TNFMedicine

Therapeutic potential of cytokine and chemokine antagonists in cancer therapy

This excellent 2006 review from the group at Centocor discusses the therapeutic potential of biologic TNF-alpha antagonists for the treatment of patients with cancer. The article cites and discusses my 2003 article reporting a therapeutic response in two patients with cancer metastases to the spine, which was the first report in the literature of this nature. (see Edward Tobinick MD, Targeted etanercept for treatment-refractory pain due to bone metastasis: two case reports. [Case Reports, Journal Article] Clinical Therapeutics 2003 Aug; 25(8) :2279-88).

Therapeutic potential of cytokine and chemokine antagonists in cancer therapy.
Yan L,
Anderson GM,
DeWitte M,
Nakada MT.
Centocor R&D Inc., 145 King of Prussia Road, Radnor, PA 19087, USA.
A new paradigm is becoming widely accepted, that chronic inflammation, driven in part by chemokines and cytokines at the site of a tumour, may facilitate tumour progression instead of promoting anti-tumour immunity. Tumours and activated stromal cells secrete pro-inflammatory chemokines and cytokines that act either directly or indirectly through stimulation of the vascular endothelium to recruit leukocytes to the tumour. After activation, these tumour-associated leukocytes release angiogenic factors, mitogens, proteolytic enzymes, and chemotactic factors, recruiting more inflammatory cells and stimulating angiogenesis to sustain tumour growth and facilitate tumour metastasis. Breaking this cycle by inhibiting targets such as cytokines, chemokines and other inflammatory mediators, either alone, or more realistically, in combination with other therapies, such as anti-angiogenic or cytotoxic agents, may provide highly efficacious therapeutic regimens for the treatment of malignancies. This article reviews anti-cytokine and anti-chemokine therapies being pursued in cancer, and discusses in more detail anti-tumour necrosis factor-alpha (TNF) approaches.
Eur J Cancer. 2006 Apr;42(6):793-802. Epub 2006 Mar 9
PMID: 16524718 [PubMed - indexed for MEDLINE]

Editorial: cytokine inhibition for treatment of Alzheimer's disease

This editorial, by a well-respected expert on the mechanisms of molecular inflammation in Alzheimer's disease, was commissioned to discuss our pilot study, which was the first article in the medical literature to report the use of perispinal administration of a biologic TNF antagonist for Alzheimer's:
Edward Tobinick MD, Hyman Gross MD, Alan Weinberger MD, and Hart Cohen, MD,
TNF-alpha Modulation for Treatment of Alzheimer's Disease: A 6-Month Pilot Study. [Journal Article]
MedGenMed 2006; 8(2):25.

Title Editorial: Cytokine inhibition for treatment of Alzheimer's disease.
Author(s) Rosenberg PB 
Institution Assistant Professor of Psychiatry and Behavioral Sciences, Division of Geriatric Psychiatry and Neuropsychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Source MedGenMed 2006; 8(2) :24.
Language eng
Pub Type(s) Journal Article
PubMed ID 16926763

The role of neuroinflammation in neuropathic pain: mechanisms and therapeutic targets

This article, an excellent review, whose lead author is Robert Myers, MD, editor of the Journal of the Peripheral Nervous System and a leading researcher into the role of TNF-alpha and neuroinflammation, cited our article:
Edward Tobinick MD and Susan Davoodifar MD,
Efficacy of etanercept delivered by perispinal administration for chronic back and/or neck disc-related pain: a study of clinical observations in 143 patients. [Case Reports, Journal Article]
Curr Med Res Opin 2004 Jul; 20(7) :1075-85.

Title The role of neuroinflammation in neuropathic pain: mechanisms and therapeutic targets.
Author(s) Myers RR, Campana WM, Shubayev VI 
Institution Department of Anesthesiology (0629), University of California-San Diego, La Jolla, CA 92093-0629, USA. rmyers@ucsd.edu
Source Drug Discov Today 2006 Jan; 11(1-2) :8-20.
MeSH Animals
Cytokines
Humans
Neuralgia
Neurogenic Inflammation
Peripheral Nerves
Abstract Neuroinflammation is a proinflammatory cytokine-mediated process that can be provoked by systemic tissue injury but it is most often associated with direct injury to the nervous system. It involves neural-immune interactions that activate immune cells, glial cells and neurons and can lead to the debilitating pain state known as neuropathic pain. It occurs most commonly with injury to peripheral nerves and involves axonal injury with Wallerian degeneration mediated by hematogenous macrophages. Therapy is problematic but new trials with anti-cytokine agents, cytokine receptor antibodies, cytokine-signaling inhibitors, and glial and neuron stabilizers provide hope for future success in treating neuropathic pain.
Language eng
Pub Type(s) Journal Article
Review
PubMed ID 16478686

Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2006

This article, representing the official consensus statement of a group of 143 rheumatologists and bioscientists chosen from 21 countries, cited our article:
Edward Tobinick MD and Susan Davoodifar MD
Efficacy of etanercept delivered by perispinal administration for chronic back and/or neck disc-related pain: a study of clinical observations in 143 patients. [Case Reports, Journal Article]
Curr Med Res Opin 2004 Jul; 20(7) :1075-85.

