Search

B-cell maturation antigen (BCMA) is a prominent tumor-associated target for chimeric antigen receptor (CAR)-T cell therapy in multiple myeloma (MM). Here, we describe the case of a patient with MM who was enrolled in the CARTITUDE-1 trial (NCT03548207) and who developed a progressive movement disorder with features of parkinsonism approximately 3 months after ciltacabtagene autoleucel BCMA-targeted CAR-T cell infusion, associated with CAR-T cell persistence in the blood and cerebrospinal fluid, and basal ganglia lymphocytic infiltration. We show BCMA expression on neurons and astrocytes in the patient's basal ganglia. Public transcriptomic datasets further confirm BCMA RNA expression in the caudate of normal human brains, suggesting that this might be an on-target effect of anti-BCMA therapy. Given reports of three patients with grade 3 or higher parkinsonism on the phase 2 ciltacabtagene autoleucel trial and of grade 3 parkinsonism in the idecabtagene vicleucel package insert, our findings support close neurological monitoring of patients on BCMA-targeted T cell therapies. A progressive movement disorder in a patient with multiple myeloma treated with anti-BCMA CAR-T cells that might have been related to on-target activity in the brain supports prospective neurologic monitoring after BCMA-targeting therapies., Author(s): Oliver Van Oekelen [sup.1] [sup.2] , Adolfo Aleman [sup.1] [sup.2] , Bhaskar Upadhyaya [sup.2] [sup.3] [sup.4] , Sandra Schnakenberg [sup.5] [sup.6] , Deepu Madduri [sup.2] [sup.3] , Somali Gavane [...]

Chimeric antigen receptor (CAR) T cells mediate anti-tumour effects in a small subset of patients with cancer.sup.1-3, but dysfunction due to T cell exhaustion is an important barrier to progress.sup.4-6. To investigate the biology of exhaustion in human T cells expressing CAR receptors, we used a model system with a tonically signaling CAR, which induces hallmark features of exhaustion.sup.6. Exhaustion was associated with a profound defect in the production of IL-2, along with increased chromatin accessibility of AP-1 transcription factor motifs and overexpression of the bZIP and IRF transcription factors that have been implicated in mediating dysfunction in exhausted T cells.sup.7-10. Here we show that CAR T cells engineered to overexpress the canonical AP-1 factor c-Jun have enhanced expansion potential, increased functional capacity, diminished terminal differentiation and improved anti-tumour potency in five different mouse tumour models in vivo. We conclude that a functional deficiency in c-Jun mediates dysfunction in exhausted human T cells, and that engineering CAR T cells to overexpress c-Jun renders them resistant to exhaustion, thereby addressing a major barrier to progress for this emerging class of therapeutic agents. Chimeric antigen receptor (CAR) T cells engineered to overexpress the canonical AP-1 transcription factor c-Jun are resistant to T cell exhaustion, and provide enhanced therapeutic benefit in mouse tumour models., Author(s): Rachel C. Lynn [sup.1] [sup.11] , Evan W. Weber [sup.1] , Elena Sotillo [sup.1] , David Gennert [sup.2] , Peng Xu [sup.1] , Zinaida Good [sup.1] [sup.3] [sup.4] , [...]

To delineate the in vivo role of different costimulatory signals in activating and expanding highly functional virus-specific cytotoxic [CD8.sup.+] T cells, we designed synTacs, infusible biologics that recapitulate antigen-specific T cell activation signals delivered by antigen-presenting cells. We constructed synTacs consisting of dimeric Fc-domain scaffolds linking CD28- or 4-1BB-specific ligands to HLA-A2 MHC molecules covalently tethered to HIV- or CMV-derived peptides. Treatment of HIV-infected donor PBMCs with synTacs bearing HIV- or CMV-derived peptides induced vigorous and selective ex vivo expansion of highly functional HIV- and/or CMV-specific [CD8.sup.+] T cells, respectively, with potent antiviral activities. Intravenous injection of HIV- or CMV-specific synTacs into immunodeficient mice intrasplenically engrafted with donor PBMCs markedly and selectively expanded HIV-specific (32-fold) or CMV-specific (46-fold) human [CD8.sup.+] T cells populating their spleens. Notably, these expanded HIV- or CMV-specific [CD8.sup.+] T cells directed potent in vivo suppression of HIV or CMV infections in the humanized mice, providing strong rationale for consideration of synTac-based approaches as a therapeutic strategy to cure HIV and treat CMV and other viral infections. The synTac platform flexibility supports facile delineation of in vivo effects of different costimulatory signals on patient-derived virus-specific [CD8.sup.+] T cells, enabling optimization of individualized therapies, including HIV cure strategies., Introduction Naive T cells are activated and expanded by 3 coordinated signals elicited by antigen-presenting cells (APCs): signal 1, an antigen-specific signal provided by TCR recognition of its cognate peptide/ [...]

