Medical Research Agency

Autologous T lymphocytes modified with the gene encoding the chimeric antigen receptor (CAR-T lymphocytes) are one of the most innovative therapies in medicine. They belong to the ATMP products. Briefly, lymphocytes are collected from an oncological patient and transduced in a GMP-class laboratory with viral vectors with a construct encoding the receptor responsible for recognition of the tumor antigen. When administered to a patient, they actively fight cancer cells with unprecedented effectiveness. Currently, 2 products of international concerns are commercially available based on CAR T lymphocytes directed against CD19 antigen, registered for the treatment of B-cell acute lymphoblastic leukemia (B-OBL) in children and young adults and for the treatment of lymphomas. Unfortunately, the costs of treatment with commercial products seem to exceed the financial capabilities of the richest countries.

Treatment is sometimes associated with high toxicity, and registration restrictions do not allow their use in the adult B-OBL patients. Aim: The aim of the project is to conduct advanced research and development works in the field of a non-commercial phase I / II clinical trial of a multicentre, single-arm study with the use of ATIMP - anti-CD19 CAR -T lymphocytes produced in Poland for the treatment of adult patients with refractory and recurrent B-OBL in the context of genetic factors of tumor and patient.

Population and methods: The study will be conducted on a group of 20 adult (18-65 years old) patients with refractory or recurrent B-OBL (primary resistance or at least 1 relapse) according to the developed inclusion and exclusion criteria. Will be required, inter alia expression of CD19 antigens on> 90% of cells, good general condition (ECOG <= 2), efficient internal organs. The affection of the central nervous system will be allowed if it is not the only localization of the disease. Inter alia, patients with coexisting infections, another neoplasm, in the early period after transplantation of hematopoietic cells won’t be eligible. Patients will be closely monitored using standard methods, but also cytokine profile assessment and complex genetic tests (WES, RNASeq) to assess the correlation with the effectiveness and toxicity of the treatment.

Intervention: Peripheral blood mononuclear cells will be collected by leukapheresis from patients who successfully pass the screening phase and are included in the study. In the manufacturer's laboratory, they will be genetically modified with a licensed, innovative CAR anti-CD19 construct. After the product is released, the patient will receive lymphodepletion chemotherapy followed by CAR T lymphocytes infusion. For the first 15 days, he will be intensively monitored in a hospital setting, and then on an outpatient basis.

The course of the study: At the first stage of the project, under a tender, the Polish manufacturer CAR T, the CRO company will be selected as well as the equipment will be purchased.

The study protocol will be reported to the Bioethics Committee and the Office for Registration of Medicinal Products. The phase I / II study was divided into 3 stages. The first one will take place at the University Clinical Center of the Medical University of Warsaw and will aim at precise monitoring of safety and procedures (5 patients). In stage 2, patients will be treated in all three Partner institutions (the University Clinical Center of the Medical University of Warsaw, National Institute of Oncology and Institute of Hematology and Transfusion Medicine, 3 patients each) up to a total of 14 patients. After the preliminary statistical analysis of the treatment effectiveness, the third stage of the study will take place, during which two patients will be treated in each center.

Endpoints: The primary endpoints will be safety assessment and overall response rate (ORR). Secondary endpoints will include duration of response, PFS, OS, CAR T lymphocytes kinetics and cytokines. Moreover, exploratory endpoints based on the assessment of genetic factors related to the underlying disease and the patient's immune system were included.

Summary: The proposed study will allow to assess the safety and effects of treatment of adult patients with relapsed / refractory B-OBL using an innovative therapy based on CAR T lymphocytes. Until now, the effects of treatment in this group have been highly unsatisfactory, and alternative therapies have a cost that exceeds the cost of the test product. Actions will be taken to reduce the toxicity of therapy and to optimize the selection of patients based on genetic factors in the future. The project activities will also allow the implementation of the ATMP product, manufactured for the first time in Poland, on the Polish market.

The project is a response to the needs and goals formulated in NATIONAL ONCOLOGY STRATEGY program for the years 2020-2030, inter alia it improves access to innovative methods of treatment and is a very important supplement to treatment procedures for people who have exhausted standard therapeutic methods.

