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1
Younes, A., U. Consoli, V. Snell, K. Clodi, K. O. Kliche, J. L. Palmer, H. J. Gruss, et al. "CD30 ligand in lymphoma patients with CD30+ tumors." Journal of Clinical Oncology 15, no. 11 (November 1997): 3355–62. http://dx.doi.org/10.1200/jco.1997.15.11.3355.
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PURPOSE CD30 ligand (CD30L), which is expressed on resting B and activated T lymphocytes, can induce cell death in several CD30+ cell lines. Patients with CD30+ tumors (Hodgkin's disease and Ki-1+ non-Hodgkin's lymphoma) frequently have elevated soluble CD30 (sCD30) levels in their serum, which correlates with a poor prognosis. The role of sCD30 in protecting tumor cells from CD30L-mediated cell death and the pattern of CD30L expression on human peripheral-blood lymphocytes (PBLs) of normal donors and patients with CD30+ tumors are investigated. MATERIALS AND METHODS CD30L surface protein expression was determined by two-color flow cytometry on PBLs of patients with CD30+ tumors and normal individuals. CD30L levels were determined on subsets of PBLs before and after stimulation with phytohemagglutinin (PHA), anti-CD3 antibody, or CD40L. sCD30 was measured by enzyme-linked immunosorbent assay (ELISA). The apoptotic activity of membrane-bound CD30L was tested in a CD30+ cell line by the annexin V-binding method. RESULTS Unstimulated T lymphocytes of normal donors and patients with lymphoma rarely expressed CD30L surface protein, but were able to express it after stimulation with PHA or anti-CD3 antibody. Resting B cells of patients with CD30+ tumors had lower levels of detectable surface CD30L compared with normal donors (mean, 55% and 80.6%, respectively; P = .0008). Patients with high levels of serum sCD30 had lower detectable levels of CD30L on their PBLs (R2 = .72, P = .0008) and exogenous sCD30 blocked membrane-bound CD30L-mediated apoptosis in a CD30+ cell line. CONCLUSION In patients with CD30+ tumors, sCD30 can decrease the availability of CD30L on PBLs. Blocking the apoptosis-inducing activity of CD30L by its soluble receptor may explain how CD30+ tumors escape immunosurveillance and may be related to the reported poor prognosis of patients who have elevated sCD30 levels.
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Willis, Cynthia R., Yi-Ling Hu, Anh Leith, and James B. Rottman. "CD30 / CD30L interactions promote class-switched antibody responses to T-dependent antigens (34.3)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 34.3. http://dx.doi.org/10.4049/jimmunol.182.supp.34.3.
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Abstract The cell-surface glycoproteins CD30 and CD30L are members of the TNFR and TNF superfamilies, respectively. CD30 is expressed on subpopulations of activated T and B cells. CD30L is expressed on activated T cells, macrophages, and dendritic cells, as well as germinal center B cells. CD30 / CD30L interactions provide activation-induced costimulatory signals that sustain T-cell responses, mediate B-cell activity, and generate long-lived memory T cells for chronic B-cell help. Although other activation-induced costimulatory molecules induce antibody isotype class switching, it is less clear what the function is of CD30 signaling on class switching and antibody production. Therefore, we tested the effect of in vivo blockade of the CD30 / CD30L pathway on antibody class switching in response to T-dependent antigens using two systems that require activated-T cells to stimulate B-cell responses. First, BALB/c mice immunized with a T-dependent antigen and treated with anti-CD30L antibodies produced less antigen-specific antibodies of IgG1 and IgE isotypes as compared to control-treated mice, whereas antigen-specific antibodies of the IgM isotype were similar in all groups. Likewise, NZB/W F1 lupus-prone mice treated with anti-CD30L antibodies produced less anti-dsDNA antibodies of the IgG1 and IgG2a isotypes as compared to control-treated mice, whereas anti-dsDNA antibodies of the IgM isotype were similar in all groups. In both systems, specific subpopulations of lymphocytes necessary for responses to T-dependent antigens were reduced by blockade of the CD30 / CD30L pathway. Our results demonstrate that CD30 / CD30L interactions positively regulate T-cell dependent B-cell responses necessary for class-switched antibody responses.
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Mori, M., C. Manuelli, N. Pimpinelli, C. Mavilia, E. Maggi, M. Santucci, B. Bianchi, P. Cappugi, B. Giannotti, and M. E. Kadin. "CD30-CD30 Ligand Interaction in Primary Cutaneous CD30+T-Cell Lymphomas: A Clue to the Pathophysiology of Clinical Regression." Blood 94, no. 9 (November 1, 1999): 3077–83. http://dx.doi.org/10.1182/blood.v94.9.3077.
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Abstract Primary CD30+ cutaneous T-cell lymphomas (CTCLs) represent a spectrum of non-Hodgkin’s lymphomas (NHLs) that have been well defined at the clinical, histologic, and immunologic level. This group, which includes 2 main entities (large cell lymphoma and lymphomatoid papulosis [LyP]) and borderline cases, is characterized by the expression of CD30 antigen by neoplastic large cells at presentation, possible spontaneous regression of the skin lesions, and generally favorable clinical course. Although the functional relevance of CD30 and its natural ligand (CD30L) expression in most cases of NHL is presently undefined, previous studies indicate that CD30L is likely to mediate reduction of proliferation in CD30+ anaplastic large-cell NHL. No information is currently available concerning the expression of CD30L in primary CD30+ CTCLs. In this study, we investigated the immunophenotypic and genotypic expression of CD30 and CD30L in different developmental phases of skin lesions (growing v spontaneously regressing). By immunohistochemistry, CD30L expression was detected in regressing lesions only; by molecular analysis, the expression of CD30L was clearly higher in regressing lesions than in growing ones. CD30L, while expressed by some small lymphocytes, was most often coexpressed by CD30+neoplastic large cells, as demonstrated by 2-color immunofluorescence and by immunohistochemistry on paraffin sections. Taken together, these data suggest that CD30-CD30L interaction may play a role in the pathobiology of primary cutaneous CD30+lymphoproliferative disorders. In particular, CD30L (over)expression might have a major role in the mechanism of self-regression of skin lesions, the most distinctive clinical feature of this cutaneous lymphoma subtype.
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Mori, M., C. Manuelli, N. Pimpinelli, C. Mavilia, E. Maggi, M. Santucci, B. Bianchi, P. Cappugi, B. Giannotti, and M. E. Kadin. "CD30-CD30 Ligand Interaction in Primary Cutaneous CD30+T-Cell Lymphomas: A Clue to the Pathophysiology of Clinical Regression." Blood 94, no. 9 (November 1, 1999): 3077–83. http://dx.doi.org/10.1182/blood.v94.9.3077.421k28_3077_3083.
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Primary CD30+ cutaneous T-cell lymphomas (CTCLs) represent a spectrum of non-Hodgkin’s lymphomas (NHLs) that have been well defined at the clinical, histologic, and immunologic level. This group, which includes 2 main entities (large cell lymphoma and lymphomatoid papulosis [LyP]) and borderline cases, is characterized by the expression of CD30 antigen by neoplastic large cells at presentation, possible spontaneous regression of the skin lesions, and generally favorable clinical course. Although the functional relevance of CD30 and its natural ligand (CD30L) expression in most cases of NHL is presently undefined, previous studies indicate that CD30L is likely to mediate reduction of proliferation in CD30+ anaplastic large-cell NHL. No information is currently available concerning the expression of CD30L in primary CD30+ CTCLs. In this study, we investigated the immunophenotypic and genotypic expression of CD30 and CD30L in different developmental phases of skin lesions (growing v spontaneously regressing). By immunohistochemistry, CD30L expression was detected in regressing lesions only; by molecular analysis, the expression of CD30L was clearly higher in regressing lesions than in growing ones. CD30L, while expressed by some small lymphocytes, was most often coexpressed by CD30+neoplastic large cells, as demonstrated by 2-color immunofluorescence and by immunohistochemistry on paraffin sections. Taken together, these data suggest that CD30-CD30L interaction may play a role in the pathobiology of primary cutaneous CD30+lymphoproliferative disorders. In particular, CD30L (over)expression might have a major role in the mechanism of self-regression of skin lesions, the most distinctive clinical feature of this cutaneous lymphoma subtype.
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Barbieri, Alessandro, Marzia Dolcino, Elisa Tinazzi, Antonella Rigo, Giuseppe Argentino, Giuseppe Patuzzo, Andrea Ottria, Ruggero Beri, Antonio Puccetti, and Claudio Lunardi. "Characterization of CD30/CD30L+Cells in Peripheral Blood and Synovial Fluid of Patients with Rheumatoid Arthritis." Journal of Immunology Research 2015 (2015): 1–10. http://dx.doi.org/10.1155/2015/729654.
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The CD30/CD30L signalling system has been implicated in the pathogenesis of several autoimmune and inflammatory conditions. In rheumatoid arthritis (RA), soluble CD30 (sCD30) levels reflect the recruitment of CD30+T cells into the inflamed joints and correlate with a positive response to immunosuppressive therapy. The aim of our report was to clarify the role of CD30/CD30L signalling system in the pathogenesis of RA. Our analysis of the CD30L+T cell subsets in peripheral blood (PB) and synovial fluid (SF) of RA patients and of the related cytokine profiles suggests the involvement of CD30/CD30L signalling in polarization of T cells towards a Th17 phenotype with proinflammatory features. Moreover, in RA SF nearly 50% of Treg cells express CD30, probably as an attempt to downmodulate the ongoing inflammation. We also show here that the engagement of CD30L on neutrophils stimulated with CD30/Fc chimera may play a crucial role in RA inflammation since activated neutrophils release IL-8, thus potentially amplifying the local inflammatory damage. In conclusion, the results obtained suggest that the complex CD30/CD30L signalling pathway is implicated in the pathogenesis and progression of RA synovitis through a concerted action on several immune effector cells.
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Romagnani, Paola, Francesco Annunziato, Roberto Manetti, Carmelo Mavilia, Laura Lasagni, Cinzia Manuelli, Gabriella B. Vannelli, et al. "High CD30 Ligand Expression by Epithelial Cells and Hassal's Corpuscles in the Medulla of Human Thymus." Blood 91, no. 9 (May 1, 1998): 3323–32. http://dx.doi.org/10.1182/blood.v91.9.3323.