Title Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2006.
Author(s) Furst DE, Breedveld FC, Kalden JR, Smolen JS, Burmester GR, Emery P, Keystone EC, Schiff MH, van Riel PL, Weinblatt ME, Weisman MH 
Institution David Geffen School of Medicine, UCLA - RM 32-59, 1000 Veteran Avenue, Los Angeles, CA 90025, USA. defurst@mednet.ucla.edu.
Source Ann Rheum Dis 2006 Nov.:iii2-iii15.
Language eng
Pub Type(s) Journal Article
PubMed ID 17038465

Pathophysiology of disk-related low back pain and sciatica. II. Evidence supporting treatment with TNF-alpha antagonists

This article, from a group in France which has professed no experience with perispinal administration of TNF-antagonists for disc-related pain, is less notable for its conclusion than for its positive discussion of the scientific evidence supporting a central role of TNF in the pathogenesis of disc-related pain.

Title Pathophysiology of disk-related low back pain and sciatica. II. Evidence supporting treatment with TNF-alpha antagonists.
Author(s) Mulleman D, Mammou S, Griffoul I, Watier H, Goupille P 
Institution François Rabelais de Tours University, EA 3853 Immuno-Pharmaco-genetics of Therapeutic Antibodies (IPGA), France.
Source Joint Bone Spine 2006 May; 73(3) :270-7.
Abstract Strong evidence suggests that TNF-alpha may be among the chemical factors involved in disk-related sciatica. TNF-alpha is involved in the genesis of nerve pain in animal models and may promote pain-signal production from nerve roots previously subjected to mechanical deformation. In animal experiments, TNF-alpha has been identified in nucleus pulposus and Schwann cells. Local production of endogenous TNF-alpha may occur early in the pathogenic process. Exposure to exogenous TNF-alpha induces electrophysiological, histological, and behavioral changes similar to those seen after exposure to nucleus pulposus, and these changes are more severe when mechanical compression is applied concomitantly. TNF-alpha antagonists diminish or abolish abnormalities in animal models. Other cytokines may be involved also, as suggested by the potent inhibitory effects of compounds such as doxycycline. Two open-label studies in humans suggest dramatic efficacy of TNF-alpha antagonists in alleviating disk-related sciatica. In contrast, the results of the only controlled study available to date do not support a therapeutic effect of TNF-alpha antagonists. Thus, whether TNF-alpha antagonist therapy is warranted in patients with disk-related sciatica remains an open question, and further randomized controlled studies are needed.
Language eng
Pub Type(s) Journal Article
PubMed ID 16046171

The Craniospinal Venous System

Imitation (and in this case what appears to be just short of outright plagurism) is said to be the sincerest form of flattery. I was, however, pleased inasmuch as this new article will result in further dissemination of my concepts to the medical community abroad. It should be noted that there is indeed a citation to my original article (which had published six months prior to this European Neurology article) contained within this clearly derivative work, and the citation is as follows:
Edward Tobinick MD,
The Cerebrospinal Venous System: Anatomy, Physiology, and Clinical Implications. [JOURNAL ARTICLE]
MedGenMed 2006 February 22; 8(1):53.

Title The Craniospinal Venous System.
Author(s) Pearce JM 
Institution Emeritus Consultant Neurologist, Department of Neurology, Hull Royal Infirmary, Hull, UK.
Source Eur Neurol 2006 Sep 8; 56(2) :136-138.
Abstract The valveless craniospinal venous system consists of veins and plexuses that communicate freely and whose flow is bidirectional. It comprises (1) the intracranial-cortical veins, dural sinuses, cavernous sinuses and ophthalmic veins, and (2) the vertebral venous plexuses, which freely anastomose with the intracranial venous system. The vertebral venous plexuses anastamose with the sacral, pelvic and prostatic venous plexus. It is clinically important since it provides a route for the spread of tumours, infection or emboli. This route may go unrecognised. Copyright (c) 2006 S. Karger AG, Basel.
Language ENG
Pub Type(s) JOURNAL ARTICLE
PubMed ID 16960456

Long-lasting neuropathic pain induced by brachial plexus injury in mice: Role triggered by the pro-inflammatory cytokine, tumour necrosis factor alpha

