Chimeric antigen receptor (car) tcells expressing b cell maturation (bcma) and other survival nf-kappa light chain antigens baff (blys) april taci and baff-r in treatment of multiple myeloma
1. SBMU (Shahid Beheshti Medical University)/ Shahid Rahimi Medical And Educational Center
The modern concept of targeted therapy in hematologic malignancies in general, aims at generating agents committed to targeting malignant cells more specifically, with less toxicity. using of car t-cells can be applicable to a broad range of patients irrespective of mhc type. based on 3 bold advantages: few side effects, working in a non-major histocompatibility complex-restricted manner and target non-protein taas; adoptive transfer of car-modified t cells is a promising strategy for remission of some specific malignancies
The chimeric antigen receptor (car) is a t cell surface receptor that simulates the physiological functions of the native t cell receptor (tcr). it is composed of an extracellular antigen recognition domain, a spacer, a transmembrane domain and an intracellular t cell activation domain.in 1989 gross et al. constructed a chimeric tcr (ctcr) gene made by replacing extracellular domains of the tcr with immunoglobulin homologs. the resulting ctcr was expressed on the surface of cytotoxic t lymphocytes, recognized antigen in a non-mhc-restricted manner. chimeric proteins have resulted in biochemical events of early t cell activation such as interleukin-2 (il-2) production and ca2+ influx. in 1993 eshhar et al. pioneered to design a gene composed of a single chain variable fragment (scfv) of an antibody linked with ζ chains, which is aimed to overcome the difficulty in activating anti-tumor tcells through the tcr. zhong et. al., have demonstrated enhanced cytokine production, improved in vivo t-cell survival, enhanced tumor elimination, improved pi3k/akt pathway activation, enhanced bcl-xl expression and reduced t cell apoptosis for a third generation car.
cars for general hematological malignancies
cd19 is a transmembrane glycoprotein that is involved in the regulation of the activation of b-cells. cd19 express uniformly at all stages of b-cell differentiation in over 95% of b-cell malignancies. malignancies such as chronic lymphocytic leukemia, b-cell nhl and b-cell acute lymphoblastic leukemia. cd19 has shown success in clinical settings to treat all of these disorders. despite the high levels of complete response rates in patients, relapse from cd19 car therapy can occur also long-term persistence of cd19-specific car-t cells is associated with elimination of normal b lymphocytes, resulting impairment of humoral immunity. with this in mind, new targets are being identified and evaluated.
multiple myeloma (mm) is a malignancy defined by the accumulation of clonal plasma cells within the bone marrow with evidence of end organ damage. evidence of disease includes lytic bone lesions, pathologic fractures, hypercalcemia, anemia, renal impairment and increased susceptibility to opportunistic infections
proliferation and survival antigens
1- il-6, ifnα and il-6 related family of cytokines
2- pi3 kinase /akt pathway related factors
3- factors activating nf-kappa b: the tnf family ligands, april interact with three tnfr family members: taci, baffr and bcma. april and taci bind independently to glycosaminoglycan structures such as those in syndecan-1 (cd138), or other proteoglycans. the interaction pattern between baff april and their receptors is both specific and redundant.
b-lymphocyte stimulator (blys), is a tumor necrosis factor (tnf) homologue that activates apoptosis.
the architecture of the april gene resembles that of baff. however, april does not form 60-mers, but possesses residues that are crucial for binding to glycosaminoglycans.
the genomic organization of taci is similar to that of bcma and baff-r, but the ligand-binding region is duplicated.
bcma (b cell maturation antigen) is a tnf receptor (tnfr) family member that is express on terminally differentiated b cells; a cell surface glycoprotein and non–tyrosine kinase receptor expressed on mm cell lines and patient mm cells at high levels
Bcma is an attractive antigen for car t therapy. based upon the highly restricted normal tissue expression of bcma along with its high expression on malignant plasma cells, de-xiu bu, et al did an effort to minimize the clinical risk of car directed immunity that could result in anaphylaxis or immune-mediated loss of car t cells. they generate a car targeting bcma for adoptive t cell therapy of multiple myeloma
Anti bcma car t-cells, targeting an antigen other than cd19 can induce complete remissions of a hematologic malignancy. engineered car-bcma t cells have powerful activity against mm that was resistant to standard therapies. these results should encourage further efforts to enhance anti-bcma car t cell therapies
Anti-bcma cars, multiple myeloma