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Abstract CD30 is a member of tumor necrosis factor (TNF) receptor superfamily that is expressed by activated T cells in the presence of interleukin-4 (IL-4). Although CD30 can mediate a variety of signals, CD30-deficient mice have impaired negative selection of T cells, suggesting that at least in the context of murine thymus, CD30 is a cell death–mediating molecule. The ligand for CD30 (CD30L) is a membrane-associated glycoprotein related to TNF, which is known to be expressed mainly by activated T cells and other leukocytes. However, the nature of CD30L-expressing cells involved in the interaction with CD30+ thymocytes is unclear. We report here that in postnatal human thymus the great majority of CD30+ cells are double positive (CD4+CD8+), activated, IL-4 receptor–expressing T cells which selectively localize in the medullary areas. Moreover, many medullary epithelial cells and Hassal's corpuscles in the same thymus specimens showed unusually high expression of CD30L in comparison with other lymphoid or nonlymphoid tissues. These findings provide additional information on the nature and localization of CD30+ thymocytes and show that epithelial cells are the major holder of CD30L in the thymic medulla.
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Romagnani, Paola, Francesco Annunziato, Roberto Manetti, Carmelo Mavilia, Laura Lasagni, Cinzia Manuelli, Gabriella B. Vannelli, et al. "High CD30 Ligand Expression by Epithelial Cells and Hassal's Corpuscles in the Medulla of Human Thymus." Blood 91, no. 9 (May 1, 1998): 3323–32. http://dx.doi.org/10.1182/blood.v91.9.3323.3323_3323_3332.
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CD30 is a member of tumor necrosis factor (TNF) receptor superfamily that is expressed by activated T cells in the presence of interleukin-4 (IL-4). Although CD30 can mediate a variety of signals, CD30-deficient mice have impaired negative selection of T cells, suggesting that at least in the context of murine thymus, CD30 is a cell death–mediating molecule. The ligand for CD30 (CD30L) is a membrane-associated glycoprotein related to TNF, which is known to be expressed mainly by activated T cells and other leukocytes. However, the nature of CD30L-expressing cells involved in the interaction with CD30+ thymocytes is unclear. We report here that in postnatal human thymus the great majority of CD30+ cells are double positive (CD4+CD8+), activated, IL-4 receptor–expressing T cells which selectively localize in the medullary areas. Moreover, many medullary epithelial cells and Hassal's corpuscles in the same thymus specimens showed unusually high expression of CD30L in comparison with other lymphoid or nonlymphoid tissues. These findings provide additional information on the nature and localization of CD30+ thymocytes and show that epithelial cells are the major holder of CD30L in the thymic medulla.
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Rottman, James B., Yi-Ling Hu, and Cynthia Willis. "Blockade of the CD30/CD30L pathway inhibits renal disease in young, SLE-prone NZB/W F1 mice (50.41)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 50.41. http://dx.doi.org/10.4049/jimmunol.182.supp.50.41.
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Abstract CD30 and CD30L are interacting members of the TNFR and TNF family, respectively. CD30 is expressed by subsets of activated T and B cells, whereas CD30L is expressed by subsets of activated T cells, macrophages and dendritic cells. The CD30 / CD30L interaction modulates T cell activation, germinal center formation and antibody isotype class switching. Given the importance of this pathway to B cell function, we tested the hypothesis that blockade of the CD30 / CD30L pathway would decrease or abrogate autoantibody formation and renal disease in the NZB/W F1 murine model of systemic lupus erythematosis (SLE). Young (5 mo) NZB/W F1 mice were treated with 300 μg CD30L blocking (M15-N297A) or blocking / depleting (M15-IgG2a) antibody weekly for 3 months during the onset of autoimmunity. Both treatments a) reduced the onset and severity of proteinuria, b) significantly decreased the severity of renal histologic scores, c) decreased glomerular immune complex and complement deposition and d) these effects were associated with reduced production of anti-DNA antibodies of the IgG, but not IgM isotype. CD30 / CD30L blockade may be a viable approach for the treatment of SLE.
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Gattei, Valter, Massimo Degan, Annunziata Gloghini, Angela De Iuliis, Salvatore Improta, Francesca Maria Rossi, Donatella Aldinucci, et al. "CD30 Ligand Is Frequently Expressed in Human Hematopoietic Malignancies of Myeloid and Lymphoid Origin." Blood 89, no. 6 (March 15, 1997): 2048–59. http://dx.doi.org/10.1182/blood.v89.6.2048.
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Abstract CD30 ligand (CD30L) is a type-II membrane glycoprotein capable of transducing signals leading to either cell death or proliferation through its specific counterstructure CD30. Although several lines of evidence indicate that CD30L plays a key role as a paracrine- or autocrine-acting surface molecule in the deregulated cytokine cascade of Hodgkin's disease, little is known regarding its distribution and biologic significance in other human hematopoietic malignancies. By analyzing tumor cells from 181 patients with RNA studies and immunostaining by the anti-CD30L monoclonal antibody M80, we were able to show that human hematopoietic malignancies of different lineage and maturation stage display a frequent and broad expression of the ligand. CD30L mRNA and surface protein were detected in 60% of acute myeloid leukemias (AMLs), 54% of B-lineage acute lymphoblastic leukemias (ALLs), and in a consistent fraction (68%) of B-cell lymphoproliferative disorders. In this latter group, hairy cell leukemia and high-grade B-cell non-Hodgkin's lymphoma (B-NHL) expressed a higher surface density of CD30L as compared with B-cell chronic lymphocytic leukemia and low-grade B-NHL. Purified plasmacells from a fraction of multiple myeloma patients also displayed CD30L mRNA and protein. A more restricted expression of CD30L was found in T-cell tumors that was mainly confined to neoplasms with an activated peripheral T-cell phenotype, such as T-cell prolymphocytic leukemia, peripheral T-NHL, and adult T-cell leukemia/lymphoma. In contrast, none of the T-lineage ALLs analyzed expressed the ligand. In AML, a high cellular density of CD30L was detected in French-American-British M3, M4, and M5 phenotypes, which are directly associated with the presence on tumor cells of certain surface structures, including the p55 interleukin-2 receptor α-chain, the αM (CD11b) chain of β2 integrins, and the intercellular adhesion molecule-1 (CD54). Analysis of normal hematopoietic cells evidenced that, in addition to circulating and tonsil B cells, a fraction of bone marrow myeloid precursors, erythroblasts, and subsets of megakaryocytes also express CD30L. Finally, we have shown that native CD30L expressed on primary leukemic cells is functionally active by triggering both mitogenic and antiproliferative signals on CD30+ target cells. As opposed to CD30L, only 10 of 181 primary tumors expressed CD30 mRNA or protein, rendering therefore unlikely a CD30-CD30L autocrine loop in human hematopoietic neoplasms. Taken together, our data indicate that CD30L is widely expressed from early to late stages of human hematopoiesis and suggest a regulatory role for this molecule in the interactions of normal and malignant hematopoietic cells with CD30+ immune effectors and/or microenvironmental accessory cells.
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Wiley, S. R., R. G. Goodwin, and C. A. Smith. "Reverse signaling via CD30 ligand." Journal of Immunology 157, no. 8 (October 15, 1996): 3635–39. http://dx.doi.org/10.4049/jimmunol.157.8.3635.
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Abstract CD30 ligand (CD30L), a member of the TNF family, is a type II membrane protein with a C-terminal extracellular domain that is homologous with the extracellular domains of other TNF family members. Also, like most TNF family members, the N-terminal cytoplasmic domain of CD30L is conserved across species, but not between family members, suggesting a possible biological function. Motivated by this observation, we investigated the potential for CD30L, when activated by cross-linking, to directly transduce a signal to the ligand-bearing cell. Cross-linking of CD30L by a mAb or by CD30-Fc fusion protein induced the production of IL-8 by freshly isolated neutrophils. Further, both cross-linking mechanisms produced a rapid oxidative burst. Indirect effects through CD30 were ruled out, since CD30L, but not CD30, is expressed on neutrophils. Expression of CD30L can be induced in peripheral blood T cells by cross-linking the CD3 component of the TCR. Peripheral blood T cells exposed to suboptimal concentrations of anti-CD3 increased metabolic activity, proliferated, and produced IL-6 in response to cross-linking of CD30L. These results indicate that cross-linked CD30L can transduce a signal to the ligand-bearing cell. This "reverse signaling" via CD30L taken together with previously published data concerning other ligands in the TNF family strongly suggest that, as a rule, TNF family members and their cognate receptors signal bidirectionally, blurring the distinction between ligand and receptor.
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Guo, Ying, Xun Sun, Kensuke Shibata, Hisakata Yamada, Hiromi Muta, Eckhard R. Podack, and Yasunobu Yoshikai. "CD30 Is Required for Activation of a Unique Subset of Interleukin-17A-Producing γδ T Cells in Innate Immunity against Mycobacterium bovis Bacillus Calmette-Guérin Infection." Infection and Immunity 81, no. 10 (August 5, 2013): 3923–34. http://dx.doi.org/10.1128/iai.00887-13.
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ABSTRACTInterleukin-17A (IL-17A)-producing γδ T cells are known to be activated followingMycobacterium bovisbacillus Calmette-Guérin (BCG) infection. Here, we show that CD30, a member of the tumor necrosis factor (TNF) receptor superfamily, is important for activation of IL-17A-producing γδ T cells after BCG infection. Vγ1−Vγ4−γδ T cells preferentially expressing Vγ6/Vδ1 genes were identified as the major source of IL-17A in the peritoneal cavity during the early stage of BCG infection. The number of IL-17A-producing Vγ1−Vγ4−γδ T cells bearing Vγ6 increased in peritoneal exudate cells (PEC) of wild-type (WT) mice but not in those of CD30 knockout (KO) mice in response to BCG infection. Consistently, CD30 ligand (CD30L) or CD30 expression, predominantly by Vγ1−Vγ4−γδ T cells, was rapidly upregulated after BCG infection. Inhibition of CD30L/CD30 signaling byin vivoadministration of a soluble CD30 and immunoglobulin fusion protein (CD30-Ig) severely impaired activation of IL-17A-producing Vγ1−Vγ4−γδ T cells in WT mice, while stimulating CD30L/CD30 signaling byin vivoadministration of agonistic anti-CD30 monoclonal antibody (MAb) restored IL-17A production by Vγ1−Vγ4−γδ T cells in CD30L KO mice after BCG infection. These results suggest that CD30 signaling plays an important role in the activation of IL-17A-producing Vγ1−Vγ4−γδ T cells bearing Vγ6 at an early stage of BCG infection.
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Saraiva, Margarida, Philip Smith, Padraic G. Fallon, and Antonio Alcami. "Inhibition of Type 1 Cytokine–mediated Inflammation by a Soluble CD30 Homologue Encoded by Ectromelia (Mousepox) Virus." Journal of Experimental Medicine 196, no. 6 (September 16, 2002): 829–39. http://dx.doi.org/10.1084/jem.20020319.