Title Long-lasting neuropathic pain induced by brachial plexus injury in mice: Role triggered by the pro-inflammatory cytokine, tumour necrosis factor alpha.
Author(s) Quintão NL, Balz D, Santos AR, Campos MM, Calixto JB 
Institution Department of Pharmacology, Centre of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, 88049-900 Florianópolis, SC, Brazil.
Source Neuropharmacology 2006 Apr; 50(5) :614-20.
MeSH Animals
Brachial Plexus Neuropathies
Comparative Study
Female
Hyperalgesia
Mice
Mice, Inbred C57BL
Mice, Knockout
Neuralgia
Pain Measurement
Pain Threshold
Reaction Time
Research Support, Non-U.S. Gov't
Time Factors
Tumor Necrosis Factor-alpha
Abstract Brachial plexus avulsion (BPA) resulted in a marked and long-lasting mechanical hypernociception (up to 80 days) in comparison to a sham-operated group, as assessed by Von Frey filaments, in both Swiss and C57/BL6 mice. In the tail-flick test, both Swiss and C57/BL6 mice submitted to BPA showed a significant thermal hypernociception, which persisted for 10 days. Both mechanical and thermal hypernociception following BPA were abolished in tumour necrosis factor alpha (TNFalpha) p55 receptor knockout mice. Moreover, the mechanical hypernociception caused by BPA was inhibited by the local application of the anti-TNFalpha (10 and 100 ng/site) antibody at the time of the surgery or by the intravenous administration (100 microg/kg) of this antibody at the time of the surgery or 4 days after the BPA. A similar inhibition of the mechanical hypernociception was observed when treating mice with the TNFalpha synthesis inhibitor thalidomide (50 mg/kg, s.c.), either at the time of the surgery or 4 days after. The results suggest that the persistent thermal, and especially the persistent mechanical, hypernociception observed following BPA in mice is largely dependent on the generation of TNFalpha. Based on these results, it is possible to suggest that therapeutic strategies for blocking TNFalpha could represent a valuable approach for the treatment of persistent neuropathic pain.
Language eng
Pub Type(s) Journal Article
PubMed ID 16386767

A review of antibody therapeutics and antibody-related technologies for oncology

Title A review of antibody therapeutics and antibody-related technologies for oncology.
Author(s) Scallon BJ, Snyder LA, Mark Anderson G, Chen Q, Yan L, Weiner LM, Nakada MT 
Institution Centocor, Malvern, PA 19355 Fox Chase Cancer Center.
Source J Immunother 2006 Jul-Aug; 29(4) :351-64.
Language eng
Pub Type(s) Journal Article
PubMed ID 16799330

Nociceptive characteristics of tumor necrosis factor-alpha in naive and tumor-bearing mice

This excellent article, from the group at the University of Minnesota, includes a detailed analysis of the role of local anti-TNF administration in pain secondary to cancer metastasis to bone, as discussed in my 2003 article (Edward Tobinick MD Targeted etanercept for treatment-refractory pain due to bone metastasis: two case reports. Clinical Therapeutics 2003 Aug; 25(8) :2279-88). My work is both cited and carefully discussed. Highly recommended reading.

Title Nociceptive characteristics of tumor necrosis factor-alpha in naive and tumor-bearing mice.
Author(s) Wacnik PW, Eikmeier LJ, Simone DA, Wilcox GL, Beitz AJ 
Institution Department of Pharmacology, University of Minnesota, School of Medicine, Minneapolis, MN 55455, USA.
Source Neuroscience 2005; 132(2) :479-91.
MeSH Animals
Behavior, Animal
Cell Line, Tumor
Fibrosarcoma
Gene Expression Regulation, Neoplastic
Immunohistochemistry
Male
Mice
Mice, Inbred C3H
Neoplasm Transplantation
Neoplasms, Experimental
Pain
Pain Measurement
RNA, Messenger
Reverse Transcriptase Polymerase Chain Reaction
Tumor Necrosis Factor-alpha
Abstract A nociceptive role for tumor necrosis factor-alpha (TNF-alpha) in naive mice and in mice with fibrosarcoma tumor-induced primary hyperalgesia was investigated. The presence of TNF-alpha mRNA was confirmed in tumor site homogenates by reverse transcription-polymerase chain reaction (RT-PCR), and examination of TNF-alpha protein levels in tumor-bearing mice indicated a significantly higher concentration of this cytokine in tumor microperfusates and tumor site homogenates compared with that obtained from a similar site on the contralateral limb or in naive mice. Intraplantar injection of TNF-alpha into naive or fibrosarcoma tumor-bearing mice induced mechanical hypersensitivity, as measured by withdrawal responses evoked by von Frey monofilaments. This hypersensitivity suggests that TNF-alpha can excite or sensitize primary afferent fibers to mechanical stimulation in both naive and tumor-bearing mice. In addition, the hyperalgesia produced by TNF-alpha was completely eliminated when the injected TNF-alpha was pre-incubated with the soluble receptor antagonist TNFR:Fc. Importantly, pre-implantation systemic as well as post-implantation intra-tumor injection of TNFR:Fc partially blocked the mechanical hyperalgesia, indicating that local production of TNF-alpha may contribute to tumor-induced nociception.
Language eng
Pub Type(s) Comparative Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, P.H.S.
PubMed ID 15802198