Occlusive atherosclerosis of the arteries of the lower extremities is a common lifestyle disease from the group of cardiovascular diseases, which is associated with high morbidity, mortality and a significant reduction in the quality of life of patients. It is estimated that currently approximately 202 million people worldwide suffer from lower limb obliterating atherosclerosis, and in many of them the progression of the disease leads to the loss of a limb. The incidence of the disease varies, depending on the literature, from 4.3% to 57% and depends on the adopted assessment criteria, age and risk factors in individual social groups. Advanced age, male gender, coexisting diabetes and smoking are associated with a much higher risk of morbidity.

Currently, the first line of treatment is endovascular or surgical bypass grafting. Although the technical success of such treatment is relatively high, the long-term limb salvage outcomes and the rates of limb-salvage survival are no longer satisfactory. Previous attempts to use mesenchymal stem cell therapy did not significantly affect the percentage of saved limbs, but were only used in patients for whom there was no option for revascularization. The formation of a new vascular bed, or angiogenesis, is a complex, multifactorial process, and although it is possible to grow a wide variety of stem cells responsible for the angiogenesis process, from vascular endothelial progenitor cells (EPCs), to angiogenesis-promoting hemangioscites (HPCs), to vascular stabilizing mesenchymal stem cells (MSCs) still fail to successfully and predictably initiate angiogenesis in critically ischemic tissues. It is suggested that the reason may be:

1) implantation of single-line cells with a complex and not fully understood mechanism of cell-protein interaction during angiogenesis, 2) donor cell anergy resulting from chronic inflammation in generalized atherosclerosis, 3) implantation of cells that die without access to blood and metabolic substrates before they start the process of angiogenesis, 4) implantation of allogeneic cells, which are quickly rejected by the host organism without exerting a therapeutic effect.

At the same time, a number of experimental studies have recently appeared showing the remarkably angiogenic effect of platelet-rich leukocyte fibrin (L-PRF) in initiating the development of new vascular beds. L-PRF is an autologous medicinal product isolated directly from the patient's blood by centrifuging thrombocytes and leukocytes from red blood cells and suspending them in a fibrin gel. This autologous product has angiogenesis-inducing properties, accelerating healing and modulating the immune response.

In addition to restoring temporary vessel patency, it is expected that we will significantly accelerate the process of secondary angiogenesis in the ischemic limb and suppress the perivascular inflammatory response to the revascularization procedure itself. We assume that this will largely contribute to a significantly longer period of asymptomatic or completely asymptomatic disease course, which will, secondarily, result in a higher percentage of saved limbs and possibly a reduction in mortality in this group of patients. The aim of the study is to develop new intervention methods in the treatment of critical ischemia of the lower limbs with the use of a medicinal product such as LPRF.

Over 25% of patients referred for diagnostic coronary angiography and percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) suffer from non-valvular atrial fibrillation (AF). In this particular case, balancing the prevention of thrombosis with the risk of bleeding remains difficult. Oral anticoagulation (OAC) prevents stroke and systemic embolism but does not prevent in-stent thrombosis. Dual antiplatelet therapy (DAPT) reduces the incidence of recurrent ischemic events and stent thrombosis, but is less effective in reducing the incidence of cardio-embolic strokes associated with AF. It is common practice supported by the guidelines to combine all three drugs (OAC, aspirin, and clopidogrel) in triple therapy, but this approach remains the opinion of the experts. In addition, triple therapy is associated with a high annual risk (up to 25%) of major bleeding. Therefore, new therapeutic strategies are urgently needed to maintain efficacy while improving treatment safety in patients with AF and ACS undergoing PCI. We hypothesize that dual anticoagulation therapy, including a reduced dose of ticagrelor (study group, n = 1115), is not inferior in terms of bleeding risk and protection against ischemia compared to standard triple therapy (control group, n = 1115) in patients with AF and treated with PCI for ACS.

Duration of the study (project timeframe from 01/07/2020 to 06/30/2026):

Studied population. The target population for the study is male and female patients ≥18 years of age with non-valvular AF who underwent successful PCI for ACS. AF can be paroxysmal, persistent, or permanent, but cannot be secondary to a reversible disease such as myocardial infarction, pulmonary embolism, recent surgery, pericarditis, or thyrotoxicosis. ACS can be ST segment elevation myocardial infarction (STEMI), non-STEMI myocardial infarction (NSTEMI), or unstable angina (UA).

