ganglioside--gd2 and Pain

To evaluate the toxicity, immunogenicity, and pharmacokinetics of a human-mouse chimeric monoclonal antibody (mAb) ch 14.18 directed against disialoganglioside (GD2) and to obtain preliminary information on its clinical efficacy, we conducted a phase I trial in 10 patients with refractory neuroblastoma and one patient with osteosarcoma.. Eleven patients were entered onto this phase I trial. They received 20 courses of mAb ch 14.18 at dose levels of 10, 20, 50, 100, and 200 mg/m2. Dose escalation was performed in cohorts of three patients; intrapatient dose escalation was also permitted.. The most prevalent toxicities were pain, tachycardia, hypertension, fever, and urticaria. Most of these toxicities were dose-dependent and rarely noted at dosages of 20 mg/m2 and less. Although the maximum-tolerated dose was not reached in this study, clinical responses were observed. These included one partial (PR) and four mixed responses (MRs) and one stable disease (SD) among 10 assessable patients. Biologic activity of ch 14.18 in vivo was shown by binding of ch 14.18 to tumor cells and complement-dependent cytotoxicity of posttreatment sera against tumor target cells. An anti-ch 14.18 immune response was detectable in seven of 10 patients studied.. In summary, with the dose schedule used, ch 14.18 appears to be clinically safe and effective, and repeated mAb administration was not associated with increased toxicities. Further clinical trials of mAb ch 14.18 in patients with neuroblastoma are warranted.

Topics: Adult; Animals; Antibodies, Monoclonal; Child; Child, Preschool; Complement C3; Complement C4; Complement Hemolytic Activity Assay; Female; Fluorescent Antibody Technique, Indirect; Gangliosides; Humans; Infusions, Intravenous; Male; Mice; Neuroblastoma; Osteosarcoma; Pain; Recombinant Fusion Proteins; Treatment Outcome

In a phase I trial, 12 patients with GD2 antigen-positive metastatic melanoma received the murine anti-GD2 monoclonal antibody 14G2a. The monoclonal antibody was administered in four doses over an 8-day period with total dose ranging from 10 to 120 mg. All patients receiving greater than 10 mg of 14G2a experienced transient abdominal/pelvic pain during the antibody infusion. Five patients had a delayed extremity pain syndrome following the third and fourth antibody infusion. Four of the five patients developed neurological toxicity, including two patients with significant although reversible motor neuropathy. Two of the patients developed hyponatremia secondary to a syndrome of inappropriate antidiuretic hormone. All 12 patients developed high levels of human anti-14G2a antibody. The plasma half-life of 14G2a was 42 +/- 6 (SD) h. One patient each had a partial response, mixed response, and stable disease, respectively. The very modest antitumor activity accompanied by dose-limiting neurological toxicity at total doses greater than 80 mg may restrict the clinical utility of murine 14G2a.

Topics: Antibodies, Monoclonal; Antibody Formation; Drug Evaluation; Female; Gangliosides; Humans; Male; Melanoma; Pain; Pain Measurement; Recurrence; Remission Induction

Treatment of neuroblastoma with targeted immunotherapy using chimeric anti-GD2 monoclonal antibodies (ch14.18) is associated with significant pain requiring management with a high-dose opioid infusion. We present a case series of six children, for whom dexmedetomidine and hydromorphone infusions safely and effectively reduced the pain of ch14.18 therapy in the oncology ward setting.. The ch14.18 infusion is administered for ≥ 10 hr over four consecutive days in each of 5 cycles. Hydromorphone (2-8 mcg.kg(-1) .hr(-1) ) and dexmedetomidine (0.1-0.6 mcg.kg(-1) .hr(-1) ) infusions were commenced 1 hr before starting ch14.18 immunotherapy and titrated to optimal clinical effect. One hour after stopping the ch14.18 infusion, dexmedetomidine was discontinued and hydromorphone weaned as tolerated. This strategy was supervised by the Acute Pain Service with strict monitoring and nursing policies. Patient charts were reviewed for evidence of side effects and quality of analgesia.. Data from six patients, with median (range) age of 3.5 (2-12) years are reported. Median (range) utilization of hydromorphone was 2.9 (2.0-4.7) mcg.kg(-1) .hr(-1) , and of dexmedetomidine was 0.17 (0.10-0.20) mcg.kg(-1) .hr(-1) . A drop in mean arterial pressure ≥ 30% below baseline was identified during 30% of treatment days, but only prompted interrupting or reducing the ch14.18 infusion on 7% of treatment days; only one episode of grade 3 hypotension was recorded during this series. Hypoxemia occurred during 8% and bradycardia during 4% of treatment days.. Dexmedetomidine infusion may be an effective and safe pain management adjunct to opioid therapy for the pain of ch14.18 infusion.

Topics: Analgesics, Non-Narcotic; Analgesics, Opioid; Antibodies, Monoclonal; Child; Child, Preschool; Dexmedetomidine; Drug Therapy, Combination; Female; Follow-Up Studies; Gangliosides; Humans; Hydromorphone; Immunotherapy; Male; Neuroblastoma; Pain; Pain Management; Prognosis

Nonpharmacologic, mind-body interventions are used to reduce anxiety in pediatric patients. Anti-ganglioside GD2 monoclonal antibody (anti-GD2 MoAb 3F8) therapy is the standard of care for high-risk neuroblastoma and pain is its major side effect. We performed a retrospective analysis of children undergoing anti-GD2 MoAb 3F8 treatment who received guided meditation. Meditation involved concentrating on the repetition of rhythmic, melodic sounds purported to slow breathing and induce a relaxation response. A total of 71% patients completed a session at first (n=19) or second attempt (n=5). Patients received fewer analgesic doses to manage anti-GD2 MoAb 3F8-induced pain when participating in meditation (n=17, mean=-0.4 dose, P<0.01). Mantram meditation is a feasible outpatient intervention associated with reduced analgesic requirements.