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CD30 is up-regulated in several human diseases and viral infections but its role in immune regulation is poorly understood. Here, we report the expression of a functional soluble CD30 homologue, viral CD30 (vCD30), encoded by ectromelia (mousepox) virus, a poxvirus that causes a severe disease related to human smallpox. We show that vCD30 is a 12-kD secreted protein that not only binds CD30L with high affinity and prevents its interaction with CD30, but it also induces reverse signaling in cells expressing CD30L. vCD30 blocked the generation of interferon γ–producing cells in vitro and was a potent inhibitor of T helper cell (Th)1- but not Th2-mediated inflammation in vivo. The finding of a CD30 homologue encoded by ectromelia virus suggests a role for CD30 in antiviral defense. Characterization of the immunological properties of vCD30 has uncovered a role of CD30–CD30L interactions in the generation of inflammatory responses.
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Tsiagbe, Vincent, Eckhard Podack, and Yu Li. "CD30L null SJL mice exhibit reduced lymph node and spleen weights but support growth of transplantable SJL lymphoma RCS-X (48.29)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 48.29. http://dx.doi.org/10.4049/jimmunol.186.supp.48.29.
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Abstract The process by which endogenous retroviral superantigen (vSAg29) expressing SJL lymphomas (RCS) stimulate host CD4+Vβ16+ T cells, in order to elicit help (notably IL-4 and -5) for their growth, has been characterized as “reverse immune surveillance”. This response is facilitated by the high expression of an array of co-stimulating molecules on RCS cells, including B7.1, B7.2, 41BBL, CD40 and CD30. On the basis of their germinal center derivation, SJL lymphomas bear close resemblance to a subpopulation of human germinal center B cell lymphomas, such as CD30+ Hodgkin’s lymphomas. In our earlier studies, growth of transplantable SJL lymphoma (RCS-X) in vivo was inhibited by anti-CD30 mAb. While the evidence shows that this effect is indirectly on the lymphoma-responsive CD4 T cells, the mechanism of action was unclear. To shed light on the role of CD30-CD30L interactions in SJL lymphoma development, CD30L-/- were bred onto SJL background and tested for their support of transplantable lymphoma growth. A significant reduction in lymph node (17.4-54.7%) and spleen weights (21.5-38.2%) was observed for CD30 null mice, compared to wild type SJL mice. Despite this reduction in the lymphoid compartment, no reduction in lymphoma growth was observed. The results suggest that while CD30-CD30L interactions might be important for SJL lymphoma growth, other costimulating molecules might contribute significantly to the process of reverse immune surveillance in RCS lymphoma.
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Rossi, Francesca Maria, Massimo Degan, Linda Mazzocut-Zecchin, Raffaele Di Francia, Donatella Aldinucci, Antonio Pinto, and Valter Gattei. "CD30L up-regulates CD30 and IL-4 expression by T cells." FEBS Letters 508, no. 3 (November 23, 2001): 418–22. http://dx.doi.org/10.1016/s0014-5793(01)03076-9.
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Tang, Ce, Hisakata Yamada, Kensuke Shibata, Hiromi Muta, Worawidh Wajjwalku, Eckhard R. Podack, and Yasunobu Yoshikai. "A Novel Role of CD30L/CD30 Signaling by T-T Cell Interaction in Th1 Response against Mycobacterial Infection." Journal of Immunology 181, no. 9 (October 20, 2008): 6316–27. http://dx.doi.org/10.4049/jimmunol.181.9.6316.
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Ryan, Maureen, Ryan Lyski, Lauren Bou, Ryan Heiser, Bryan Grogan, Dave Meyer, Steven Jin, et al. "SGN-CD30C, an Investigational CD30-Directed Camptothecin Antibody-Drug Conjugate (ADC), Shows Strong Anti Tumor Activity and Superior Tolerability in Preclinical Studies." Blood 136, Supplement 1 (November 5, 2020): 41–42. http://dx.doi.org/10.1182/blood-2020-136577.
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SGN-CD30C, an investigational CD30-directed ADC, utilizes a potent novel camptothecin derivative as the cytotoxic payload. SGN-CD30C targets the same antigen as brentuximab vedotin (BV), though the payload has a different mechanism of action, namely inhibiting topoisomerase I rather than disrupting microtubules. Unlike monomethyl auristatin E, camptothecin-based therapies do not cause peripheral neuropathy clinically, suggesting that SGN-CD30C may have the potential to avoid one of the most common adverse events associated with BV. In preclinical studies, SGN-CD30C demonstrated strong monotherapy activity, inducing durable tumor regressions in multiple lymphoma models and eliciting cures in a BV-resistance tumor model (Figure 1). Moreover, SGN-CD30C exhibits many of the desirable attributes associated with BV, notably, bystander activity and CD30+ T regulatory cell (Treg) depletion. Using an admixed model of CD30+ and CD30-tumor cells, SGN-CD30C demonstrated robust anti-tumor activity in vivo, confirming SGN-CD30C can induce bystander killing of antigen-negative tumor cells in CD30-heterogeneous tumors. Additionally, SGN-CD30C depleted CD30+ Treg cells in vitro (Figure 2), suggesting it has the potential to exert activity through multiple mechanisms of action. SGN-CD30C was well-tolerated in non-human primate toxicology studies and demonstrated ~6-fold higher maximum tolerated dose when compared to BV. The primary toxicity for SGN-CD30C in non-human primates (NHP) studies was anemia due primarily to bone marrow suppression of erythropoiesis. SGN-CD30C had no effect on neutrophil counts and caused only minimal to mild decreases in platelets. The lack of significant neutropenia seen with SGN-CD30C contrasts with BV, indicating the two ADCs may have non-overlapping dose limiting toxicities. Hematology parameters show SGN-CD30C is tolerated at a 10-fold higher dose than BV with weekly dosing, suggesting SGN-CD30C may offer the potential for increased dose density. In summary, our data show SGN-CD30C is a compelling therapeutic candidate for CD30-positive malignancies. The distinct mechanism of action, strong anti-tumor activity, and enhanced tolerability provide a strong rationale to clinically investigate SGN-CD30C across the CD30-expressing lymphoma landscape. A Phase 1 clinical trial is planned to investigate SGN-CD30C in relapsed and refractory lymphoma. Disclosures Heiser: Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Grogan:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Jin:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Conerly:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company.
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Gruss, HJ, and SK Dower. "Tumor necrosis factor ligand superfamily: involvement in the pathology of malignant lymphomas." Blood 85, no. 12 (June 15, 1995): 3378–404. http://dx.doi.org/10.1182/blood.v85.12.3378.bloodjournal85123378.
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The TNF receptor superfamily members are all type I membrane glycoproteins with typical homology in the extracellular domain of variable numbers of cysteine-rich repeats (overall homologies, 25% to 30%). In contrast, the TNF ligand superfamily members (with the exception of LT alpha) are type II membrane glycoproteins with homology to TNF in the extracellular domain (overall homologies, 20%). TNF and LT alpha are trimeric proteins and are composed of beta-strands forming a beta-jellyroll. The homology of the beta-strand regions for the TNF ligand superfamily members suggest a similar beta-sandwich structure and possible trimeric or multimeric complex formation for most or all members. A genetic linkage, as evidence for evolutionary relatedness, is found by chromosomal cluster of TNFR p80, CD30, 4–1BB, and OX40 for 1p36; TNFR p60, TNFR-RP, and CD27 for 12p13; TNF, LT alpha, and LT beta for 6 (MHC locus); CD27L and 4–1BBL for 19p13; and FASL and OX40L for 1q25. Of the TNF ligand superfamily, TNF, LT alpha, and LT beta and their receptors (TNFR p60, TNFR p80, and TNFR-RP) interact in a complex fashion of cross-binding. However, the other family members presently have a one ligand/one receptor binding principle (CD27/CD27L, CD30/CD30L, CD40/CD40L, 4–1BB/4–1BBL, OX40/gp34, and FAS/FASL). In general, the members of the TNF ligand superfamily mediate interaction between different hematopoietic cells, such as T cell/B cell, T cell/monocyte, and T cell/T cell. Signals can be transduced not only through the receptors but also through at least some of the ligands. The transduced signals can be stimulatory or inhibitory depending on the target cell or the activation state. Taken together, TNF superfamily ligands show for the immune response an involvement in the induction of cytokine secretion and the upregulation of adhesion molecules, activation antigens, and costimulatory proteins, all known to amplify stimulatory and regulatory signals. On the other hand, differences in the distribution, kinetics of induction, and requirements for induction support a defined role for each of the ligands for T-cell-mediated immune responses. The shedding of members of the TNF receptor superfamily could limit the signals mediated by the corresponding ligands as a functional regulatory mechanism. Induction of cytotoxic cell death, observed for TNF, LT alpha, CD30L, CD95L, and 4–1BBL, is another common functional feature of this cytokine family. Further studies have to identify unique versus redundant biologic and physiologic functions for each of the TNF superfamily ligands.(ABSTRACT TRUNCATED AT 400 WORDS)
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Akiba, Hisaya, Yasushi Miyahira, Machiko Atsuta, Kazuyoshi Takeda, Chiyoko Nohara, Toshiro Futagawa, Hironori Matsuda, Takashi Aoki, Hideo Yagita, and Ko Okumura. "Critical Contribution of Ox40 Ligand to T Helper Cell Type 2 Differentiation in Experimental Leishmaniasis." Journal of Experimental Medicine 191, no. 2 (January 17, 2000): 375–80. http://dx.doi.org/10.1084/jem.191.2.375.
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Infection of inbred mouse strains with Leishmania major is a well characterized model for analysis of T helper (Th)1 and Th2 cell development in vivo. In this study, to address the role of costimulatory molecules CD27, CD30, 4-1BB, and OX40, which belong to the tumor necrosis factor receptor superfamily, in the development of Th1 and Th2 cells in vivo, we administered monoclonal antibody (mAb) against their ligands, CD70, CD30 ligand (L), 4-1BBL, and OX40L, to mice infected with L. major. Whereas anti-CD70, anti-CD30L, and anti–4-1BBL mAb exhibited no effect in either susceptible BALB/c or resistant C57BL/6 mice, the administration of anti-OX40L mAb abrogated progressive disease in BALB/c mice. Flow cytometric analysis indicated that OX40 was expressed on CD4+ T cells and OX40L was expressed on CD11c+ dendritic cells in the popliteal lymph nodes of L. major–infected BALB/c mice. In vitro stimulation of these CD4+ T cells showed that anti-OX40L mAb treatment resulted in substantially reduced production of Th2 cytokines. Moreover, this change in cytokine levels was associated with reduced levels of anti–L. major immunoglobulin (Ig)G1 and serum IgE. These results indicate that anti-OX40L mAb abrogated progressive leishmaniasis in BALB/c mice by suppressing the development of Th2 responses, substantiating a critical role of OX40–OX40L interaction in Th2 development in vivo.