Type 2 neurofibromatosis (NF-2) is an ultra-rare primary cancer and genetically determined disease, most often manifested in young adults. The childhood form of this disease is a unique presentation, but unfortunately it is burdened with many complications, it develops much faster than in adults, it is responsible for its severe course and an outstanding shortening of the survival time, and severe, complex disability.

Until recently, the therapies used, which undoubtedly made a real revolution in oncology and significantly improved the prognosis of patients with many cancers, were reserved only for the treatment of malignant tumors. Treatment of benign tumors has been and is the domain of oncological surgery, but the activities of a specialist doctor are usually associated with many serious complications and are rarely effective (the procedure is not radical).

Based on the described premises, and due to the inability to offer an effective therapy for reducing or at least inhibiting the growth of tumors, a study on the treatment of children with NF-2 with crizonitib was developed. Treatment that, even if it does not prevent the formation of tumors, should significantly reduce their complex disability and bring them back to society.

The study will include patients aged 4-15 years with confirmed type 2 neurofibromatosis (NF-2). They will be cared for for a period of 15 months, during which they will be taking the drug (daily dosing) and will undergo monthly check-ups to assess the safety of the therapy. Additionally, patients will also undergo an ophthalmological examination. The aim of the clinical trial is to evaluate the effectiveness of crizotinib therapy, resulting in at least the arrest of the growth dynamics of the tumor or many tumors of both the central and peripheral nervous systems.

The research is carried out by a team of doctors led by the main researcher - Dr. Marek Karwacki, specialist in pediatrics (2nd degree) as well as pediatric hematology and oncology with a doctorate in clinical genetics, employee of the University Clinical Center of the Medical University of Warsaw, Academic and Clinical Department of Oncology, Pediatric Hematology, Clinical Transplantology and Pediatrics.

The aim of the clinical trial is to evaluate the safety and efficacy of empagliflozin therapy in patients with GSD 1b. Type Ib glycogenosis is an ultra-rare, congenital, inherited autosomal and recessive disease. It manifests itself, inter alia, with severe hypoglycaemia, hepatomegaly and severe neutropenia with impaired neutrophil function, resulting in recurrent severe, sometimes life-threatening bacterial and fungal infections and inflammatory bowel disease. In the treatment of neutropenia in patients with GSD Ib, filgrastim is used, a drug that increases neutrophil count but does not improve neutrophil function in this group of patients, and is given by subcutaneous injection, usually daily. Some patients do not respond to filgrastim treatment, and all persist with recurrent infections despite treatment. Treatment with the preparation in most patients causes complications in the form of splenomegaly, sometimes accompanied by hypersplenism, gingival hyperplasia, and long-term complication of filgrastim treatment may be acute myeloblastic leukemia and myelodysplastic syndrome.

It is an open study. The study group will consist of pediatric and adult patients with biochemically and / or molecularly diagnosed glycogenosis Ib and neutropenia.

The study is carried out in two clinical centers in Poland: at the Children's Health Institute in Warsaw (IPCZD) and at the Medical University of Warsaw (MUW).

Project implemented in the period from  1 October 2020 to  31 March 2025

The aim of the project is to conduct a non-commercial clinical study of the safety and efficacy of an advanced therapy medicinal product, in which the active substance is allogeneic mesenchymal cells obtained from adipose tissue (ATMP-ASC) in the treatment of DFU. The study is based on the preliminary results obtained by the Research Laboratory Team - Cell Bank of the Medical University of Warsaw and the Department of Diabetology and Internal Medicine of the Medical University of Warsaw, as part of a pilot treatment experiment, where a preparation of this type was administered in an open, i.e. unblinded, observation without randomization. One hundred and five patients aged> 18 years who have been diagnosed with uninfected neuropathic diabetic foot syndrome will be enrolled in the study.

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.

