Dosage optimization of an autologous product of t-lymphocytes having a cell-surface chimeric antigenic receptor for individualized early b- leukemia eradication with negligible toxicity induction

Abstract

CAR T-cells have been proven very strong in the destruction of hematopoietic malignancy cells. In the current therapeutic strategy, doses are calculated empirically, negatively affecting the action toxicity balance of the product. In most patients, serious side effects emerge (CRS, neurotoxicity, B-aplasia), or relapses after months or years. The present invention addresses the problem of the lack of a scientific criterion for the calculation of the optimal dose of the CAR T-cells, which makes straight correlation between dose and effect impossible. The core of the invention includes: 1) theautologous IVMER-cel cell product, consisting exclusively of terminally differentiated active CAR T-lymphocytes (Fig. 10). 2) Two methods. The first determines the optimal therapeutic concentration ofthe product for early eradication of B-leukemia (Fig. 4, 5). The second method determines the maximum dose disturbing marginally the homeostasis levels of the pro- and anti-inflammatory serum cytokines and causing negligible side effects (CRS less than or equal to 1), (Fig. 7, 11). The product is intended for personalized definitive therapy of children and young adults, aged 2-24 years, and adults over 25 years old with R / R CD19+ B-ALL. Also, in CD20+ B-ALL, CD22+ B-ALL, multiple myeloma, lymphomas, adults with CLL and in autoimmune diseases.