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Martin, James M., Hong Wu, and Stefan K. Barta. "CD30+ T-cell lymphoproliferative disorders." Chinese Clinical Oncology 8, no. 1 (February 2019): 4. http://dx.doi.org/10.21037/cco.2018.09.06.
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de Leval, Laurence, David S. Rickman, Caroline Thielen, Aurélien de Reynies, Yen-Lin Huang, Georges Delsol, Laurence Lamant, et al. "The gene expression profile of nodal peripheral T-cell lymphoma demonstrates a molecular link between angioimmunoblastic T-cell lymphoma (AITL) and follicular helper T (TFH) cells." Blood 109, no. 11 (June 1, 2007): 4952–63. http://dx.doi.org/10.1182/blood-2006-10-055145.
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Abstract The molecular alterations underlying the pathogenesis of angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma, unspecified (PTCL-u) are largely unknown. In order to characterize the ontogeny and molecular differences between both entities, a series of AITLs (n = 18) and PTCLs-u (n = 16) was analyzed using gene expression profiling. Unsupervised clustering correlated with the pathological classification and with CD30 expression in PTCL-u. The molecular profile of AITLs was characterized by a strong microenvironment imprint (overexpression of B-cell– and follicular dendritic cell–related genes, chemokines, and genes related to extracellular matrix and vascular biology), and overexpression of several genes characteristic of normal follicular helper T (TFH) cells (CXCL13, BCL6, PDCD1, CD40L, NFATC1). By gene set enrichment analysis, the AITL molecular signature was significantly enriched in published TFH-specific genes. The enrichment was higher for sorted AITL cells than for tissue samples. Overexpression of several TFH genes was validated by immunohistochemistry in AITLs. A few cases with molecular TFH-like features were identified among CD30− PTCLs-u. Our findings strongly support that TFH cells represent the normal counterpart of AITL, and suggest that the AITL spectrum may be wider than suspected, as a subset of CD30− PTCLs-u may derive from or be related to AITL.
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Steinhoff, Matthias, Michael Hummel, Ioannis Anagnostopoulos, Peter Kaudewitz, Volkhard Seitz, Chalid Assaf, Christian Sander, and Harald Stein. "Single-cell analysis of CD30+ cells in lymphomatoid papulosis demonstrates a common clonal T-cell origin." Blood 100, no. 2 (July 15, 2002): 578–84. http://dx.doi.org/10.1182/blood-2001-12-0199.
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Abstract Lymphomatoid papulosis (LyP) represents an intriguing cutaneous T-cell lymphoproliferative disorder with a histologic appearance resembling malignant lymphoma. This finding strongly contrasts with the benign clinical course of the disease. However, in 10% to 20% of cases, LyP can precede, coexist with, or follow malignant lymphoma. In these cases, the same T-cell population has been shown to be present in the LyP as well as in the associated lymphoma. In most LyP cases, there is—despite the sometimes extremely long course of the disease—no evolution of a secondary lymphoma. The investigation of these uncomplicated LyP cases for the presence of clonal T-cell receptor rearrangements has produced heterogeneous results. This might be explained by biologic or technical reasons arising from analyzing whole tissue DNA extracts. To definitively clarify whether the large atypical CD30+ cells in LyP without associated lymphoma all belong to the same clone or represent individually rearranged T cells, we analyzed the T-cell receptor–γ rearrangements of single CD30+ as well as of single CD30− cells isolated from 14 LyP lesions of 11 patients. By using this approach we could demonstrate that the CD30+ cells represent members of a single T-cell clone in all LyP cases. Moreover, in 3 patients the same CD30+ cell clone was found in anatomically and temporally separate lesions. In contrast, with only a few exceptions, the CD30− cells were polyclonal in all instances and unrelated to the CD30+ cell clone. Our results demonstrate that LyP unequivocally represents a monoclonal T-cell disorder of CD30+ cells in all instances.
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Alzona, M., H. M. Jäck, R. I. Fisher, and T. M. Ellis. "CD30 defines a subset of activated human T cells that produce IFN-gamma and IL-5 and exhibit enhanced B cell helper activity." Journal of Immunology 153, no. 7 (October 1, 1994): 2861–67. http://dx.doi.org/10.4049/jimmunol.153.7.2861.
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Abstract CD30 is a lymphoid activation Ag expressed by activated B and T lymphocytes, as well as selected lymphoid malignancies. In T cells, CD30 expression is limited to a minority (15 to 25%) of activated CD45RO+ T cells. Studies were undertaken to define unique functional properties of CD30+ T cells by identifying the profile of cytokine production by CD30+ T cells, and by assessing their ability to provide help for B cell Ig production. Assessment of cytokine mRNA transcripts by reverse transcription-PCR (RT-PCR) revealed the presence of IFN-gamma mRNA transcripts only in CD30+ T cells derived from FACS purified from activated CD45RO+ T cells. IFN-gamma mRNA was present neither in the CD30- subset of activated CD45RO+ T cells, nor in activated CD45RA+ T cells. Both CD30+ and CD30- subsets expressed IL-10 and IL-2R alpha mRNAs after 3 days of activation, but neither population expressed IL-4 or IL-6 transcripts at this time. Furthermore, production of secreted IFN-gamma was significantly greater in activated CD30+CD45RO+ cells (564 +/- 250 pg/ml) than in CD30-CD45RO+ (50 +/- 33 pg/ml) or CD45RA+ (0 +/- 0) T cells. CD30+ T cells also expressed IL-5 mRNA and secreted significantly higher levels of IL-5 (320 +/- 73) than activated CD30-CD45RO+ (17 +/- 5) T cells. In contrast, CD30- T cells produced significantly higher levels of IL-2 than CD30+ T cells (1270 +/- 380 vs 450 +/- 128). Induction of IFN-gamma in CD30+ T cells was not a result of CD30 engagement by Abs used during the isolation process, although an anti-CD30 Ab (M44) known to exert agonist activity was capable of inducing IFN-gamma production by T cells when immobilized to plastic. Finally, CD30+CD4+ T cells exhibit significantly greater helper activity for B cell Ig production than CD30-CD4+ T cells. These results demonstrate that CD30 identifies a unique subset of T cells that comprise the major IFN-gamma- and IL-5-producing cells in the T cell compartment, and exhibit potent helper activity for B cell Ig production.
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Yue, Dan, Yong You, Xiaoqing Zhang, Biao Wang, Xiao Wang, Ruiqun Qi, Fan Yang, et al. "CD30L/CD30 protects against psoriasiform skin inflammation by suppressing Th17-related cytokine production by Vγ4+ γδ T cells." Journal of Autoimmunity 101 (July 2019): 70–85. http://dx.doi.org/10.1016/j.jaut.2019.04.009.
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Lee, S. Y., C. G. Park, and Y. Choi. "T cell receptor-dependent cell death of T cell hybridomas mediated by the CD30 cytoplasmic domain in association with tumor necrosis factor receptor-associated factors." Journal of Experimental Medicine 183, no. 2 (February 1, 1996): 669–74. http://dx.doi.org/10.1084/jem.183.2.669.
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CD30 is a member of the tumor necrosis factor superfamily and a surface marker for Hodgkin's disease. Normal activated T cells and several virally transformed T or B cell lines also show CD30 expression. The interaction of CD30 with its ligand induces cell death or proliferation, depending on the cell type. In this report we characterize the signals mediated by the intracellular domain of CD30 and show that, in combination with signal(s) transduced by the T cell receptor, the multimerization of CD30 cytoplasmic domain induces Fas(CD95)-independent cell death in T cell hybridomas. Deletion analysis shows that the COOH-terminal 66 amino acids of CD30 are required to induce cell death. Using the yeast two-hybrid system, we have identified that the same region of CD30 interacts with tumor necrosis factor receptor-associated factor (TRAF)1 and TRAF2. These results indicate that TRAF1 and/or TRAF2 play an important role in cell death in addition to their previously identified roles in cell proliferation.
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Gruss, HJ, N. Boiani, DE Williams, RJ Armitage, CA Smith, and RG Goodwin. "Pleiotropic effects of the CD30 ligand on CD30-expressing cells and lymphoma cell lines." Blood 83, no. 8 (April 15, 1994): 2045–56. http://dx.doi.org/10.1182/blood.v83.8.2045.2045.
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Abstract CD30 is a member of the tumor necrosis factor receptor superfamily. CD30 was originally described as a cell surface antigen on primary and cultured Hodgkin's and Reed-Sternberg cells. In this study, recombinant human CD30 ligand was expressed on the surface of CV-1/EBNA cells and tested for biologic activities on a variety of different CD30+ human lymphoma cell lines. CD30 ligand enhanced Ig secretion of Epstein-Barr virus (EBV)-immortalized, CD30+ lymphoblastoid B-cell lines, but not Burkitt lymphoma lines. Recombinant CD30 ligand enhanced proliferation of “T-cell-like” Hodgkin's disease-derived cell lines and an adult T- cell leukemia cell line, but not “B-cell-like” Hodgkin's disease- derived cell lines, CD30+, EBV-immortalized lymphoblastoid B-cell lines, or CD30+ and EBV+ tumor B-cell non-Hodgkin's lymphoma cell lines. In addition, CD30 ligand mediated reduction of proliferation and viability, by induction of cytolytic cell death, of CD30+, large-cell anaplastic lymphoma cell lines. Two new antibodies, M44 and M67, against the CD30 antigen demonstrated similar biologic activities to the CD30 ligand. Taken together, these data demonstrate pleiotropic biologic activities of the CD30 ligand on different CD30+ lymphoma cell lines and indicate that the CD30-CD30 ligand interaction might have a pathophysiologic role in Hodgkin's and some non-Hodgkin's lymphomas.
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Gruss, HJ, N. Boiani, DE Williams, RJ Armitage, CA Smith, and RG Goodwin. "Pleiotropic effects of the CD30 ligand on CD30-expressing cells and lymphoma cell lines." Blood 83, no. 8 (April 15, 1994): 2045–56. http://dx.doi.org/10.1182/blood.v83.8.2045.bloodjournal8382045.
