The use of double staining with CD 5/CD 19 antibodies accompanied by two-color flow cytometric analysis clearly defined the chronic lymphocytic leukemia population and separated it from the lymphoma population.
In contrast, one case of nasal lymphoma with CD2+CD3(Leu4)+CD8+CD19-CD56+ phenotype expressed full-length Talpha, Tbeta, and Tgamma transcripts rearranged TCR beta, gamma, and deleted TCR delta genes, indicating T-lineage, These results support the view that nasal lymphomas can separated into NK-cell and T-cell neoplasms, based on differences genotypic characteristics.
The MP1-specific CTLs are amenable to subsequent genetic modification to express a CD19-specific CAR, designated CD19R, and acquire HLA-unrestricted reactivity toward CD19(+) leukemia and lymphoma tumor targets while maintaining HLA-restricted MP1 specificity.
A dimeric protein of 114kDa was obtained that showed proper bispecific binding to CD3- and CD19-positive cells and could redirect both pre-stimulated and unstimulated human T cells for lysis of human B lymphoma lines Raji, MEC-1 and Nalm-6.
The engineered CD4(+) T cells and CD8(+) T cells both exhibited specific cytotoxicity against CD19(+) leukemia and lymphoma cell lines, as well as against CD19 transfectants, and produced high-levels of antigen-dependent Th1 (but not Th2) cytokines.
In vitro, XmAb5574 enhanced antibody-dependent cell-mediated cytotoxicity 100-fold to 1,000-fold relative to an anti-CD19 IgG1 analogue against a broad range of B-lymphoma and leukemia cell lines.
We found that UCB-19BBzeta and UCB-28BBzeta T cells exhibited more cytotoxicity to CD19(+) leukemia and lymphoma cell lines than UCB-19zeta and UCB-1928zeta, although differences in secretion of interleukin-2 and interferon-gamma by these T cells were not evident.
We used T cells that were retrovirally transduced with this CAR to treat mice bearing a syngeneic lymphoma that naturally expressed the self-antigen murine CD19.
Adoptive therapy using purified T(CM) cells is now the subject of a Food and Drug Administration-authorized clinical trial for the treatment of CD19(+) B-cell malignancies, and 3 clinical cell products expressing a CD19-specific CAR for IND #14645 have already been successfully generated from lymphoma patients using this manufacturing platform.
Effective clinical treatment with anti-CD19 CAR T cells was first reported in 2010 after a patient with advanced-stage lymphoma treated at the NCI experienced a partial remission of lymphoma and long-term eradication of normal B cells.
Our data provide evidence that CD19 plays an important role in transmitting survival and proliferation signals downstream of CD40 and therefore might be an interesting therapeutic target for the treatment of lymphoma undergoing chronic CD40 signaling.
By targeting CD19, a marker expressed most B-cell tumors, as well as normal B cells, CAR T-cell therapy has been investigated as a treatment strategy for B-cell leukemia and lymphoma.
T cells can also be genetically modified with chimeric antigen receptors (CARs) to confer specificity for surface antigens, and studies of CD19 CARs in lymphoma also have had encouraging response rates.
To understand the mechanism whereby allogeneic CD19 CAR T cells may mediate anti-lymphoma activity without causing a significant increase in the incidence of GVHD, we studied donor-derived CD19 CAR T cells in allo-HSCT and lymphoma models in mice.
We transduced CB-derived NK cells with a retroviral vector incorporating the genes for CAR-CD19, IL-15 and inducible caspase-9-based suicide gene (iC9), and demonstrated efficient killing of CD19-expressing cell lines and primary leukemia cells in vitro, with marked prolongation of survival in a xenograft Raji lymphoma murine model.
More than 200 CAR T cell clinical trials have been initiated so far, most of which aim to treat lymphoma or leukemia patients using CD19-specific CARs.
The remarkable clinical response rates achieved by adoptive transfer of T cells that target CD19 in patients with leukemia and lymphoma have led to a growing number of clinical trials exploring CAR T-cell therapy for solid tumors.
The treatment of leukemia/lymphoma by chimeric antigen receptor (CAR) redirected T cells with specificity for CD19 induced complete remissions in the majority of patients, with a realistic hope for cure.