Phase I Study of Recombinant Human CD40 Ligand in Cancer Patients

Vonderheide, Robert H.; Dutcher, Janice P.; Anderson, Jeanne E.; Eckhardt, S. Gail; Stephans, Katherine; Razvillas, Betty; Garl, Susan; Butine, Michael D.; Perry, Vicki P.; Armitage, Richard J.; Ghalie, Richard; Caron, Dania; Gribben, John G.

doi:10.1200/jco.2001.19.13.3280

Cited by 201 publications

(158 citation statements)

References 40 publications

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“…21 In the human study, recombinant human CD40L protein had been administered subcutaneously to patients with advanced solid tumors and non-Hodgkin's lymphomas. Transient, dose-dependent ALT elevations peaking at day 6 with subsequent ALT normalization within 2 weeks had been observed in this trial.…”

Section: Discussionmentioning

confidence: 99%

Induction of murine liver damage by overexpression of CD40 ligand provides an experimental model to study fulminant hepatic failure

et al. 2006

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Previously, we demonstrated that intrahepatic upregulation of the immunoactivating molecules CD40 and CD40 ligand (CD40L) are early mechanisms for liver cell damage in human and murine fulminant hepatic failure (FHF). In the present study, we investigated the functional effects of intrahepatic overexpression of CD40L by adenoviral-mediated gene transfer (AdCD40L) in mice. AdCD40L injection induced severe liver cell damage, which was associated with increased alanine aminotransferase (ALT) levels peaking at day 5 after vector administration (AdCD40L, 1,707 ؎ 279 U/L; AdLacZ, 213 ؎ 25 U/L) and with lethality in half of the mice. Except for mild splenomegaly, no organs other than the liver were involved in inflammatory reactions. CD40 -CD40L interaction was mandatory for liver damage, because CD40 ؊/؊ mice were completely protected. F ulminant hepatic failure (FHF) is a life-threatening condition induced by pathogens such as hepatitis B virus infection and drug toxicity. The underlying pathophysiological mechanisms are not fully understood. This renders a causal therapeutic approach difficult. 1,2 Uncontrolled hepatic immunoactivation is discussed as a pivotal pathomechanism of FHF. 3-5 Recently, we described significant intrahepatic upregulation of the immunoactivating molecules CD40 and its ligand (CD40L/ CD154) in patients with FHF. 3 In human FHF, CD40 was upregulated in hepatocytes, sinusoidal and vascular endothelial cells, and macrophages/Kupffer cells, whereas CD40L was expressed in an increased number of intrahepatic lymphocytes. Taking into account our observation of strongly enhanced hepatic CD40 and CD40L expression in FHF and the potent immunoactivating properties of the CD40 -CD40L interaction, we hypothesized that the interaction of CD40 with CD40L is a pivotal trigger of immune cascade-inducing FHF.CD40L is a member of the tumor necrosis factor receptor superfamily and is expressed on activated CD4 ϩ T cells and platelets. 6,7 The CD40 -CD40L interaction induces strong immunoactivation at different levels of the immune system, including T cells, B cells, macrophages, and dendritic cells. Interaction of CD40 -CD40L on dendritic cells and other antigen-presenting cells such as monocytes/macrophages and B lymphocytes upregulates Abbreviations: FHF, fulminant hepatic failure; CD40L, CD40 ligand; AdCD40L, adenoviral CD40 ligand; ALT, alanine aminotransferase; NKT cell, natural killer T cell; pfu,

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Section: Discussionmentioning

confidence: 99%

Induction of murine liver damage by overexpression of CD40 ligand provides an experimental model to study fulminant hepatic failure

et al. 2006

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“…There is evidence to support the notion of CD40 ligation-induced apoptosis as a mechanism for eliminating neoplastically transformed urothelial cells (Bugajska et al, 2002). A phase I study of recombinant Human CD40L in patients with advanced solid tumours or intermediate-or high-grade non-Hodgkin's lymphoma demonstrated encouraging antitumour activity, including a longterm complete remission (Vonderheide et al, 2001). Therapeutic use of CD40L in future will be incorporated into radical treatment of bladder cancer to get a clear picture of their efficacy and toxicity.…”

Section: Discussionmentioning

confidence: 99%

Proapoptotic genes BAX and CD40L are predictors of survival in transitional cell carcinoma of the bladder

et al. 2003

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The purpose of the study was to investigate the effects of expression of a range of genes involved in apoptosis on outcome in bladder cancer. Immunohistochemistry was used to examine expression of BCL2, BAX, P53, CD40 and CD40L in archival tissues of patients In conclusion, it was seen that overexpressions of BAX and CD40L are prognostic of better survival in TCC of the bladder. Our results also raise the possibility of the future development of CD40-and CD40 ligand-based immunotherapy for bladder cancer. This study links proapoptotic and antiapoptotic markers to overall survival.