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CD30 is a member of the tumor necrosis factor receptor superfamily. CD30 was originally described as a cell surface antigen on primary and cultured Hodgkin's and Reed-Sternberg cells. In this study, recombinant human CD30 ligand was expressed on the surface of CV-1/EBNA cells and tested for biologic activities on a variety of different CD30+ human lymphoma cell lines. CD30 ligand enhanced Ig secretion of Epstein-Barr virus (EBV)-immortalized, CD30+ lymphoblastoid B-cell lines, but not Burkitt lymphoma lines. Recombinant CD30 ligand enhanced proliferation of “T-cell-like” Hodgkin's disease-derived cell lines and an adult T- cell leukemia cell line, but not “B-cell-like” Hodgkin's disease- derived cell lines, CD30+, EBV-immortalized lymphoblastoid B-cell lines, or CD30+ and EBV+ tumor B-cell non-Hodgkin's lymphoma cell lines. In addition, CD30 ligand mediated reduction of proliferation and viability, by induction of cytolytic cell death, of CD30+, large-cell anaplastic lymphoma cell lines. Two new antibodies, M44 and M67, against the CD30 antigen demonstrated similar biologic activities to the CD30 ligand. Taken together, these data demonstrate pleiotropic biologic activities of the CD30 ligand on different CD30+ lymphoma cell lines and indicate that the CD30-CD30 ligand interaction might have a pathophysiologic role in Hodgkin's and some non-Hodgkin's lymphomas.
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de Leval, Laurence, David Rickman, Caroline Thielen, Aurélien de Reynies, Yen-Lin Huang, Georges Delsol, Laurence Lamant, et al. "The Gene Expression Profile of Nodal T-Cell Lymphomas Identifies a Molecular Link between Angioimmunoblastic T-Cell Lymphoma (AITL) and Follicular Helper T Cells (TFH), and between CD30+ Peripheral T-Cell Lymphoma and ALK-Negative Anaplastic Large Cell Lymphoma (ALCL)." Blood 108, no. 11 (November 16, 2006): 289. http://dx.doi.org/10.1182/blood.v108.11.289.289.
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Abstract AITL and PTCL-U, the two most common forms of T-cell lymphomas in western countries, usually present as nodal disease and pursue an aggressive clinical course. AITL is commonly associated with a constellation of clinical symptoms and distinct pathological features. Conversely, PTCL-U lacks precise diagnostic criteria, and by default comprises cases not fulfilling criteria for other entities, including tumors with borderline features to ALCL and AITL. The genetic alterations and pathogenic mechanisms underlying AITL and PTCL-U are largely unknown. To determine whether the molecular signature of AITL and PTCL-U could help in distinguishing both entities and in understanding ther ontogeny, we performed gene expression profile (GEP) analysis of 15 PTCL-U tissue samples (6 CD30+ and 9 CD30−) and 19 AITL samples (including 2 sorted tumor cell suspensions) using Affymetrix HG-U133A Plus2.0 pan-genomic oligonucleotide microarrays, with comparison to that of previously published normal T-cell subsets (J Immunol173:68; J Immunol175: 7837; Blood 104: 1952). Principle component analysis (PCA, accumulated variance 95%) of all 33 tissue samples yielded three groups of tumors: one group of 12 AITLs, one group of 10 PTCLs-U and one mixed group comprising 5 AITLs (some with features borderline to PTCL-U) and 6 PTCLs-U (including 5 of 6 CD30+ tumors). The AITL molecular signature consisted of 442 genes with increased levels of expression in AITL compared to PTCL-U (t test, p<0.002), including genes encoding cell adhesion molecules, immune receptors, extracellular matrix components and several chemokines, B-cell-related and follicular dendritic cell-related genes, genes involved in endothelial and vascular biology, and several genes reported to belong to the gene expression signature of normal TFH cells (CXCL13, BCL6, PDCD1, CD40L, CD200). To specifically address the question of a molecular link beween AITL and TFH cells, we performed gene set enrichment analysis (GSEA) of our dataset using published gene sets specific of distinct normal T-cell subsets (TFH, TH1, TH2). Compared to that of PTCL-U, the molecular signature of AITL was significantly enriched in TFH-specific genes, and the enrichment was even higher for sorted AITL cells compared to AITL tissues. GSEA failed to disclose a molecular link between PTCL-U and known T-cell subsets (TH1, TH2, TFH). Compared to CD30− PTCL-U, CD30+ PTCL-U had lower expression of genes involved in TCR signalling (t test, p<0.002), and showed molecular similarities with ALK-negative ALCL. In conclusion, GEP of non-anaplastic nodal PTCL (1) segregates AITL and PTCL-U, supporting the basis for histotyping; (2) shows molecular analogies between AITL and TFH cells, strongly supporting the hypothesis of a histogenetic link; (3) suggests molecular analogies between CD30+ PTCL-U and ALK-negative ALCL.
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Alzona, M., H. M. Jäck, R. I. Fisher, and T. M. Ellis. "IL-12 activates IFN-gamma production through the preferential activation of CD30+ T cells." Journal of Immunology 154, no. 1 (January 1, 1995): 9–16. http://dx.doi.org/10.4049/jimmunol.154.1.9.
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Abstract CD30 is normally expressed by a subset (15 to 20%) of CD45RO+ T cells after activation by a variety of T cell stimuli and defines the principal IFN-gamma-producing T cells subset. Inasmuch as the production of IFN-gamma is regulated by IL-2 and IL-12, we have examined the effects of these cytokines on the proliferation, induction, and function of CD30+ and CD30- T cell subsets. Upon isolation, CD30+CD25+ T cells exhibit high levels of baseline proliferation compared with CD30-CD25+ T cells. Neutralizing Abs specific for IL-2, IL-4, IL-6, or IL-12 had no effect on basal levels of proliferation in CD30+CD25+ T cells, whereas anti-IL-2 inhibited the basal proliferative activity of CD30-CD25+ T cells. The addition of exogenous rIL-12 to purified CD30+CD25+ and CD30-CD25+ T cells subsets induced significantly higher maximal levels of proliferation in the CD30+ subset, whereas rIL-2 supported comparable levels of maximal proliferation in each subset. The addition of rIL-2 to anti-CD3-activated PBMC increased the relative numbers of CD30+ T cells by expansion of CD30+ T cells, as opposed to recruitment of CD30+ T cells from the CD30- population. Furthermore, the development of the CD30+ T cell subset was inhibited by either anti-IL-2, anti-IL-12, or rIL-10. Inhibition by anti-IL-2 and rIL-10 was overcome by the addition of rIL-12, but not IL-2, to the cultures. Finally, rIL-12 increased IFN-gamma production by CD30+ T cells, yet had little effect on IFN-gamma production by CD30- T cells. Thus, CD30+ T cells are preferentially regulated by IL-12, and the effects of IL-12 on T cell IFN-gamma production are mediated largely through its effects on the CD30+ subset.
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Carbone, Antonino, Annunziata Gloghini, Gianluca Gaidano, Riccardo Dalla-Favera, and Brunangelo Falini. "BCL-6 Protein Expression in Human Peripheral T-Cell Neoplasms Is Restricted to CD30+ Anaplastic Large-Cell Lymphomas." Blood 90, no. 6 (September 15, 1997): 2445–50. http://dx.doi.org/10.1182/blood.v90.6.2445.
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Abstract The expression pattern of the BCL-6 transcription factor has been assessed in normal and neoplastic B-cell populations and in Hodgkin's disease. However, little is known about BCL-6 expression and its biological significance in T-cell neoplasms. In this study, a series of 59 lymphoma samples, including 27 CD30+ anaplastic large-cell lymphomas (ALCLs), 24 other peripheral T-cell neoplasms, and 8 T-cell lymphoblastic lymphomas (T-LBLs), as well as a panel of t(2; 5)-positive lymphoma-derived human cell lines, were evaluated for BCL-6 protein expression by immunohistochemistry on frozen sections and cell smears. To define the relationship between BCL-6 protein and CD30 antigen in CD30+ ALCLs and in non-neoplastic lymph nodes, serial section immunohistochemistry and two-color staining were used in selected CD30+ ALCLs as well as in reactive lymph nodes with non-neoplastic T-cell proliferations. BCL-6 protein was expressed in 12 of 27 (45%) CD30+ ALCL cases, irrespective of their antigenic phenotypes (T-cell or null-cell type), and in the t(2; 5)-positive cell lines. In contrast, the remaining 24 peripheral T-cell neoplasms as well as the 8 T-LBLs were considered negative for BCL-6 expression. Coexpression of CD30 and BCL-6, as detected in CD30+ ALCLs, was also found in a subset of non-neoplastic lymphoid elements, namely the large lymphoid cells scattered in the interfollicular areas of reactive lymph nodes. These findings suggest that CD30+ ALCLs may represent the neoplastic transformation of extrafollicular CD30+ cells and that BCL-6 may provide an additional marker for characterizing CD30+ ALCLs.
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Carbone, Antonino, Annunziata Gloghini, Gianluca Gaidano, Riccardo Dalla-Favera, and Brunangelo Falini. "BCL-6 Protein Expression in Human Peripheral T-Cell Neoplasms Is Restricted to CD30+ Anaplastic Large-Cell Lymphomas." Blood 90, no. 6 (September 15, 1997): 2445–50. http://dx.doi.org/10.1182/blood.v90.6.2445.2445_2445_2450.
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The expression pattern of the BCL-6 transcription factor has been assessed in normal and neoplastic B-cell populations and in Hodgkin's disease. However, little is known about BCL-6 expression and its biological significance in T-cell neoplasms. In this study, a series of 59 lymphoma samples, including 27 CD30+ anaplastic large-cell lymphomas (ALCLs), 24 other peripheral T-cell neoplasms, and 8 T-cell lymphoblastic lymphomas (T-LBLs), as well as a panel of t(2; 5)-positive lymphoma-derived human cell lines, were evaluated for BCL-6 protein expression by immunohistochemistry on frozen sections and cell smears. To define the relationship between BCL-6 protein and CD30 antigen in CD30+ ALCLs and in non-neoplastic lymph nodes, serial section immunohistochemistry and two-color staining were used in selected CD30+ ALCLs as well as in reactive lymph nodes with non-neoplastic T-cell proliferations. BCL-6 protein was expressed in 12 of 27 (45%) CD30+ ALCL cases, irrespective of their antigenic phenotypes (T-cell or null-cell type), and in the t(2; 5)-positive cell lines. In contrast, the remaining 24 peripheral T-cell neoplasms as well as the 8 T-LBLs were considered negative for BCL-6 expression. Coexpression of CD30 and BCL-6, as detected in CD30+ ALCLs, was also found in a subset of non-neoplastic lymphoid elements, namely the large lymphoid cells scattered in the interfollicular areas of reactive lymph nodes. These findings suggest that CD30+ ALCLs may represent the neoplastic transformation of extrafollicular CD30+ cells and that BCL-6 may provide an additional marker for characterizing CD30+ ALCLs.