Multicenter open study of the use of targeted therapy in pediatric patients from 3 to 18 years of age with diagnosis of diffuse intrinsic pontine glioma (DIPG) based on genetic test results (Gen) - DIPGen. Diffuse infiltrating gliomas of the bridge constitute about 8-10% of all tumors of the central nervous system (CNS) in children. While there has been spectacular progress in the treatment of childhood cancers in recent decades, this does not apply to DIPG, where the median overall survival varies between 8 and 12 months. The cause of these failures should be associated with the location of the tumor, its infiltrating nature in eloquent areas of the brainstem, which makes it impossible to perform complete tumor resection. In addition, approximately 80% of patients are diagnosed with high-grade gliomas, which undoubtedly have a negative impact on survival. The mainstay of DIPG treatment is radiation therapy. Numerous clinical trials have not shown a significant benefit from the use of chemotherapy, leaving irradiation as the only treatment option for these patients.

Moreover, due to the neurological condition of patients and the risk of its deterioration after neurosurgical interventions, with the simultaneous lack of influence of the obtained pathomorphological examination of the tumor on the patient's treatment and its survival, until recently, biopsies of this type of tumors have not been routinely performed. Hence the lack of comprehensive knowledge about the molecular properties of these tumors in children. In the last decade, the development of molecular research in human neoplasms has contributed to the development of new effective targeted therapies and improved treatment outcomes in selected neoplasms. Therefore, such solutions should be sought in children with DIPG. Identification of biomarkers, including molecular changes differentiating neoplasms with similar histological features, prognostic and prognostic markers, and molecular targets will allow for correct diagnosis, prognosis of neoplastic disease and optimization of its treatment by introducing targeted therapies. As a result, improvement in treatment outcomes in this group of patients is expected.

The project envisages a standardized diagnostic and therapeutic procedure in approximately 100 children with DIPG.

MRI scans will be performed for each patient included in the project, followed by a tumor biopsy to establish a histopathological diagnosis and identify significant molecular markers.

Molecular analysis will be carried out with the use of NGS (Next Generation Sequencing) technology at the DNA and RNA level through Whole Exome Sequencing (WES) and with the use of targeted panels (identification of gene fusions). Both the genetic material from the neoplastic tissue and the reference material from the patient's peripheral blood lymphocytes will be analyzed. The research will be conducted in two ways. In the first stage, molecular changes will be identified that will enable patients to be included in the therapeutic groups selected in the project (Annex 3). The aim of the second stage of molecular research will be to determine the full molecular profile of DIPG and to identify possible new, important therapeutic targets.

Following biopsy, patients will be scheduled for irradiation according to standard DIPG treatment. All patients will receive sirolimus during radiotherapy. Research conducted at the National Cancer Institute has shown that Rapamycin inhibits the proliferation of cells of various types of human tumors, including gliomas, and studies are currently being conducted using this medicinal product in selected diseases. The above facts justify the inclusion of sirolimus in the treatment of DIPG. Further systemic treatment will be determined based on the identified molecular targets with medicinal products licensed for other indications, which in preclinical or clinical studies show an inhibitory effect on the development of glioblastoma (sirolimus vs sirolimus in combination with trametinib).

The project is of innovative, cognitive and applied nature.

Until now, in Poland, no regular molecular tests have been conducted in children with DIPG. The number of patients planned in the project will ensure the credibility of the results and will contribute to broadening the knowledge in this field. We expect that the introduction of targeted therapies will improve treatment outcomes in the form of prolonged progression-free and overall survival, as well as improve the quality of life of patients. Assessment of the complete molecular profile may reveal new therapeutic targets for this patient group.

The aim of the RaRE-TS study is to establish the effectiveness and safety of rapamycin treatment of drug-resistant epilepsy in tuberous sclerosis (TSC).
The drug will be administered off-label; rapamycin is currently registered in transplantology; in TSC, under therapeutic experiments, it was administered in cases of organ tumours, skin lesions and in few centres as a drug added to antiepileptic drugs.
 

The aim of the project is the assessment of:
1) influence of SGLT-2 inhibitors (Empagliflozin and Dapagliflozin) on primary and secondary clinical end-points in patients with acute/unstable heart failure (AHF);
2) influence of SGLT-2 inhibitors on heart rate;
3) influence of SGLT-2 inhibitors on biomarkers and circulating micro RNA (miRNA) and microbiome metabolites
4) proposing a risk prognosis scale in order to closely monitor the course of AHF and its treatment with SGLT-2 inhibitors based on selected miRNA and biomarkers related to molecular trails related to the course of the disease