Use of anti-CD19 CAR-T lymphocytes in the treatment of adult patients with relapsed and refractory acute lymphoblastic leukemia. Phase I / II clinical trial

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.