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Gilfillan, Molly C., Patricia J. Noel, Eckhard R. Podack, Steven L. Reiner, and Craig B. Thompson. "Expression of the Costimulatory Receptor CD30 Is Regulated by Both CD28 and Cytokines." Journal of Immunology 160, no. 5 (March 1, 1998): 2180–87. http://dx.doi.org/10.4049/jimmunol.160.5.2180.
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Abstract Costimulation was originally defined and characterized during primary T cell activation. The signaling events that regulate subsequent antigen encounters by T cells are less well defined. In this study we examined the role of CD30 in T cell activation and defined factors that regulate expression of CD30 on T cells. We demonstrate that CD30 expression is restricted to activated T cells and regulated by CD28 signal transduction. In contrast to CD28-expressing TCR Tg cells, CD28-deficient TCR Tg cells did not express CD30 when cultured with peptide and APCs. However, rIL-4 reconstituted CD30 expression on CD28-deficient TCR Tg cells. Blockade of CD28 interactions or depletion of IL-4 inhibited the induction of CD30, suggesting that both CD28 and IL-4 play important roles in the induction of CD30 expression on wild-type cells. However, CD28 signaling did not up-regulate CD30 expression solely through its ability to augment IL-4 production because IL-4-deficient T cells stimulated with anti-CD3 and anti-CD28 expressed CD30. Induction of CD30 in the absence of IL-4 was not due to the IL-4-related cytokine IL-13. CD30, when expressed on an activated T cell, can act as a signal transducing receptor that enhances the proliferation of T cells responding to CD3 crosslinking. Collectively, the data suggest that T cell expression of CD30 is dependent on the presence of CD28 costimulatory signals or exogenous IL-4 during primary T cell activation. Once expressed on the cell surface, CD30 can serve as a positive regulator of mature T cell function.
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Fukamachi, Shoko, Kazunari Sugita, Yu Sawada, Toshinori Bito, Motonobu Nakamura, and Yoshiki Tokura. "Drug-induced CD30+ T cell pseudolymphoma." European Journal of Dermatology 19, no. 3 (May 2009): 292–94. http://dx.doi.org/10.1684/ejd.2009.0667.
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Estrada, S., and W. Anderson. "CD30-Positive Peripheral T-Cell Lymphoma." Journal of Cutaneous Pathology 32, no. 1 (June 28, 2008): 86. http://dx.doi.org/10.1111/j.0303-6987.2005.320bq.x.
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Del Prete, G., M. De Carli, M. M. D'Elios, K. C. Daniel, F. Almerigogna, M. Alderson, C. A. Smith, E. Thomas, and S. Romagnani. "CD30-mediated signaling promotes the development of human T helper type 2-like T cells." Journal of Experimental Medicine 182, no. 6 (December 1, 1995): 1655–61. http://dx.doi.org/10.1084/jem.182.6.1655.
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We have recently shown that CD30, a member of the tumor necrosis factor/nerve growth factor receptor superfamily, is preferentially expressed by human T cell clones producing T helper (Th) type 2 cytokines. We report here that costimulation with an agonistic anti-CD30 monoclonal antibody enhanced antigen (Ag)-induced proliferation and cytokine secretion by established human Th2 and Th0 clones. Moreover, costimulation of peripheral blood mononuclear cells with the same anti-CD30 monoclonal antibody resulted in the preferential development of Ag-specific T cell lines and clones showing a Th2-like profile of cytokine secretion. In contrast, early blockade in bulk culture of CD30 ligand-CD30 interaction shifted the development of Ag-specific T cells towards the opposite (Th1-like) phenotype. Taken together, these data suggest that CD30 triggering of activated Th cells by CD30 ligand-expressing Ag-presenting cells may represent an important costimulatory signaling for the development of Th2-type responses.
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Ellis, T. M., P. E. Simms, D. J. Slivnick, H. M. Jäck, and R. I. Fisher. "CD30 is a signal-transducing molecule that defines a subset of human activated CD45RO+ T cells." Journal of Immunology 151, no. 5 (September 1, 1993): 2380–89. http://dx.doi.org/10.4049/jimmunol.151.5.2380.
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Abstract CD30 has been extensively studied as a cell surface marker expressed by Reed-Sternberg cells of Hodgkin's disease and other hematologic malignancies, although little is known about its expression by normal lymphoid cells. We therefore characterized the requirements for the induction of CD30 expression and identified the subsets of T cells that express CD30. CD30 is inducible on approximately 15% of normal PBMC stimulated with any of a variety of nonspecific T cell activators, including PHA, Con A, anti-T11(2) + T11(3), and anti-CD3; ionomycin alone induced lower percentages of CD30+ T cells (3 +/- 2%) compared to other stimuli. Maximal numbers of CD30+ cells were observed at 48 to 72 h of activation and the addition of rIL-2 did not affect these kinetics. However, CD30 expression was enhanced by the addition of exogenous rIL-2 to any of the stimuli tested, although rIL-2 alone did not lead to CD30 expression. The induction of CD30 during anti-CD3 mitogenesis was completely inhibitable by anti-IL-2 antibodies and partially inhibitable by rIL-4, indicating a requirement for both TCR triggering and IL-2 for its expression. Dual immunofluorescence analysis revealed that CD30+ cells were confined to CD3+ T cells that coexpressed higher levels of the p55 IL-2 receptor (CD25) than the CD30- population. Furthermore, CD30 expression was restricted to a subset of cells derived from CD45RO+ T cell precursors. Cell cycle analysis showed that CD30+ expression was not cell cycle dependent. Cross-linking of membrane CD30 induced Ca2+ in TCR+, but not TCR- Jurkat T cells. These results demonstrate that CD30 can serve as a T cell signal-transducing molecule and expressed by a unique subset of activated CD45RO+ T cells.
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Chen, Yi-Bin, Sean McDonough, Robert Hasserjian, Heidi Chen, Erin Coughlin, Christina Illiano, In Sun Park, et al. "Expression of CD30 in patients with acute graft-versus-host disease." Blood 120, no. 3 (July 19, 2012): 691–96. http://dx.doi.org/10.1182/blood-2012-03-415422.
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Abstract Acute GVHD (aGVHD) remains a major source of morbidity after allogeneic hematopoietic cell transplantation. CD30 is a cell-surface protein expressed on certain activated T cells. We analyzed CD30 expression on peripheral blood T-cell subsets and soluble CD30 levels in 26 patients at the time of presentation of aGVHD, before the initiation of treatment, compared with 27 patients after hematopoietic cell transplantation without aGVHD (NONE). Analysis by flow cytometry showed that patients with aGVHD had a greater percentage of CD30 expressing CD8+ T cells with the difference especially pronounced in the central memory subset (CD8+CD45RO+CD62L+): GVHD median 12.4% (range, 0.8%-33.4%) versus NONE 2.1% (0.7%, 17.5%), P < .001. There were similar levels of CD30 expression in naive T cells, CD4+ T cells, and regulatory (CD4+CD127lowCD25+) T cells. Plasma levels of soluble CD30 were significantly greater in patients with GVHD: median 61.7 ng/mL (range, 9.8-357.1 ng/mL) versus 17.4 (range, 3.7-142.4 ng/mL) in NONE (P < .001). Immunohistochemical analysis of affected intestinal tissue showed many CD30+ infiltrating lymphocytes present. These results suggest that CD30 expression on CD8+ T-cell subsets or plasma levels of soluble CD30 may be a potential biomarker for aGVHD. CD30 may also represent a target for novel therapeutic approaches for aGVHD.
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Agrawal, B., M. Reddish, and B. M. Longenecker. "CD30 expression on human CD8+ T cells isolated from peripheral blood lymphocytes of normal donors." Journal of Immunology 157, no. 8 (October 15, 1996): 3229–34. http://dx.doi.org/10.4049/jimmunol.157.8.3229.
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Abstract By direct or indirect immunofluorescence using FITC as a fluorochrome, 0 to 2% of the T cells isolated from peripheral blood of normal healthy individuals was found to be CD30+. Using indirect immunofluorescence and phycoerythrin-labeled Ab, higher percentages of CD30+ T cells (3-31%) were repeatedly found in the peripheral blood of normal healthy donors. The majority (85-90%) of CD30+ T cells obtained from PBLs of normal healthy donors were found in the CD8+ cell population. Following FACS sorting of the T cell populations into CD30+ and CD30- subpopulations, approximately 85 to 90% CD30+ T cells were CD8+, whereas the CD30- T cells were CD4+. Upon activation, the sorted CD30+ T cells produced both IFN-gamma and IL-4. In contrast to previous reports, these results demonstrate that CD30+CD8+ T cells are present in significant numbers in the PBLs of normal healthy individuals.
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Aneja, Amandeep, Raghava LevakaVeera, Viren Patel, and Ashish Bains. "Aggressive Subcutaneous Panniculitis-Like CD30+ Peripheral T-Cell Lymphoma with Diffuse EBER Expression." Case Reports in Hematology 2014 (2014): 1–4. http://dx.doi.org/10.1155/2014/874725.
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T-cell lineage lymphoma with an intense membranous and paranuclear CD30 expression in the absence of ALK1 raises a differential diagnosis of peripheral T-cell lymphoma (PTCL), NOS and anaplastic large cell lymphoma (ALCL), ALK negative. However, Epstein-Barr virus is consistently negative in ALCL and is not considered an implicating factor in its pathogenesis. We describe a case of T-cell lymphoma showing anaplastic large cell morphology with scattered hallmark cells and a uniform CD30 and Epstein-Barr virus encoded early RNA (EBER) expression that primarily involved the subcutaneous tissue at presentation. On incisional biopsy, the neoplastic cells were positive for CD3, CD2, and CD30 while negative for LCA, CD20, PAX5, CD56, ALK1, and cytotoxic granules. Molecular analysis identified a positive T-cell receptor (beta and gamma) gene rearrangement by PCR. Proliferation index approached 100% and the patient had a rapidly progressive course; the subcutaneous lesions more than doubled in size within couple of weeks with new evidence for widespread systemic involvement. This case emphasizes a rare EBV association with a CD30 positive T-cell lymphoma where the morphologic and immunophenotypic findings are otherwise nondiscriminatory between PTCL, NOS and ALCL, ALK negative.
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Prator, Cecilia A., Cassandra Thanh, Shreya Kumar, Tony Pan, Michael J. Peluso, Ronald Bosch, Norman Jones, et al. "Circulating CD30+CD4+ T Cells Increase Before Human Immunodeficiency Virus Rebound After Analytical Antiretroviral Treatment Interruption." Journal of Infectious Diseases 221, no. 7 (November 2, 2019): 1146–55. http://dx.doi.org/10.1093/infdis/jiz572.
