the preinfusion cells determine the success of the adoptive cell therapy and, thus, the “fitness” of preinfused CAR-T cells contributes to treatment effectiveness.

Despite the significant success of chimeric antigen receptor (CAR) T-cells in the treatment of haematological malignancies, little is known about the molecular factors predicting clinical outcome of this therapy and there are a non-negligible number of cases that do not respond to treatment or suffer severe side effects. It is therefore crucial to find reliable biomarkers of cell therapy efficacy and/or associated toxicities and cover this unmet need. The aim of this project is to develop an in vitro diagnostic kit to predict clinical response and prognosis in patients with B-cell malignancies undergoing CAR-T therapy and therefore improve clinical decision-making. Indeed, DNA methylation is a well-characterized epigenetic mechanism that regulates gene expression and, as a consequence, epigenetic dysregulation plays an important role in pathologic processes such as diseases initiation and progression, regulating immune related-genes expression and affecting treatment response.

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Out-licensing to a pharmaceutical company and/or medical device manufacturer.

Haematological malignancies are extremely relevant diseases in the human population and it has been estimated that more than 1.85 million of new blood cancers will be diagnosed globally in 2040, accounting for approximately 6% of all new cancer cases. Despite the success of CAR-T approach, there are still 30% of patients with refractory malignancies and the treatment itself may lead to important adverse toxicities. Furthermore, this occurs in the context of a personalized cellular treatment that it is so far extremely expensive.

- B-cell acute lymphoblastic leukemia (B-ALL) - B-cell non-Hodgkin lymphoma (B-NHL)

To further validate EPICART signature in an independent cohort of B-ALL ad B-NHL patients and study dual CD19/CD22 and NKG2D CAR-T cells in vivo behavior at high-resolution by means of state-of-the-art NGS and single cell technologies.

Co-development and licensing partner (already found)

Technical validation of EPICART signature by pirosequencing and NGS technologies.

Dr. Manel Esteller’s group has identified a methylation signature consisting of 984 genomic sites with differential DNA methylation between CAR-untransduced and CAR-transduced T cells before infusion into the patient, which are associated with increased both overall and event-free survival. In particular, this methylation signature has already been tested in a cohort of 114 patients diagnosed with B-cell malignancies, comprising acute lymphocytic leukaemia (ALL) and non-Hodgkin lymphoma (NHL), that were treated with CART19 therapy. At the moment, beyond clinical indicators such as CD19 expression levels on malignant cells, cytokine expression profile or CAR-T cells expansion and persistence in patients, there is no specific biomarker of clinical response, prognosis or toxicity, or medical devices approved to this end.

Validation of the technology in the individual cohort and in the clinics prospectively

PCT has entered in national phases in US, JP, EP, UK, Korea and CA

IPR is co-owned by IJC (69,9%), ICREA (13,6%), BSC (16,5%).

CE IVD mark and ISO or GMP procedures to develop the IVD kit (to be done by the licensor)

Patents: EP21382168 - EP21382815 - Date: Feb 2nd, 2021

Our up-to-date findings support that intrinsic molecular features of the preinfusion cells determine the success of the adoptive cell therapy and, thus, the “fitness” of preinfused CAR-T cells contributes to treatment effectiveness. Moreover, differences in the conditions of the manufacturing process from commercially available treatments and the unique functional background of the transduced T cells of each patient can modify the “omics” landscape of preinfused cells, directly affecting their activity. Overall, this new predictive information will allow, through personalized medicine, not only a better clinical decision-making that will improve patient’s clinical outcome in a global basis, which will directly have impact in clinical trials design and treatment procedures, but also in the production process of CAR-T cells..