T cell receptors (TCR) recognize antigenic peptides displayed by MHC molecules. Whereas T-cell recognition of foreign peptides is essential for immune defense against microbial pathogens, recognition of self-peptides can cause autoimmune disease. Structural studies of anti-foreign TCR showed remarkable similarities in the topology of TCR binding to peptide--MHC, which maximize interactions with the ligand. However, recent structures involving autoimmune and tumor-specific TCR have revealed that they engage self-peptide-MHC with different topologies, which are suboptimal for TCR binding. These differences might reflect the distinct selection pressures exerted on anti-microbial versus autoreactive T cells. The structures also provide new insights into TCR cross-reactivity, which can contribute to autoimmunity by increasing the likelihood of selfpeptide--MHC recognition.

Recent laboratory studies show that the immune system not only practices clonal selection of lymphocytes but also engages in molecular selection of receptors. Immune cells have been demonstrated to change their antigen receptors before cellular selection. Developing lymphocytes and more mature T and B cells play host to secondary antigen receptor gene recombination. A form of 'editing' takes place in the developing lymphocyte as a result of autoantigen receptor ligation. Antigen-generated receptor selection can potentially influence immune responses.

Omenn syndrome refers to a rare autosomal recessive genetic disorder with severe combined immunodeficiency symptom associated with erythrodermia, eosinophilia, hepatosplenomegaly and lymphadenopathy. Such a disorder can be attributed to recessive mutations in the Rag-1 or Rag-2 genes. These mutations have resulted to reduced V(D)J activity and immunodeficiency of patients suffering from Omenn syndrome. Thus, V(D)J recombination deficiencies can be a molecular basis of such a disease.

The strong expression of major histocompatibility complex and the minor expression of some adhesion and B7 costimulatory molecules do not present alloantigen efficiently in humans follicular lymphoma cells. However, in vitro, the activation of follicular lymphoma cells via CD40 pathway provides signals to T cells to become efficient alloantigen-presenting cells. This evidence implies that expression of major histocompatibility complex and expression of multiple adhesion and costimulatory molecules are required for the correction of defective tumor immunity.

Modified forms of the antigenic peptide cause positive selection in beta 2M(-/-) TCR transgenic mice. Addition of single synthetic peptides to fetal thymic organ culture initiates a differentiation pathway that results in functional maturation. The phenotype of the peptide-selected thymocytes resembles that of CD8+ T cells and enables response to antigens. Low efficiency ligands possibly mediate the positive selection process.

The expression of high levels of the gamma chain of the high-affinity receptor for IgE (Fc-epsilon-RI-gamma) as one invariant subunit of their T-cell antigen receptor (TCR)/CD3 complex results from the isolation of gamma delta T-cells from spleen and intestinal epithelial tissues. This is not evident in most alpha beta T-cells. Fc-epsilon-RI-gamma is present as a homodimer and a heterodimer, linked to the TCR gamma chain.

In vitro mutagenesis analysis of the H-2T region gene product T22b gene, in which a self-reactive gamma delta T-cell clone (KN6) is specific, was used to explore the possible role of a peptide in the association between the KN6 gamma delta T-cell receptor and T22b. Recognition by the gamma delta T-cell receptor is influenced by mutations at the bottom of the putative antigen-binding groove of T22b. The association does involve a peptide.