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Abstract Background Identification of nonviral markers of human immunodeficiency virus (HIV) infection that increase before viral rebound during analytical treatment interruption (ATI) may affect HIV persistence research. We previously showed that HIV ribonucleic acid (RNA) is enriched in CD30+CD4+ T cells in many individuals. Here, we studied CD30+CD4+ T-cell dynamics before ATI, during ATI (before detectable plasma RNA), and after HIV rebound. Methods Peripheral blood mononuclear cells from 23 participants collected longitudinally from 5 Adult AIDS Clinical Trials Group studies incorporating ATI were included in this study. Flow cytometric characterization of expression of CD30 and markers of T-cell activation and exhaustion were performed along with HIV-1 RNA and deoxyribonucleic acid quantification and measurement of soluble plasma CD30 and CD30 ligand. Results The percentage of CD4+ T cells expressing CD30 significantly increased from pre-ATI to postinterruption time points before detectible viremia (1.65 mean relative increase, P = .005). Seventy-seven percent of participants experienced an increase in CD30+ cells before viral rebound. In contrast, there were no significant differences between pre-ATI and postinterruption pre-rebound time points in percentages of lymphocytes expressing CD69, CD38/HLA-DR, or PD-1 until after HIV recrudescence. Conclusions CD30 may be a surrogate marker of early replication or viral transcriptional activity before detection by routine peripheral blood sampling.
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Grover, Natalie S., Anastasia Ivanova, Dominic T. Moore, Catherine Joyce Arago Cheng, Caroline Babinec, John West, Tammy Cavallo, et al. "CD30-Directed CAR-T Cells Co-Expressing CCR4 in Relapsed/Refractory Hodgkin Lymphoma and CD30+ Cutaneous T Cell Lymphoma." Blood 138, Supplement 1 (November 5, 2021): 742. http://dx.doi.org/10.1182/blood-2021-148102.
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Abstract Chimeric antigen receptor T cells targeting CD30 (CD30.CAR-T) have shown high response rates, including some durable remissions, in patients with relapsed/refractory (r/r) classical Hodgkin lymphoma (HL) (Ramos et al., JCO 2020). However, some patients are non-responders or eventually relapse after therapy. Because CD30 expression is retained in relapsing tumors, recurrence may be due to the insufficient persistence of CAR-Ts within the highly immunosuppressive tumor microenvironment of HL. We therefore reasoned that with enhanced trafficking to the tumor site, CD30.CAR-Ts would have increased opportunities to eliminate tumors before inhibitory mechanisms become predominant. This is especially relevant for HL, where Hodgkin Reed Sternberg (HRS) cells produce CCL17 (thymus and activation-regulated chemokine) to create a physical and inhibitory barrier to cytotoxic T cells. We have previously shown that CD30.CAR-Ts co-expressing the cognate receptor for CCL17, CCR4 (CCR4.CD30.CAR-Ts), have improved tumor homing and anti-lymphoma activity compared with CD30.CAR-Ts that do not express CCR4 (Di Stasi et al., Blood 2009). CCR4.CD30.CAR-Ts should also be more effective in CD30+ cutaneous T-cell lymphomas (CTCL) due to enhanced trafficking to the skin. We present the preliminary results of a clinical trial assessing the safety (primary objective) of this novel strategy and its efficacy compared to CD30.CAR-Ts lacking CCR4 in patients with r/r HL and CD30+ CTCL (NCT03602157). CCR4.CD30.CAR-Ts are infused in patients in a dose escalation fashion (DL1=2x10 7 CAR-Ts/m 2, DL3=5x10 7 CAR-Ts/m 2, DL5=1x10 8 CAR-Ts/m 2,). To provide definitive conclusions on the role of CAR-T tumor homing, after completion of each dose level, patients receive the dose of CCR4.CD30.CAR-Ts established to be safe in the prior DL, combined with a fixed dose of CD30.CAR-Ts (1x10 8 CAR-Ts/m 2) (DL2, DL4, DL6). All patients receive lymphodepletion with 3 days of bendamustine 70 mg/m 2 and fludarabine 30 mg/m 2. Key inclusion criteria are age ≥ 18 years and r/r HL or CTCL having failed ≥2 prior therapies. At the time of data cut off (8/1/2021), 6 patients were treated on DL1, 3 patients on DL2, and 3 patients on DL3. The median age is 43.5 (range 27-75) with a median of 5.5 prior lines of therapy (range 2-10). Ten patients had HL and 2 patients had CTCL. All patients had received prior brentuximab vedotin. Eleven patients received prior checkpoint inhibitors, 9 had prior autologous stem cell transplant, and 5 had prior allogeneic stem cell transplant. The treatment was well tolerated with no dose limiting toxicities observed. Two patients had grade 2 cytokine release syndrome (CRS) which resolved with tocilizumab, and 1 had self-limiting grade 1 CRS. None of the treated patients developed immune effector cell-associated neurotoxicity syndrome. All of the 8 patients with HL who have had disease assessment have responded with 6 complete responses (CR) (75%) and 2 partial responses (PR). Five patients are in remission to date, with one patient still in CR at 2.5 years post treatment. Two patients with HL have responses pending at time of data cut off. Among the 2 patients with CTCL, 1 patient had stable disease and went on to receive alternative therapy and 1 patient had progressive disease. At a median follow up of 12.7 months, the median progression free survival (PFS) for all 10 evaluable patients is 5.2 months and the median PFS for HL patients has not been reached. The median overall survival for all patients has not been reached. Plasma CCL17, a biomarker of disease response for HL, was reduced by 83±15% by week 2 post infusion in patients treated with CCR4.CD30.CAR-Ts as compared to 52±38% in patients on our previous trial that had received CD30.CAR-Ts lacking CCR4 (p=0.02). In a HL patient on DL1 biopsied 3 weeks post infusion, we found markedly enriched CAR-T signals at the tumor site (14.4 x10 5 copies/ug of DNA) as compared to the signals found at the same time point in the peripheral blood (4.3 x10 5 copies/ug of DNA). Our data confirm the safety of CCR4.CD30.CAR-Ts as well as their promising efficacy in patients with r/r HL. Interestingly, responses are already seen at the lowest dose level, suggesting that early tumor homing driven by CCR4 may allow more fitted cells to better exploit their antitumor potential. Our data serve as a proof of concept for future modifications of CAR-T cells to improve their localization to disease sites. Figure 1 Figure 1. Disclosures Grover: Kite: Other: Advisory Board; Tessa: Consultancy; ADC: Other: Advisory Board; Novartis: Consultancy; Genentech: Research Funding. Morrison: Vesselon: Consultancy. Dittus: BeiGene: Other: Advisory Board; Seattle Genetics: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding. Dotti: Tessa: Patents & Royalties: Approach for CD30.CAR-T Cells for Hodgkin Lymphoma. Serody: Tessa: Patents & Royalties: Approach for CD30.CAR-T Cells for Hodgkin Lymphoma. Savoldo: Tessa: Patents & Royalties: Approach for CD30.CAR-T Cells for Hodgkin Lymphoma.
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Hutchison, R. E., C. W. Berard, J. J. Shuster, M. P. Link, T. E. Pick, and S. B. Murphy. "B-cell lineage confers a favorable outcome among children and adolescents with large-cell lymphoma: a Pediatric Oncology Group study." Journal of Clinical Oncology 13, no. 8 (August 1995): 2023–32. http://dx.doi.org/10.1200/jco.1995.13.8.2023.
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PURPOSE The goal of this study was to assess the immunophenotype of uniformly treated cases of pediatric large-cell non-Hodgkin's lymphoma (NHL) to determine the prognostic importance of B-cell and T-cell lineages and of CD30 positivity. PATIENTS AND METHODS Sixty-nine patients were analyzed by immunochemistry. All patients were classified histologically, staged in a uniform manner, and treated according to one of two protocols for localized (stage I and II) NHL or advanced (stage III and IV) large-cell NHL. Antibodies included anti-CD45, CD20, CD45Ra, MB-2 (not clustered), CD3, CD45Ro, CD43, CD15, CD30, and CD68. Statistical analysis used the exact conditional chi 2 and Kruskall-Wallace tests for clinical features and the log-rank test to evaluate event-free survival (EFS). RESULTS Immunophenotypic results demonstrated 25 B-cell, 23 T-cell, and 21 indeterminate lineage. Twenty-seven patients expressed CD30 (17 T-cell and 10 indeterminate lineage), and of these, 22 showed histology of anaplastic large-cell lymphoma (ALCL). B-cell patients were older (P = .018) and showed more favorable survival than patients with T-cell or indeterminate lineage (96% EFS at 3 years, 96% v 67% and 74%, B v T and indeterminate lineage [P = .027]). B-cell lineage was seen more frequently in limited-stage patients, but was also associated with favorable survival when stratified for stage (P = .036). CD30 expression (P = .96) and ALCL histology (P = .90) did not show significant associations with survival. CONCLUSION We conclude that among pediatric large-cell lymphomas, B-cell lineage is proportionately less frequent than in adults and CD30 antigen-expressing lymphomas are frequent among patients with T-cell and indeterminate lineage. B-cell phenotype tends to occur in older children and is associated with superior survival.
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Manetti, R., F. Annunziato, R. Biagiotti, M. G. Giudizi, M. P. Piccinni, L. Giannarini, S. Sampognaro, et al. "CD30 expression by CD8+ T cells producing type 2 helper cytokines. Evidence for large numbers of CD8+CD30+ T cell clones in human immunodeficiency virus infection." Journal of Experimental Medicine 180, no. 6 (December 1, 1994): 2407–11. http://dx.doi.org/10.1084/jem.180.6.2407.
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A large panel of CD8+ T cell clones generated from peripheral blood lymphocytes (PBL) of healthy donors or human immunodeficiency virus (HIV)-infected individuals were assessed for both cytokine secretion profile and CD30 expression and release. The great majority of CD8+ T cell clones generated from healthy individuals showed the ability to produce interferon gamma (IFN-gamma), but not interleukin 4 (IL-4), and none of them either expressed membrane CD30 or released substantial amounts of soluble CD30 (sCD30) in their supernatant. In contrast, high numbers of CD8+ T cell clones generated from HIV-infected individuals, which produced IL-4 (and IL-5) in addition to IFN-gamma or IL-4 (and IL-5) alone, expressed membrane CD30 and released detectable amounts of sCD30 in their supernatants. Indeed, CD30 expression appeared to be positively correlated with the ability of CD8+ T cell clones to produce IL-4 and IL-5 and inversely correlated with their ability to produce IFN-gamma, whereas no correlation between CD30 expression and production of IL-10 was observed. These data suggest that CD30 is a marker for CD8+ T cells that have switched to the production of type 2 helper cytokines.