Topics: Adolescent; Antibodies, Monoclonal; Antineoplastic Agents; Child; Child, Preschool; Female; Gangliosides; Humans; Male; Meditation; Neuroblastoma; Pain; Retrospective Studies

Anti-GD(2) antibodies have been shown to be effective for immunotherapy of neuroblastoma and other GD(2) enriched malignancies. Infusion of anti-GD(2) antibodies frequently causes spontaneous pain and allodynia for the duration of the immunotherapy and occasionally longer lasting neuropathic pain. Bolus intravenous injection of anti-GD(2) in rats initiates mechanical allodynia as measured by withdrawal threshold of the hindpaws. In this study, thermal thresholds were measured prior to and for up to 6 h following systemic anti-GD(2) administration in adult rats. In addition, both thermal and mechanical thresholds were tested following intrathecal administration of anti-GD(2) and IgG(2a). Murine anti-GD(2) elicited mechanical allodynia when administered into either the vasculature or the intrathecal space. Effective systemic doses were 1--3 mg/kg as previously shown. Intrathecally, optimal doses ranged from 0.01 to 0.1 ng; a higher dose was ineffective. Thermal hyperalgesia was not observed via either route of administration. Intrathecal pretreatment 48--72 h prior to the experiment with capsaicin at doses sufficient to cause a 50% depletion of dorsal horn CGRP, caused a total blockade of the mechanical allodynia indicating an involvement of peptidergic fine afferent fibers. It is likely that the antibody reacts with an antigen on peripheral nerve and/or myelin to initiate its effect. The lack of observed thermal hyperalgesia is surprising especially in light of the capsaicin-associated blockade, however, it is consistent with several other immune system related models of pain.

Topics: Animals; Antibodies, Blocking; Antibodies, Monoclonal; Behavior, Animal; Capsaicin; Gangliosides; Hyperalgesia; Infusions, Intravenous; Injections, Spinal; Male; Neurons, Afferent; Nociceptors; Pain; Pain Measurement; Pain Threshold; Physical Stimulation; Rats; Rats, Sprague-Dawley

Systemically administered, the anti-GD2 antibody produces allodynia demonstrated by decreased mechanical withdrawal threshold. Electrophysiologic recordings indicate a probable neuropathic origin, as small-diameter sensory fibers develop continuous high-frequency discharge after antibody administration. Gabapentin (GBP) is a gamma-aminobutyric acid analog originally synthesized for its anticonvulsant actions. Several open-label clinical studies, as well as a wealth of anecdotal evidence, suggest that GBP may be beneficial for the treatment of neuropathic pain. This study examined the effects of GBP given as a posttreatment after induction of an anti-GD2-associated allodynia. Anti-GD2 (1 mg/kg intravenously [i.v.]) administered to Sprague-Dawley rats reduced the mean withdrawal threshold from 14.71 to 4.95 g (P < 0.001), as measured by using von Frey hairs. This was reversed by GBP in a dose-dependent fashion; the minimal effective dose was between 3 and 30 mg/kg i.v. The maximal percent analgesic effect of GBP was 76% and 93% at doses of 30 and 100 mg/kg, respectively (P < 0.001). With these doses, side effects were minimal and were manifested as slightly decreased spontaneous movement and startle response. No changes were seen in reflex responses to corneal or pinna stimulation, and no motor deficits were observed. These data support the use of GBP as an effective therapy for neuropathic pain.. After the administration of anti-GD2 antibody, rats display an escape reaction to light touch, increased blood pressure, and aberrant firing in nerve fibers associated with pain transmission. Systemic gabapentin reduced or eliminated the escape response and reversed the hypertension with minimal side effects. This suggests that gabapentin blocked the antibody-associated (neuropathic) pain.

Topics: Acetates; Amines; Analgesics; Animals; Antibodies, Monoclonal; Blood Pressure; Cyclohexanecarboxylic Acids; Dose-Response Relationship, Drug; Gabapentin; gamma-Aminobutyric Acid; Gangliosides; Male; Pain; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Serine

For the management of pediatric neuroblastoma, a promising experimental treatment includes slow systemic infusion of a human/ mouse chimeric monoclonal antibody against the GD2 ganglioside. Beneficial actions are however, accompanied by severe pain and altered cardiovascular tone. The pain is conventionally controllable with moderate to relatively high doses of intravenous morphine. An animal model was established to examine the change in nociceptive threshold produced by anti-GD2-antibody. Rats given bolus injections of antibody through an in-dwelling jugular catheter developed a quantifiable mechanical allodynia. At higher doses, allodynia and touch evoked agitation began within the first 15-min test interval, was maximal within the first hour, and for some doses was still present, although greatly reduced at 24 and 48 h. Rapid administration of antibody led to an increase in mean resting blood pressure of 12 mmHg +/- 1.8 (P < or = 0.02) and the development of a prolonged cardiovascular response to an otherwise innocuous stimulus. These observations demonstrate that the pain associated with monoclonal antibody treatment can be modeled in animals. This approach has potential for defining the pharmacology of the allodynia and ways in which the pain state may be ameliorated.

Topics: Animals; Antibodies, Monoclonal; Behavior, Animal; Gangliosides; Hemodynamics; Humans; Hyperalgesia; Immunotherapy; Injections, Intravenous; Male; Mice; Pain; Pain Threshold; Physical Stimulation; Rats; Rats, Sprague-Dawley

Topics: Antibodies, Monoclonal; Child; Child, Preschool; Female; Gangliosides; Humans; Infusions, Intravenous; Lidocaine; Male; Neuroblastoma; Pain