Abstract 2704: A role of the ADCC in the antibody therapy for gastrointestinal carcinoma

2011 ◽  
Author(s):  
Tatsuzo Matsuyama ◽  
Satoshi Kokura ◽  
Tsuguhiro Matsumoto ◽  
Manabu Okajima ◽  
Manabu Okajima ◽  
...  
Keyword(s):  
Antibody Therapy ◽  
Gastrointestinal Carcinoma

scholarly journals Immunosenescence: a key player in cancer development

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Jingyao Lian ◽  
Ying Yue ◽  
Weina Yu ◽  
Yi Zhang
Keyword(s):  
T Cells ◽  
Cytotoxic T Lymphocyte ◽  
Malignant Tumors ◽  
Killer Cell ◽  
Antibody Therapy ◽  
The Elderly ◽  
Mtor Inhibition ◽  
Interleukin 7 ◽  
The Many

Abstract Immunosenescence is a process of immune dysfunction that occurs with age and includes remodeling of lymphoid organs, leading to changes in the immune function of the elderly, which is closely related to the development of infections, autoimmune diseases, and malignant tumors. T cell–output decline is an important feature of immunosenescence as well as the production of senescence-associated secretory phenotype, increased glycolysis, and reactive oxygen species. Senescent T cells exhibit abnormal phenotypes, including downregulation of CD27, CD28, and upregulation of CD57, killer cell lectin-like receptor subfamily G, Tim-3, Tight, and cytotoxic T-lymphocyte-associated protein 4, which are tightly related to malignant tumors. The role of immunosenescence in tumors is sophisticated: the many factors involved include cAMP, glucose competition, and oncogenic stress in the tumor microenvironment, which can induce the senescence of T cells, macrophages, natural killer cells, and dendritic cells. Accordingly, these senescent immune cells could also affect tumor progression. In addition, the effect of immunosenescence on the response to immune checkpoint blocking antibody therapy so far is ambiguous due to the low participation of elderly cancer patients in clinical trials. Furthermore, many other senescence-related interventions could be possible with genetic and pharmacological methods, including mTOR inhibition, interleukin-7 recombination, and NAD+ activation. Overall, this review aims to highlight the characteristics of immunosenescence and its impact on malignant tumors and immunotherapy, especially the future directions of tumor treatment through senescence-focused strategies.

scholarly journals CD4+ but not CD8+ cells are essential for allorejection.

1996 ◽  
Vol 184 (5) ◽  
pp. 2013-2018 ◽  
Author(s):  
N R Krieger ◽  
D P Yin ◽  
C G Fathman
Keyword(s):  
Cd8 T Cells ◽  
Knockout Mice ◽  
Antibody Therapy ◽  
Major Histocompatibility ◽  
Cd4 Cells ◽  
Cd8 Cells ◽  
Targeted Gene Disruption ◽  
Histocompatibility Complex ◽  
Skin Allografts

The generation of knockout mice with targeted gene disruption has provided a valuable tool for studying the immune response. Here we describe the use of CD4 and CD8 knockout mice to examine the role of CD4+ and CD8+ cells in initiating allotransplantation rejection. Pretreatment with a brief course of depletive anti-CD4 monoclonal antibody therapy allowed permanent survival of heart, but not skin, allografts transplanted across a major histocompatibility barrier. However, skin as well as heart grafts were permanently accepted in the CD4 knockout mice. Transfer of CD4+ cells into CD4 knockout recipient mice 1 d before skin engraftment reconstituted rejection, demonstrating that CD4+ cells are necessary for initiating rejection of allogeneic transplants. Major histocompatibility complex disparate heart and skin allografts transplanted into CD8 knockout recipients were rejected within 10 d. This study demonstrates that CD4+ but not CD8+ T cells are absolutely required to initiate allograft rejection.

scholarly journals A Novel Role for the Interleukin-1 Receptor Axis in Resistance to Anti-EGFR Therapy