Efficacy of infliximab for disc herniation-induced sciatica: one-year follow-up

Both this article and a previous publication from this excellent Finnish group cited our earlier work, published in 2003, which was the first peer-reviewed article to present the results of biologic anti-TNF treatment for disc-related pain in humans (Edward Tobinick MD, et. al. Perispinal TNF-alpha inhibition for discogenic pain. Swiss Med Wkly 2003 Mar 22; 133(11-12) :170-7). I had the pleasure of speaking at length with Drs. Hurri and Karppinen at the 2003 International Society for the Study of the Lumbar Spine meeting in Vancouver, and found them both to be highly knowledgeable. A subsequent RCT by this Finnish group utilizing systemically delivered (intravenous) infliximab for acute-subacute sciatica failed to show superiority over placebo. This result produced a great deal of discussion in the spinal community. An RCT is only as good as its design; if improperly designed, then an RCT may fail to show a treatment effect even if the therapeutic is, in reality, effective. In the case of this RCT there were multiple potential problems in design. The first confounding factor is that the great majority of patients with acute sciatica experience dramatic pain reduction over time even without treatment. Based on this fact alone it would appear that this might not be the optimal group in which to try and demonstrate a treatment effect. In addition, systemic delivery of anti-TNF biologics may not be the ideal method to reduce localized increased concentrations of TNF at a spinal nerve root. (This, of course, is the rationale behind anatomically localized perispinal administration of etanercept, a concept which I developed and pioneered for the treatment of intractable disc-related pain, as detailed in our 2003 article, which discussed treatment of patients with this method beginning in 2001 or earlier).

Title Efficacy of infliximab for disc herniation-induced sciatica: one-year follow-up.
Author(s) Korhonen T, Karppinen J, Malmivaara A, Autio R, Niinimäki J, Paimela L, Kyllönen E, Lindgren KA, Tervonen O, Seitsalo S, Hurri H 
Institution Department of Physical Medicine and Rehabilitation, Oulu University Hospital, Oulu, Finland.
Source Spine 2004 Oct 1; 29(19) :2115-9.
MeSH Antibodies, Monoclonal
Comparative Study
Drug Administration Schedule
Female
Follow-Up Studies
Humans
Infusions, Intravenous
Intervertebral Disk Displacement
Leg
Male
Pain
Research Support, Non-U.S. Gov't
Sciatica
Time
Treatment Outcome
Tumor Necrosis Factor-alpha
Abstract STUDY DESIGN: An open-label trial.
OBJECTIVES: To test the long-term efficacy of infliximab, a monoclonal antibody against tumor necrosis factor-alpha (TNF-alpha), in disc herniation-induced sciatica.
SUMMARY OF BACKGROUND DATA: Our recent trial indicated that a single infusion of 3 mg/weight-kg of infliximab produced a rapid curative effect in disc herniation-induced sciatica. Here, we describe the 1-year effect of a 3 mg/kg of infliximab in these 10 patients and our experience with a lower dose of 1 mg/kg of infliximab for the same indication in 2 additional patients.
METHODS: Patients with severe sciatica were treated with a single infusion of infliximab, 3 mg/weight-kg in 10 patients and 1 mg/kg in 2 patients, intravenously over 2 hours. The outcomes (leg and back pain on a 100-mm visual scale, Oswestry disability, clinical signs) were assessed at 1 week, 2 weeks, 1 month, 3 months, 6 months, and 1 year after the infusion. The outcomes with 3 mg/kg of infliximab were compared to 62 patients who received periradicular saline for sciatica in a previous trial. The resorption rate of disc herniations from baseline to 1 year was compared between infliximab and control groups.
RESULTS: The response to 1 mg/kg of infliximab for leg pain was good only in 1 of the 2 patients treated, whereas the response to 3 mg/kg of infliximab for leg pain was sustained in most patients over the 1-year follow-up. The 1-year response significantly favored 3 mg/kg of infliximab over periradicular saline in leg pain (P = 0.005) and disability (P = 0.003). Neurologic abnormalities normalized more comprehensively in the infliximab group (P = 0.001). Reduction in disc herniation volume did not differ between the infliximab-treated patients and controls.
CONCLUSIONS: The results showed that the beneficial effect of a single infusion of 3 mg/kg of infliximab for herniation-induced sciatica is sustained in most patients over a 1-year follow-up period. Furthermore, infliximab does not seem to interfere with the spontaneous resorption of disc herniations.
Language eng
Pub Type(s) Clinical Trial
Journal Article
PubMed ID 15454701