Panel A shows tumor cell recognition occurs when a CAR on a T cell ligates its antigen on the tumor. Signaling and activation is mediated by the intra-cytoplasmic signaling domains within the CAR. Activation can lead to direct cytotoxicity of tumor target by CAR T cell mediated release of granzyme and perforin. Tumor killing can also be mediated by activation of other components of the immune system through release of cytokines by CD4+ T cells. Long-term eradication and prevention against tumor relapse may be provided by long-term memory CAR T cells that form after the initial activation.
Panel B shows bone marrow-biopsy specimens obtained 3 days after chemotherapy (day -1, before CART19-cell infusion) and 6 months after CART19-cell infusion (hematoxylin and eosin). The baseline specimen shows hypercellular bone marrow (60%) with trilineage hematopoiesis, infiltrated by predominantly interstitial aggregates of small, mature lymphocytes that account for 40% of total cellularity. The specimen obtained 6 months after infusion shows trilineage hematopoiesis, without lymphoid aggregates and continued absence of CLL [10].
Panel C shows bone marrow core-biopsy samples of a multiple myeloma patient whose cancer had stopped responding after receiving an investigational personalized cellular therapy known as CTL019. The investigational treatment was combined with chemotherapy and an autologous stem cell transplant-a new strategy designed to target and kills the cells that give rise to myeloma cells. The bone marrow sample obtained before the second Autologous Stem-Cell Transplantations (ASCT) shows more than 95% involvement by multiple myeloma on hematoxylin and eosin staining. The sample obtained 100 days after the ASCT shows 1 to 2% overall cellularity and no plasma cells on hematoxylin and eosin staining [4].