Cancers ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 355 ◽  
Author(s):  
Valerio Gelfo ◽  
Martina Mazzeschi ◽  
Giada Grilli ◽  
Moshit Lindzen ◽  
Spartaco Santi ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Molecular Subtype ◽  
Interleukin 1 ◽  
Antibody Therapy ◽  
Growth Factor Receptor ◽  
Poor Response ◽  
Extracellular Region ◽  
Epidermal Growth ◽  
Consensus Molecular Subtype

Cetuximab (CTX) is a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), commonly used to treat patients with metastatic colorectal cancer (mCRC). Unfortunately, objective remissions occur only in a minority of patients and are of short duration, with a population of cells surviving the treatment and eventually enabling CTX resistance. Our previous study on CRC xenopatients associated poor response to CTX with increased abundance of a set of pro-inflammatory cytokines, including the interleukins IL-1A, IL-1B and IL-8. Stemming from these observations, our current work aimed to assess the role of IL-1 pathway activity in CTX resistance. We employed a recombinant decoy TRAP IL-1, a soluble protein combining the human immunoglobulin Fc portion linked to the extracellular region of the IL-1-receptor (IL-1R1), able to sequester IL-1 directly from the medium. We generated stable clones expressing and secreting a functional TRAP IL-1 into the culture medium. Our results show that IL-1R1 inhibition leads to a decreased cell proliferation and a dampened MAPK and AKT axes. Moreover, CRC patients not responding to CTX blockage displayed higher levels of IL-1R1 than responsive subjects, and abundant IL-1R1 is predictive of survival in patient datasets specifically for the consensus molecular subtype 1 (CMS1). We conclude that IL-1R1 abundance may represent a therapeutic marker for patients who become refractory to monoclonal antibody therapy, while inhibition of IL-1R1 by TRAP IL-1 may offer a novel therapeutic strategy.

Investigation of FcγR Polymorphisms and Response to IL-2 (Proleukin®) and Rituximab Treatment in Rituximab-Resistant NHL Patients: Importance of the F/F Polymorphism at Position 158 of the Fcγ.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4621-4621
Author(s):  
Sandra Milan ◽  
Susan E. Wilson ◽  
K.D. Kahn ◽  
Heidi Giordano
Keyword(s):  
Antibody Therapy ◽  
Critical Threshold ◽  
Polymorphism Analysis ◽  
Low Grade ◽  
Response Data ◽  
Injection Site Reactions ◽  
Best Response ◽  
Grade 3

Abstract Background: Antibody-dependent cellular cytotoxicty (ADCC) is an important mechanism of rituximab activity. Genetic polymorphisms in FcγRIIIa have been reported to influence response to rituximab in follicular non-Hodgkin’s lymphoma (NHL) patients, and the F/F polymorphism at position 158 has been associated with decreased response (Cartron, et al. Blood 2004). IL-2 induces expansion and activation of FcR bearing cells, enhancing ADCC (Gluck, et al. Clin Cancer Res 2004). Methods: The combination therapy of IL-2 and rituximab (IL-2+R) was evaluated in low grade NHL patients who were rituximab-resistant by standard criteria. Rituximab was administered weeks (wks) 1–4 at 375 mg/m2 IV; IL-2 was administered SC 3 times/wk at 14 MIU wks 2–5 and at 10 MIU wks 6–9. Results: 57 patients (pts) were enrolled. Twenty-nine pts are evaluable with at least week 8 response data, all of whom have been genotyped. Best response to date: 4 responders (1 CR, 3 PR), 22 patients with stable disease (SD), and 3 pts have progressed (PD) on therapy. Follow-up is on-going. FcγRIIIa polymorphism analysis at position 158 from 36 pts typed to date shows a frequency of 53% F/F, 36% V/F, and 11% V/V as compared to 35%F/F, 45%V/F and 20% V/V in previously untreated pts (Cartron et al, 2004). To date, the data has shown a higher response rate for the F/F pts (4/17; 24%) than the overall population (4/29; 14%). Best response to date for 17 F/F pts: 4 responders and 13 SD; for the 9 V/F pts: 0 responders, 7 SD, and 2 PD; for the 3 V/V pts: 0 responders, 2 SD, and 1PD. In addition, 9 pts had responses lasting = 4 months with 6/9 being F/F and 3/9 being V/F. Patients will be followed periodically up to 2 years or until disease progression. The regimen was well tolerated and the majority of adverse events (AEs) were CTC grade 0, 1, or 2 (flu like symptoms, injection site reactions and rash). No grade 3 or 4 AEs occurred in 10% or more of pts. Conclusions: These data support an association of the genetic polymorphism of FcγRIIIa 158F/F with prior failure to respond to rituximab. Immunotherapy with IL-2+R may achieve a critical threshold to drive ADCC more effectively in patients carrying the low affinity F/F IgG FcR polymorphism, restoring their response to monoclonal antibody therapy. All pts with this F/F polymorphism either responded to therapy or achieved SD as their best response to date. This outpatient regimen was generally well tolerated. The role of the FcγRIIIa F/F polymorphism is currently being evaluated in a prospective randomized trial comparing rituximab to rituximab + IL-2 in patients with follicular lymphoma.

