Polish Chimeric Antigen Receptor T-cell Network

Acronym
CAR-NET
Project Title
Polish Chimeric Antigen Receptor T-cell Network
Financing Institution

Medical Research Agency

Medical Research Agency

Lead
dr hab. n. med. Radosław Zagożdżon (Kierownik Projektu) / prof. dr hab. Sebastian Giebel (Główny Badacz)
Project Objective

 

Research "Polish Chimeric Antigen Receptor T-cell Network, Project number 2020/ABM/04/00002-00, financed by the Medical Agency, Poland, from the state budget funds

The aim of the Project is to develop practically from scratch the Polish CAR-T drug with a similar effectiveness to the currently existing ones, and at a much better price. For this purpose, innovative solutions will be developed which, after the pre-clinical phase, will be verified during a multicentre clinical trial. Importantly - the CAR T cells production process will take place in Poland in a dedicated GMP laboratory, the creation of which will also be possible thanks to the ABM subsidy. 

The specific goals are:

  1. optimization of therapy based on research and production in Poland,
  2. development of CAR T-cells in new indications,
  3. increasing availability by reducing product costs and creating a network of competent centers,
  4. creating a modern scientific and clinical base for the development of this therapy.

The optimization of therapy is based on the assumption that early uptake, by reducing the exposure of lymphocytes to chemotherapy, may contribute to a better quality of the product. The feasibility of this strategy will be the subject of a pilot study (CAR-NET-1) using a commercial product. Lymphocytes will be collected after failure of first-line treatment and used only in patients who do not achieve complete remission with second-line treatment. CAR-T is planned to be treated in 40 out of approximately 60 patients with aggressive B-cell lymphomas (B-NHL) and acute lymphoblastic leukemia (ALL), included in the study in 2022-2023.

Subsequently, clinical trials will be carried out on the proprietary solutions of the CAR-NET Consortium researchers:

a) with the use of nanoparticles (VHH), which may contribute to increasing the efficiency of transduction, assembly, specificity and, consequently, the effectiveness of the therapy. Their use will be the subject of a phase I / II study (CAR-NET-2) to determine the maximum tolerated dose, and in the extended phase - safety and efficacy in patients with aggressive B-NHL. In this phase, a "sell-off" lymphocyte donation strategy will be used. It is planned to use treatment in 110 out of approximately 160 patients included in the study in the years 2024-2025;

b) CAR T-cells with anti-CD19 / CD22 specificity with a pharmacological "off" and "on" mechanism. Initially, only anti-CD19 stimulation will be active. In the case of resistance / recurrence or excessive toxicity, it will be silenced and anti-CD22 stimulation will be activated. It is assumed that this therapy is more effective and safe than the currently available CAR T-cells. This will be the subject of a phase I trial (CAR-NET-3) to establish the maximum tolerated dose. 30 ALL patients are planned to be included in the period 2024-2025.

Clinical studies will be accompanied by a number of translational studies aimed at assessing the expansion of CAR T-cells in vivo, the mechanisms of lymphocyte depletion, and other resistance mechanisms.

In parallel, preclinical studies on cell lines and in animal models will be carried out on the use of CAR T-cells in alternative indications: such as solid tumors (including glioblastoma multiforme) and in patients with IgA nephropathy (autoimmune disease).

The partners include: Maria Sklodowska-Curie National Research Institute of Oncology, University Clinical Center of the Medical University of Warsaw, Institute of Hematology and Transfusion Medicine, Przemienienia Pańskiego Teaching Hospital of Karol Marcinkowski Medical University in Poznań, University Hospital No. 1 of Dr. Antoni Jurasz in Bydgoszcz, Karol Marcinkowski Medical University in Poznań, Pomeranian Medical University in Szczecin, Provincial Multidisciplinary Center of Oncology and Traumatology of M. Kopernik in Łódź, Independent Public Teaching Hospital No. 1 of Prof. Tadeusz Sokołowski of the Pomeranian Medical University in Szczecin, the Świętokrzyskie Cancer Center and the Medical University of Łódź.

 

The initiator of the Project, and ultimately the coordinator of the Clinical Trial (Principal Investigator) is prof. dr hab. Sebastian Giebel - Head of the Department of Bone Marrow Transplantation and Oncohematology in the Gliwice branch of the National Research Institute of Oncology.

Currently, CAR-T therapies are treated as breakthrough strategies in which the cells of the immune system (e.g. T lymphocytes) isolated from the cancer patient are introduced in the laboratory with genetic material for very sophisticated synthetic proteins called chimeric antigen receptors (CARs) and then such modified lymphocytes are administered into the patient's blood. CAR proteins are designed to recognize a specific protein (e.g. CD19 molecule) on the surface of a target cell, and then activate a T cell to kill that target cell. In this way, we can precisely remove a specific type of cell from the body, e.g. cells of those leukemias or lymphomas that have the CD19 molecule on their surface. This means that patients with such diseases could potentially be eligible for CAR-T therapy. In practice, however, CAR-T therapies are used only when all other therapies (e.g. chemotherapy or other types of immunotherapy) for these cancers fail. The reason is the significant cost and complexity of CAR-T therapy production.