An analysis of the CD45 human leukocyte antigen reveals that one CD45 molecule has about six bi-, tri, and tetraantennary complex sugar chains with poly(N-acetyllactosamine) groups and alpha-2,6-linked residual sialic acid. The 220 K isotype of CD45 has 17 N-glycosylation sites, implying that the sugar chains occupy one-third of the sites. The partial occupation of sites by the sugar chains is due to site variation in each CD45 isotype occurring due to variable use of site encoding exons.

Influence of CD4 overexpression in CD4+ CD8+ thymocytes on CD4-related p56lck tyrosine kinase activity and on the modulation of T-cell antigen receptor expression, is analyzed. Decline in signaling commitment of a T-cell antigen surface receptor is ascribed to CD4 overexpression which incapacitates its crosscoupling, resulting in the activation of p56lck molecules and inhibiting the regulatory function of CD4 during T-cell antigen receptor expression.

Bound antigen for the subsequent processing and presentation to T cells is internalized by membrane immunoglobulin. Significant differences in cytoplasmic domains are exhibited by the five immunoglobulin isotypes. A high efficacy in the antigen presentation is manifested by the usage of matched B lymphoma transfectants. The alpha/beta sheath of the receptor, which has a correlation with the internalization of polyvalent antigen, causes the efficiency. The provision of the cytoplasmic domain of the beta-sheath polypeptide enables the resolution of the efficient presentation to a sheathless antigen receptor.

Anti-CD3 and anti-Fyn immunoprecipitates have PI 3-kinase activity as evaluated by TLC and HPLC. Free and receptor-bound Src-related tyrosine kinase p59fyn(T) bound to the lipid kinase. A unique process of interaction with PI 3-kinase has been evolved by Src-related kinases. PI-3 primarily bound to the SH3 region of Fyn. PI 3-kinase is a target of SH3 regions and probably will significantly influence the signals obtained from the T-cell antigen receptor zeta/CD3-p59fyn complex, because Fyn SH3 directly bound to the p85 subunit of PI 3-kinase, and an enhancement in the identification of Fyn SH3-related PI3-kinase activity is caused by anti-CD3 crosslinking.

The potential processes of immunosuppression by 7,12-dimethylbenz(a)anthracene (DMBA) and the influence on antigen-receptor signaling and Ca2+ homeostasis in human T-cells were studied. DMBA induced a quick and prolonged rise in Ca2+ levels in HPB-ALL cells, through the release of cytoplasmic Ca2+. The anti-CD3/CD4 mobilization of Ca2+ was impaired by DMBA. The quick rise in intracellular Ca2+ generated in human T cells by DMBA, may be because DMBA enhances the development of lP3. DMBA enhances the tyrosine phosphorylation of PLC-gamma 1 and arbitrarily the protein kinases Fyn and Lck.

A study demonstrates that the acute generation interleukin 2(IL-1) and interferon-gamma (IFN-gamma) by naive CD4+ and CD8+ T cells in response to accessory cell-dependent activation with soluble anti-CD3 is strongly inhibited by IL-4. The IL-2 generation in response to antigen and antigen-presenting cells (APCs) of T cells from T-cell antigen receptor (TCR)-transgenic mice is inhibited by IL-4. IL-2 and IFN-gamma generation by primed T cells or T-cell clones or by naive T cells activated with phorbol ester and calcium ionophore in response to antigen plus APCs are not inhibited by IL-4.

The rapid degradation of the T-cell antigen receptor (TCK) beta-chain is prevented when it assembles with single CD3 delta, gamma and epsilon subunits in the endoplasmic reticulum (ER). The associations between membrane spanning domains and the presence of receptor ectodomains is necessary for the neutralization of transmembrane proteolylic targeting information. The marking of transmembrane targeting information between receptor ectodomains slows the dissociation of CD3 subunits from the beta-chains.

The mechanisms by which protein-tyrosine kinase (PTK) is activated by the T cell antigen receptor (TCR) are reviewed. TCR has alpha, beta, CD3 and zeta chains, wherein the last two are responsible for signal transduction. Three distinct PTKs implicated in TCR function are Fyn, Lck and ZAP-70. A model of TCR-mediated PTK activation suggests that antigen recognition activation motifs couple the TCR to intracellular PTKs with Lck or Fyn required for ZAP-70 activation.