Antihypertensive effects of chronic anti-TGF-β antibody therapy in Dahl S rats

2002 ◽  
Vol 283 (3) ◽  
pp. R757-R767 ◽  
Author(s):  
Annette J. Dahly ◽  
Kimberly M. Hoagland ◽  
Averia K. Flasch ◽  
Sharda Jha ◽  
Steven R. Ledbetter ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Blood Flow ◽  
Transforming Growth Factor ◽  
Antibody Therapy ◽  
Transforming Growth Factor Β ◽  
Type Iii Collagen ◽  
Renal Hypertrophy ◽  
Medullary Blood Flow ◽  
Tgf Β1

This study examined the role of transforming growth factor-β (TGF-β) in the development of hypertension and renal disease in 9-wk-old male Dahl salt-sensitive (Dahl S) rats fed an 8% NaCl diet for 3 wk. The rats received an intraperitoneal injection of a control or an anti-TGF-β antibody (anti-TGF-β Ab) every other day for 2 wk. Mean arterial pressure was significantly lower in Dahl S rats treated with anti-TGF-β Ab (177 ± 3 mmHg, n = 12) than in control rats (190 ± 4 mmHg, n = 17). Anti-TGF-β Ab therapy also reduced proteinuria from 226 ± 20 to 154 ± 16 mg/day. Renal blood flow, cortical blood flow, and creatinine clearance were not significantly different in control and treated rats; however, medullary blood flow was threefold higher in the treated rats than in the controls. Despite the reduction in proteinuria, the degree of glomerulosclerosis and renal hypertrophy was similar in control and anti-TGF-β Ab-treated rats. Renal levels of TGF-β1 and -β2, α-actin, type III collagen, and fibronectin mRNA decreased in rats treated with anti-TGF-β Ab. To examine whether an earlier intervention with anti-TGF-β Ab would confer additional renoprotection, these studies were repeated in a group of 6-wk-old Dahl S rats. Anti-TGF-β Ab therapy significantly reduced blood pressure, proteinuria, and the degree of glomerulosclerosis and renal medullary fibrosis in this group of rats. The results indicate that anti-TGF-β Ab therapy reduces blood pressure, proteinuria, and the renal injury associated with hypertension.

An inhibitory role of complement in monoclonal antibody therapy of lymphoma

2010 ◽  
Vol 47 (13) ◽  
pp. 2268-2268
Author(s):  
David C. Fritzinger ◽  
Carl-Wilhelm Vogel ◽  
Bassam B. Damaj ◽  
Paul W. Finnegan
Keyword(s):  
Monoclonal Antibody ◽  
Antibody Therapy ◽  
Monoclonal Antibody Therapy ◽  
Inhibitory Role
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