Chimeric antigen receptor T cell therapy

A method of manufacturing an anti-CD19 immunotherapy infusion T cell product with improved durable clinical efficacy and increased likelihood of a rapid response within approximately two weeks in the treatment of Non-Hodgkin's Lymphoma (NHL) in a human subject in need thereof, with decreased toxicity, comprising:

• (i) Preparing a baseline T cell product from an expanded population of lymphocytes comprising anti-CD19 chimeric antigen receptor (CAR)-T cells with various baseline T cell phenotypes;
• and
• (ii) Preparing an immunotherapy infusion T cell product from the baseline T cell product by increasing or maximizing a percentage of CD4+ T cells and CD8+ T cells with a CD45RA+ CCR7+ naïve phenotype in the immunotherapy infusion T cell product and normalizing the number of said cells to the subject's tumor burden;
• wherein the immunotherapy infusion T cell product comprises anti-CD19 CAR-T cells;
• wherein the various baseline T cell phenotypes comprise CD45RA-CCR7+ TCM, central memory T cells;
• CD45RA+CCR7− TEFF, effector T cells;
• CD45RA−CCR7− TEM, effector memory T cells;
• and/or TN, CD45RA+CCR7+ naïve T cells, and
• wherein the step of increasing or maximizing a percentage of CD4+ T cells and CD8+ T cells with a CD45RA+ CCR7+ naïve phenotype in the T cell product comprises ensuring that the immunotherapy infusion T cell product includes at least a total of 20×106 CD4+ T cells and CD8+ T cells with the CD45RA+ CCR7+ naïve phenotype in the immunotherapy infusion T cell product for administration to the human subject, thereby manufacturing an immunotherapy infusion T cell product with improved durable clinical efficacy, as measured by durable clinical response, wherein durable clinical response is defined as ongoing response at a median follow up time of 1 year after administration of the immunotherapy infusion T cell product, and increased likelihood of a rapid response within approximately two weeks, with decreased toxicity in terms of Grade >3 neurologic events (NE) and Grade >3 cytokine release syndrome (CRS) after infusion, said improvement in durable clinical efficacy and said increased likelihood of rapid response within approximately two weeks being relative to that of the baseline T cell product without said increase or maximization of the percentage of CD4+ T cells and CD8+ T cells with a CD45RA+ CCR7+ naïve phenotype, and wherein treatment comprises reversing, alleviating, ameliorating, or slowing lymphoma progression, wherein decreased toxicity means that the higher the number of CD45RA+ CCR7+ in the infusion product normalized to the subject's tumor burden, the lower the probability of the subject experiencing post-infusion Grade >3 NE and Grade >3 CRS.