The binding of the p70 lupus autoantigen tothe transcriptional enhancer of the T-cell receptor beta-chain gene is discussed. Experiments involve the in vivo footprinting, gel shift assaying, UVcrosslinking, Southwestern blot and Western immunoblot analyses of cell samples. The sequence specific binding of the DNA and the transcription regulation of it by the p70 lupus were demonstrated.

The absence of extra, functionally polymorphic structures in an in vitro mouse major histocompatibility complex class I-restricted cytotoxic T-cell response to vaccinia and influenza viruses is discussed. Mousestrains were subjected to split-clone limiting dilution analysis, target cell treatments and fluorescence-activated cell sorter analysis. The almost completeabsence of functional polymorphism in human and mice pathway antigen presentations was established.

The retinoblastoma (RB) protein can be phosphorylated in vitro by purified cyclin-dependent kinase/cell division kinase 2 (cdk2) at the areas phosphorylated in the cell. cdk2 developed a complex with the RB protein in vitro, and the simian virus 40 large T antigen failed to competitively inhibit its development. The cell-dependent phosphorylation of the RB protein involves cdk2 or a cdk2-related protein.

The T cell receptor (TCR) from T cell clone 2C is examined to understand the mechanisms that govern TCR-peptide MHC (pMHC) binding and the role of different regions of the TCR in affinity and antigen specificity. The subtle changes observed in individual complementary determining regions (CDRs) account for the diverse thermodynamic and kinetic binding mechanisms and for the different peptide fine specificities.

SLAP-130/Fyb (SLP-76-associated phosphoprotein or Fyn-binding protein; also known as Fyb/Slap) is a hematopoietic-specific adapter, which associates with and modulates function of SH2-containing leukocyte phosphoprotein of 76 kilodaltons (SLP-T6). T cells from mice lacking SLAP-130/Fyb show markedly impaired proliferation following CD3 engagement. In addition, the T cell receptor (TCR) in SLAP-130/Fyb mutant cells fails to enhance integrin-dependent adhesion. Although TCR-induced actin polymerization is normal TCR-stimulated clustering of the integrin LFA-1 is defective in SLAP-130/Fyb-deficient cells. These data indicate that SLAP-130/Fyb is important for coupling TCR-mediated actin cytoskeletal rearrangement with activation of integrin function, and for T cells to respond fully to activating signals., Following the engagement of lymphocyte surface receptors, adapter proteins play critical roles in regulating second messenger signaling cascades (1). T cell receptor (TCR) signaling (2) and murine thymocyte development (3, [...]

The activation of T cells depends on the interaction of T cell receptors with peptides (the products of viral or bacterial degradation) that are displayed on the surface of antigen [...]

Anti-Specific Helper Function of Cell-Free T Cell Products Bearing TCR V.sub.β.8 Determinants THE TCRαβ HETEROMIDER HAS been identified, and both its glyco-protein structure and its encoding genes have been characterized. [...]

The phenomena of cell rejection which takes place in failed organ transplants and bone grafts provides an opportunity to study cellular interactions. The molecular mechanism involved in this process was recently addressed in a conference in Milwaukee, Wisconsin. The focus of the conference was to develop a model of alloreactivity which conforms to both the actions which take place during the rejection process and in the observed molecular structures of the cell components. Alloreactivity refers to the immune response of cells to other cells of the same species which are composed of different genetic constituents. An example of this phenomena is the interaction of T lymphocytes and the cells that they target called the major histocompatibility complex (MHC), and the cells that they are stimulated by, which are the T-cell receptors. The primary area of discussion surrounded the specific nature of the T-cell receptor's composition. Specifically, theories on how the T-cell receptor interacts with the MHC molecule were debated. A variety of proposed models were presented and two opposing theories were discussed. It has been hypothesized that T-cell receptors react with the 'naked' MHC, the molecule in its most simple form. Others argue that a reaction can occur only when the MHC molecule is complexed with a specific series of peptides (contain amino acids which make up proteins). The formation of a clear model of the mechanism of alloreactivity is difficult because the T-cell receptors are capable of a wide range of interactions. The model which was developed that received the most support incorporated aspects of both of these theories.