Investigational Immunotherapeutics for B-Cell Malignancies

Quintás‐Cardama, Alfonso; Wierda, William G.; O’Brien, Susan

doi:10.1200/jco.2009.22.8254

Cited by 22 publications

(13 citation statements)

References 93 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The toxin or drug moieties of these biotherapeutic agents are delivered into target leukemia cells together with the targeted CD22 molecules by antibody-mediated endocytosis (56)(57)(58)(59). Antibody-mediated internalization of CD22 is dependent on its physical interaction with the clathrin-associated AP-2 adapter complex via tyrosinebased specific internalization motifs within its cytoplasmic domain (59,60). Tyr 843 or Tyr 863 and surrounding amino acids in the cytoplasmic tail of CD22 comprise the primary binding site for the AP50 subunit of AP-2 (60,61).…”

Section: Resultsmentioning

confidence: 99%

CD22 EXON 12 deletion as a pathogenic mechanism of human B-precursor leukemia

Uckun

Goodman

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Here, we report that primary leukemic cells from infants with newly diagnosed B-precursor leukemia express a truncated and functionally defective CD22 coreceptor protein that is unable to transmit apoptotic signals because it lacks most of the intracellular domain, including the key regulatory signal transduction elements and all of the cytoplasmic tyrosine residues. Expression of this structurally and functionally abnormal CD22 protein is associated with a very aggressive in vivo growth of patients' primary leukemia cells causing disseminated overt leukemia in SCID mice. The abnormal CD22 coreceptor is encoded by a profoundly aberrant mRNA arising from a splicing defect that causes the deletion of exon 12 (c.2208-c.2327) (CD22ΔE12) and results in a truncating frameshift mutation. The splicing defect is associated with multiple homozygous mutations within a 132-bp segment of the intronic sequence between exons 12 and 13. These mutations cause marked changes in the predicted secondary structures of the mutant CD22 pre-mRNA sequences that affect the target motifs for the splicing factors hnRNP-L, PTB, and PCBP that are up-regulated in infant leukemia cells. Forced expression of the mutant CD22ΔE12 protein in transgenic mice perturbs B-cell development, as evidenced by B-precursor/B-cell hyperplasia, and corrupts the regulation of gene expression, causing reduced expression levels of several genes with a tumor suppressor function. We further show that CD22ΔE12-associated unique gene expression signature is a discriminating feature of newly diagnosed infant leukemia patients. These striking findings implicate CD22ΔE12 as a previously undescribed pathogenic mechanism in human B-precursor leukemia.

show abstract

Section: Resultsmentioning

confidence: 99%

CD22 EXON 12 deletion as a pathogenic mechanism of human B-precursor leukemia

Uckun

Goodman

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…[13][14][15] Therefore, new therapeutics with known but also alternative mode of action and lower toxicity profile are necessary. [16][17][18][19] The novel class of bispecific single-chain antibody construct (BiTE) blinatumomab is currently under investigation. Blinatumomab recruits and activates T cells through CD3 of the T-cell receptor (TCR) complex for redirected lysis of malignant cells and non-malignant cells expressing CD19.…”

Section: Introductionmentioning

confidence: 99%

Pediatric posttransplant relapsed/refractory B-precursor acute lymphoblastic leukemia shows durable remission by therapy with the T-cell engaging bispecific antibody blinatumomab

et al. 2014

View full text Add to dashboard Cite

“…Monoclonal antibodies (mAb) specific for tumor antigens are efficacious in the treatment of cancers (1); these include anti-CD20 mAb (rituximab) for CD20 þ lymphoid malignancies (2) and anti-Her2/Neu mAb (trastuzumab) for Her2/Neu þ solid tumors (3). A major mechanism for the tumoricidal activity is antibody-dependent cell-mediated cytotoxicity (ADCC), which is executed by the Fc receptor-bearing innate immune cells including natural killer (NK) cells, gd-T cells, macrophages, and neutrophils against the opsonized cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Gene-Modified Human α/β-T Cells Expressing a Chimeric CD16-CD3ζ Receptor as Adoptively Transferable Effector Cells for Anticancer Monoclonal Antibody Therapy

Ochi

Fujiwara

Tanimoto

et al. 2014

Cancer Immunology Research

View full text Add to dashboard Cite

The central tumoricidal activity of anticancer monoclonal antibodies (mAb) is exerted by FcgR IIIa (CD16)-expressing effector cells in vivo via antibody-dependent cell-mediated cytotoxicity (ADCC), as observed for natural killer (NK) cells. In practice, chemotherapy-induced leukopenia and exhaustion of NK cells resulting from ADCC often hamper the clinical efficacy of cancer treatment. To circumvent this drawback, we examined in vivo the feasibility of T cells, gene-modified to express a newly generated affinity-matured (158V/V) chimeric CD16-CD3z receptor (cCD16z-T cells), as a transferable alternative effector for cancer mAb therapy. cCD16z-T cells were readily expandable in ex vivo culture using anti-CD2/CD3/CD28 beads and recombinant human interleukin-2 (rhIL-2), and they successfully displayed ADCC-mediated tumoricidal activity in vitro. During ADCC, ligation of opsonized cancer cells to the introduced cCD16z-T cells stimulated the effector cells to produce proinflammatory cytokines and release toxic granules through the activation of the Nuclear factor of activated T cells (NFAT) pathway after phosphorylation of the CD3z chain. In parallel, these stimulated cCD16z-T cells transiently proliferated and differentiated into effector memory T cells. In contrast, NK cells activated by rhIL-2 displayed similar ADCC activity, but failed to proliferate. Human cCD16z-T cells infused concomitantly with anti-CD20 mAb synergistically inhibited the growth of disseminated Raji cells, a CD20þ lymphoma cell line, in immunodeficient mice, whereas similarly infused rhIL-2-treated NK cells survived for a shorter time and displayed less effective tumor suppression. Our findings strongly suggest the clinical feasibility of cCD16z-T cells as adoptively transferable ADCC effector cells that could potentially enhance the clinical responses mediated by currently available anticancer mAbs.

show abstract

Investigational Immunotherapeutics for B-Cell Malignancies

Cited by 22 publications

References 93 publications

CD22 EXON 12 deletion as a pathogenic mechanism of human B-precursor leukemia

CD22 EXON 12 deletion as a pathogenic mechanism of human B-precursor leukemia

Pediatric posttransplant relapsed/refractory B-precursor acute lymphoblastic leukemia shows durable remission by therapy with the T-cell engaging bispecific antibody blinatumomab

Gene-Modified Human α/β-T Cells Expressing a Chimeric CD16-CD3ζ Receptor as Adoptively Transferable Effector Cells for Anticancer Monoclonal Antibody Therapy

Contact Info

Product

Resources

About