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“…On the basis of the apoptosis-dependent or -independent growth inhibition, CD154 has been proposed to be of clinical use in some cancers. 40 Thus, in renal clear cell carcinoma, CD154 elicited biologic activities that may promote tumor growth and diffusion. This suggests that the proposed CD154-based therapy cannot be extended to every kind of tumor.…”

Section: Discussionmentioning

confidence: 99%

Expression of CD154 on renal cell carcinomas and effect on cell proliferation, motility and platelet‐activating factor synthesis

Bussolati

Russo

Deambrosis

et al. 2002

Intl Journal of Cancer

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CD40 activation by CD154 may trigger diverse cellular responses, ranging from proliferation and differentiation to growth suppression and cell death, in normal and malignant cells. However, the pathophysiologic role of CD154 expressed by tumor cells remains unclear. We have investigated the expression of the CD40-CD154 system in 24 primary cultures derived from renal cell carcinomas, its correlation with tumor stage and its potential functional significance. We found coexpression of CD40 and CD154 in most of the renal carcinoma cell lines. CD154, but not CD40 expression, significantly correlated with tumor stage. Moreover, renal carcinoma cell lines also released the soluble form of CD154 into the supernatant. CD40 engagement by CD154 did not affect apoptosis or survival. On the contrary, CD154 stimulated cell proliferation, motility and production of PAF, a phospholipid mediator of inflammation with angiogenic properties. Key words: CD154; platelet-activating factor; renal carcinoma; CD40; angiogenesis CD154, the ligand of CD40, is a type II integral membrane protein, related to TNF and FasL. 1 Its receptor, CD40, is a 50 kDa transmembrane glycoprotein of the TNF superfamily, which is expressed in a multitude of different cell types, including B cells, monocytes, dendritic cells, endothelial cells, fibroblasts and renal epithelial cells. 2,3 CD40 was originally identified in a bladder carcinoma cell line, 4 and it is also expressed in a number of carcinomas, such as ovarian, nasopharyngeal, bladder, lung, colon and breast carcinomas, whereas normal nonproliferating tissues are CD40-negative. 5 CD40 engagement by CD154 conveys signals regulating diverse cellular responses, ranging from proliferation and differentiation to growth suppression and apoptosis. 6,7 The CD40 cytoplasmic C terminus lacks intrinsic kinase activity and adapter proteins of the TRAF family appear to mediate the activation of CD40-signaling cascades. 8 Despite the large interest, the functional role of CD40 in cancer development remains undetermined. CD40 appears to possess an opposite effect on tumor cell survival and apoptosis. CD40-mediated signaling has been reported to induce apoptosis when expressed in certain transformed cells of mesenchymal origin 9 and in carcinomas of the breast and lung. 10,11 Conversely, Jakobson et al. 12 demonstrated that CD40 stimulation inhibits Fas-mediated apoptosis in human bladder carcinoma cells and we showed a similar protective effect of CD40 in Kaposi's sarcoma cells. 13 Moreover, immunohistochemic studies revealed that detection of CD40 in primary cutaneous malignant melanoma might have negative prognostic value, suggesting its role in tumor progression. 14 CD154 is coexpressed with CD40 in melanoma cells and some carcinomas. 10,11,14 However, the pathophysiologic role of CD40 -CD154 interaction within the tumor cell remains unclear.In the present study, we investigated expression of the CD40 -CD154 system in 24 primary cultures derived from renal clear cell carcinomas, its correlation with tumor st...

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Phase I Study of Recombinant Human CD40 Ligand in Cancer Patients

Abstract: The MTD of rhuCD40L when administered subcutaneously daily for 5 days was defined by transient serum elevations in hepatic transaminases. Encouraging antitumor activity, including a long-term complete remission, was observed. Phase II studies are warranted.

Cited by 201 publications

References 40 publications

Induction of murine liver damage by overexpression of CD40 ligand provides an experimental model to study fulminant hepatic failure

Induction of murine liver damage by overexpression of CD40 ligand provides an experimental model to study fulminant hepatic failure

Proapoptotic genes BAX and CD40L are predictors of survival in transitional cell carcinoma of the bladder

Expression of CD154 on renal cell carcinomas and effect on cell proliferation, motility and platelet‐activating factor synthesis

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