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Lezama, Lhara Sumarriva, and Dita Gratzinger. "Nodal Involvement by CD30+ Cutaneous Lymphoproliferative Disorders and Its Challenging Differentiation From Classical Hodgkin Lymphoma." Archives of Pathology & Laboratory Medicine 142, no. 1 (January 1, 2018): 139–42. http://dx.doi.org/10.5858/arpa.2016-0352-rs.
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Primary cutaneous lymphomas are defined as non-Hodgkin lymphomas that present in the skin with no evidence of extracutaneous disease at the time of diagnosis. Mycosis fungoides is the most common type of primary cutaneous T-cell lymphoma, representing almost 50% of primary cutaneous T-cell lymphomas, and primary cutaneous CD30+ T-cell lymphoproliferative disorders are the second most common group (30%). Transformed mycosis fungoides is usually CD30+ and can involve multiple nodal sites; other primary cutaneous CD30+ T-cell lymphoproliferative disorders can also involve draining regional nodes. Nodal involvement by CD30+ T-cell lymphoproliferative disorders can mimic classical Hodgkin lymphoma, which can aberrantly express T-cell antigens. The aim of this article is to briefly review salient clinical, histologic, immunophenotypic, and molecular features that can be used to distinguish lymph node involvement by CD30+ cutaneous T-cell lymphomas and lymphoproliferative disorders from classical Hodgkin lymphoma, a clinically important differential diagnosis that represents a challenging task for the pathologist.
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Grogan, Bryan, Reice James, Michelle Ulrich, Shyra Gardai, Ryan Heiser, and Reice James. "696 Brentuximab vedotin, a CD30-directed antibody-drug conjugate, selectively depletes activated Tregs in vitro and in vivo." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A738. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0696.
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BackgroundRegulatory T cells (Tregs) play an important role in maintaining immune homeostasis, preventing excessive inflammation in normal tissues. In cancer, Tregs hamper anti-tumor immunosurveillance and facilitate immune evasion. Selective targeting of intratumoral Tregs is a potentially promising treatment approach. Orthogonal evaluation of tumor-infiltrating lymphocytes (TILs) in solid tumors in mice and humans have identified CCR8, and several tumor necrosis family receptors (TNFRs), including TNFSFR8 (CD30), as receptors differentially upregulated on intratumoral Tregs compared to normal tissue Tregs and other intratumoral T cells, making these intriguing therapeutic targets.Brentuximab vedotin (BV) is approved for classical Hodgkin lymphoma (cHL) across multiple lines of therapy including frontline use in stage III/IV cHL in combination with doxorubicin, vinblastine, and dacarbazine. BV is also approved for certain CD30-expressing T-cell lymphomas. BV is comprised of a CD30-directed monoclonal antibody conjugated to the highly potent microtubule-disrupting agent monomethyl auristatin E (MMAE).The activity of BV in lymphomas is thought to primarily result from tumor directed intracellular MMAE release, leading to mitotic arrest and apoptotic cell death.The role CD30 plays in normal immune function is unclear, with both costimulatory and proapoptotic roles described. CD30 is transiently upregulated following activation of memory T cells and expression has been linked to highly activated/suppressive IRF4+ effector Tregs.MethodsHere we evaluated the activity of BV on CD30-expressing T cell subsets in vitro and in vivo.ResultsTreatment of enriched T cell subsets with clinically relevant concentrations of BV drove selective depletion of CD30-expressing Tregs > CD30-expressingCD4+ T memory cells, with minimal effects on CD30-expressing CD8+ T memory cells. In a humanized xeno-GVHD model, treatment with BV selectively depleted Tregs resulting in accelerated wasting and robust T cell expansion. The observed differential activity on Tregs is likely attributable to significant increases in CD30 expression and reduced efflux pump activity relative to other T cell subsets. Interestingly, blockade of CD25 signaling prevents CD30 expression on T cell subsets without impacting proliferation, suggesting a link between CD25, the high affinity IL-2 receptor, and CD30 expression.ConclusionsTogether, these data suggest that BV may have an immunomodulatory effect through selective depletion of highly suppressive CD30-expressing Tregs.AcknowledgementsThe authors would like to thank Michael Harrison, PharmD for their assistance in abstract preparation.Ethics ApprovalAnimals studies were approved by and conducted in accordance with Seattle Genetics Institutional Care and Use Committee protocol #SGE-024.
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Advani, Ranjana H., Steven M. Horwitz, Swaminathan Padmanabhan Iyer, Nancy L. Bartlett, Won Seog Kim, Herve Tilly, David Belada, et al. "Response to A+CHP by CD30 expression in the ECHELON-2 trial." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 7538. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.7538.
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7538 Background: Brentuximab vedotin (BV) is an antibody-drug conjugate that targets CD30. The ECHELON-2 (E-2) study demonstrated significantly longer progression-free and overall survival with BV plus cyclophosphamide, doxorubicin, and prednisone (A+CHP) versus CHOP in frontline treatment of patients (pts) with CD30+ peripheral T-cell lymphoma (PTCL). Complete remission (CR) rate (A+CHP 68%; CHOP 56%) and objective response rate (ORR) (A+CHP 83%; CHOP 72%) were also significantly increased. Expression of CD30 is universal in systemic anaplastic large-cell lymphoma (sALCL) but variable among non-sALCL subtypes. As ORR is a direct measure of antitumor activity, we examined response to A+CHP by CD30 expression. Methods: Pts with CD30+ (≥10% by local review) PTCL were included in E-2. Eligible histologies included ALK+ sALCL (IPI ≥2), ALK− sALCL, PTCL-not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), adult T-cell leukemia/lymphoma, enteropathy-associated T-cell lymphoma, and hepatosplenic T-cell lymphoma. We analyzed the relationship between CD30 expression (IHC Ber H2 antibody) above and below the median (median CD30=18% PTCL-NOS; 25% AITL) and CR rate, ORR, and duration of CR (DOCR) in pts with AITL and PTCL-NOS treated with A+CHP. Results: Most (26/29, 90%) AITL pts had CD30 expression between 10% and 30%. PTCL-NOS pts were more evenly distributed across levels of CD30 expression ranging from 10% to 100%. CD30 levels were neither predictive of response (Table) nor significantly associated with DOCR in pts with AITL (P=0.30) or PTCL-NOS (P=0.90) (log-rank test). Response by CD30 expression. Clinical trial information: NCT01777152. Conclusions: CD30 expression above vs below median (or at 10%) did not predict response to A+CHP in E-2 non-ALCL subtypes, as responses were seen across CD30 levels. This may be due to intra- and inter-tumoral heterogeneity of CD30 expression, limitations of IHC, the nature of CD30 on the cell surface, and multiple mechanisms of action of BV. Further evaluation of the expression-response relationship in PTCL pts with CD30 <10% is warranted.[Table: see text]
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Gellrich, Sylke, Anke Wilks, Ansgar Lukowsky, Martin Wernicke, Astrid Müller, J. Marcus Muche, Tanja Fischer, Kim Christian Jasch, Heike Audring, and Wolfram Sterry. "T Cell Receptor-γ Gene Analysis of CD30+ Large Atypical Individual Cells in CD30+ Large Primary Cutaneous T Cell Lymphomas." Journal of Investigative Dermatology 120, no. 4 (April 2003): 670–75. http://dx.doi.org/10.1046/j.1523-1747.2003.12101.x.
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Sandlund, J. T., C. H. Pui, V. M. Santana, H. Mahmoud, W. M. Roberts, S. Morris, S. Raimondi, R. Ribeiro, W. M. Crist, and J. S. Lin. "Clinical features and treatment outcome for children with CD30+ large-cell non-Hodgkin's lymphoma." Journal of Clinical Oncology 12, no. 5 (May 1994): 895–98. http://dx.doi.org/10.1200/jco.1994.12.5.895.
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PURPOSE To determine the frequency of CD30 expression and its relationship to clinical features, immunophenotype, histotype, and outcome in childhood large-cell non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS We reviewed 45 cases of large-cell NHL in children treated at St Jude Children's Research Hospital from 1975 to 1990 for whom there was sufficient tissue to perform immunophenotypic studies. All 45 were screened with a panel of antibodies to detect the presence of CD30 and T-cell and B-cell antigens. Cases were classified according to the National Cancer Institute (NCI) Working Formulation and the Kiel classification system. Clinical features, immunophenotype, pathologic classification, and treatment outcome were compared for CD30+ and CD30- cases. RESULTS CD30 expression was documented in 18 cases (40%). These 13 boys and five girls had a median age of 13 years at diagnosis. Most (n = 14) had advanced-stage (III and IV) disease. Nodal disease was equally common in CD30+ and CD30- cases, whereas skin involvement was significantly more frequent in CD30+ cases (P = .007). There was no significant association of CD30 expression with histologic subtype according to the NCI Working Formulation, but CD30+ cases were more likely to be anaplastic by the Kiel classification (P < .001). All CD30+ cases had either T-cell or null-cell phenotype, while the majority of CD30- cases were B-cell phenotype (P < .001). Among patients with limited-stage disease, the mean +/- SE estimated 5-year event-free survival (EFS) was 75% +/- 22% for CD30+ cases and 92% +/- 9% for CD30- cases (P = .10); estimates for advanced-stage disease were 57% +/- 17% and 29% +/- 17%, respectively (P = .096). For patients with advanced-stage disease, CD30 expression was associated with a significantly better overall 5-year survival probability (84% +/- 12% v 27% +/- 16%, P = .0016). CONCLUSION CD30 is frequently expressed in pediatric large-cell NHL and is significantly associated with T-cell or null-cell phenotype, anaplastic morphology, skin involvement, and better overall survival among advanced-stage patients.
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Sabattini, E., M. Pizzi, V. Tabanelli, P. Baldin, C. S. Sacchetti, C. Agostinelli, P. L. Zinzani, and S. A. Pileri. "CD30 expression in peripheral T-cell lymphomas." Haematologica 98, no. 8 (May 28, 2013): e81-e82. http://dx.doi.org/10.3324/haematol.2013.084913.
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Kadin, Marshall E. "Pathobiology of CD30+ cutaneous T-cell lymphomas." Journal of Cutaneous Pathology 33, S1 (February 2006): 10–17. http://dx.doi.org/10.1111/j.0303-6987.2006.00507.x.
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Riveiro-Falkenbach, Erica, María Teresa Fernández-Figueras, and José Luis Rodríguez-Peralto. "Benign Atypical Intravascular CD30+ T-cell Proliferation." American Journal of Dermatopathology 35, no. 2 (April 2013): 143–50. http://dx.doi.org/10.1097/dad.0b013e3182323119.
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