Next generation, off-the-shelf, non fratricide-directed, CAR immunotherapy for relapse/refractory T-cell acute lymphoblastic leukemia

Projektinformationen

CARxALL

ID Finanzhilfevereinbarung: 101113067

DOI

10.3030/101113067

EK-Unterschriftsdatum 13 März 2023

Startdatum 1 April 2023

Enddatum 31 Juli 2026

Finanziert unter

• The European Innovation Council (EIC)

Gesamtkosten

€ 2 497 500,00

EU-Beitrag

€ 2 497 500,00

Koordiniert durch

ONECHAIN IMMUNOTHERAPEUTICS S.L.
Spain

Periodic Reporting for period 1 - CARxALL (Next generation, off-the-shelf, non fratricide-directed, CAR immunotherapy for relapse/refractory T-cell acute lymphoblastic leukemia)

Berichtszeitraum: 2023-04-01 bis 2024-03-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

R/R T-ALL remains a major clinical challenge. Despite improved survival rates thanks to intensive chemotherapy regimens, event-free (EFS) and overall (OS) survival remains <70% and R/R T-ALL has a particularly poor outcome. There are currently no potential curative options for R/R T-ALL beyond hematopoietic stem cell transplantation (HSCT) and conventional chemotherapy, which is linked to large trade-offs in toxicities. Sadly, >90% of patients with R/R T-ALL/LL ultimately die. Strategies targeting T-cell malignancies using immunotherapies (including CARTs) remain challenging because of the shared expression of target antigens between normal and malignant T-cells, ultimately leading to life-threatening immunodeficiency due to T-cell aplasia and fratricide of CARTs, which limits their therapeutic efficacy.
Here, we propose a unique and innovative approach to address this unmet clinical need based on the dual targeting of two specific antigens with expression restricted to T-cell lymphoblasts. Our consortium aims to provide a cost-effective immunotherapeutic alternative for most of the R/R T-ALL patients by the dual targeting of two tnon-fratricide antigens using our scalable, HLA-independent, allogenic, off-the-shelf, proprietary platform of CORD-GDT cells, thus overcoming the challenges of harvesting sufficient numbers of functional effector T cells from multi-treated patients with advanced disease while avoiding the toxicities derived from other shared antigens between healthy and malignant T cells . Our strategy will be preclinically assayed using cutting-edge experimental models, and we will mature and scale-up the proprietary platform of universal CORD-GDT cells redirected against these two non-fratricide antigens, expected to provide superior effector features and contribute to ad-hoc point-of-care treatment with cost-effective, ready-to-use and off-the-shelf effector cells.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

The work carried out from March 2023 to March 2024 belongs to objectives of WP1 that aim the develop a scalable platform of allogeneic off-the-shelf gamma delta (γδ) T cells. An optimal protocol for the in vitro expansion of this cell has been explored and their transduction investigated. First in vitro characterization was carried out and a interim regulatory and business plan were outlined.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

A proprietary platform of “off-the shelf” HLA-unrestricted allogeneic human gammadelta T-cells is being developed. Gammadelta T cells have gained increasingly attention as an attractive tool for cancer adoptive cellular immunotherapy due to their potent anti-viral activity, predominance in tumour infiltrates, and unique role in immunosurveillance. In contrast to αβ T cells, γδ T cells do not depend on MHC peptide presentation to recognize target cells, so they bridge innate and adaptive immunity and participate in various immune responses. The innate-like properties of γδ T cells mirror those of NK cells and high numbers of γδ T cells have been associated to better clinical outcome in several cancer types.
The proposed platform is unique: the cells are derived from stem cells and offer significantly greater scalability and consistency, as well as reduced cost compared to autologous platforms. This new platform is highly competitive amongst other allogeneic platforms, most of which rely on donor cells as starting material.
Beyond the first product, the platform will subsequently be used to develop multiple allogeneic products, supported by the same platform IP and product-specific patents.