S. D. Gillies

Anti-GD2 Antibody with GM-CSF, Interleukin-2, and Isotretinoin for Neuroblastoma

BACKGROUND Preclinical and preliminary clinical data indicate that ch14.18, a monoclonal antibody against the tumor-associated disialoganglioside GD2, has activity against neuroblastoma and that such activity is enhanced when ch14.18 is combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-2. We conducted a study to determine whether adding ch14.18, GM-CSF, and interleukin-2 to standard isotretinoin therapy after intensive multimodal therapy would improve outcomes in high-risk neuroblastoma. METHODS Patients with high-risk neuroblastoma who had a response to induction therapy and stem-cell transplantation were randomly assigned, in a 1:1 ratio, to receive standard therapy (six cycles of isotretinoin) or immunotherapy (six cycles of isotretinoin and five concomitant cycles of ch14.18 in combination with alternating GM-CSF and interleukin-2). Event-free survival and overall survival were compared between the immunotherapy group and the standard-therapy group, on an intention-to-treat basis. RESULTS A total of 226 eligible patients were randomly assigned to a treatment group. In the immunotherapy group, a total of 52% of patients had pain of grade 3, 4, or 5, and 23% and 25% of patients had capillary leak syndrome and hypersensitivity reactions, respectively. With 61% of the number of expected events observed, the study met the criteria for early stopping owing to efficacy. The median duration of follow-up was 2.1 years. Immunotherapy was superior to standard therapy with regard to rates of event-free survival (66±5% vs. 46±5% at 2 years, P=0.01) and overall survival (86±4% vs. 75±5% at 2 years, P=0.02 without adjustment for interim analyses). CONCLUSIONS Immunotherapy with ch14.18, GM-CSF, and interleukin-2 was associated with a significantly improved outcome as compared with standard therapy in patients with high-risk neuroblastoma. (Funded by the National Institutes of Health and the Food and Drug Administration; ClinicalTrials.gov number, NCT00026312.)

Phase I trial of a human-mouse chimeric anti-disialoganglioside monoclonal antibody ch14.18 in patients with refractory neuroblastoma and osteosarcoma.

PURPOSE 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. PATIENTS AND METHODS 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. RESULTS 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. CONCLUSION 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.

A phase I study of human/mouse chimeric antiganglioside GD2 antibody ch14.18 in patients with neuroblastoma

9 patients with stage IV neuroblastoma were treated with 19 courses of human/mouse chimeric monoclonal antiganglioside GD2 antibody ch14.18 at dose levels of 30, 40 and 50 mg/m2/day for 5 days per course. The maximum tolerated dose (MTD) per injection was 50 mg/m2/day. 7 patients received more than one course of treatment, and none revealed any human anti-mouse antibody (HAMA) response. Clinical side-effects of patients treated with ch14.18 were abdominal and joint pains, pruritus and urticaria. One patient presented with a transient pupillatonia, while 2 others showed a unilateral atrophy of the optical nerve that was probably attributable to prior therapies. A complete remission was seen in 2 patients, partial remission in 2 patients, a minor response in 1 patient and stable disease in 1 patient. 3 patients showed tumour progression. Thus, our results indicate that treatment with chimeric MAb ch14.18 can elicit some complete and partial tumour responses in neuroblastoma patients.

Recombinant Antibody Fusion Proteins for Cancer Immunotherapy

The last decade has seen the extensive development of monoclonal antibodies (mAb) combined with rapid advances in recombinant DNA technologies. These developments have greatly accelerated and expanded research efforts to generate new approaches for cancer therapy. The focus of many such efforts has been on immunotherapy, because of the unique specificity, diversity, and biological activity of antibodies that make them potentially ideal reagents in the laboratory and the clinic. Initial emphasis was primarily placed on mAb directed against tumor-associated antigen, including growth factor receptors, expressed to a greater extent on the cell surface of tumor cells than on normal cells and tissues. Two basic strategies were applied to substantially reduce tumor cell dissemination and growth in preclinical models as well as in clinical applications. The first of these made use of antitumor antibodies simply as vehicles to deliver to tumor cells either radionuclides, chemotherapeutic drugs, or toxins conjugated to these mAb by various means. Although several of these approaches resulted in some modest successes in the clinic, these were mainly confined to mAb conjugates with either radionuclides or toxins when applied to certain sensitive tumors, such as non-Hodgkins lymphoma. The second strategy applied to suppress tumor dissemination and growth made use of the natural effector mechanisms of antibodies to destroy tumor cells. These include triggering the complement cascade at the tumor cell surface, with consequent lysis or binding to Fc receptors on the surface of specialized effector cells, such as phagocytes or natural killer (NK) cells, thereby triggering phagocytosis or antibody-dependent cell-mediated cytolysis (ADCC).

Immunocytokines for Cancer Immunotherapy

Immunologic approaches to cancer therapy rely on two distinct capabilities of the immune system: targeting the tumor microenvironment by recognizing molecules expressed to a greater extent on tumor cells than normal cells and generating immune responses that can kill tumor cells (1,2). Immunocytokines, which are fusion proteins composed of a recombinant monoclonal antibody and a cytokine, capitalize on both of these capabilities by combining the ability of tumor-specific antibodies selectively to target tumors with the broad-based immunomodulatory activities of cytokines (3). This chapter describes the rationale for development of immunocytokines for cancer and discusses preclinical and clinical data on specific immunocytokines being investigated as potential cancer therapies.

Amplification of T Cell-Mediated Immune Responses by Antibody-Cytokine Fusion Proteins

The induction and amplification of an effective T cell-mediated immune response in malignancies characterized by poor immunogenicity is the most challenging task of tumor vaccine development. In fact, only marginal immunological responses have been reported thus far in the clinic by such tumor vaccine strategies as cytokine-transduced tumor cells, commonly referred to as gene therapy (I), tumor-peptide-pulsed dendritic cells (2) and DNA vaccines (3,4). Apparently, any measurable induction of T cell immune responses in cancer patients after such vaccination strategies does not necessarily translate into suppression of primary tumor growth and metastases, to say nothing of their eradication. The missing link between a T cell immune response induced in cancer patients by such immunotherapeutics and clinical efficacy are potent adjuvants that can switch ineffective T cell priming into an effective T cell-mediated immune response. Recombinant human IL2 is a good candidate in this regard, since this T cell growth factor is necessary for priming and expansion of this effector cell population. This was demonstrated when melanoma patients received a gp 100 melanoma-associated antigen peptide vaccine, designed to increase binding to HLA-A2 molecules. In this case, objective cancer regressions occurred in 42% of the patients, but only when high dose human IL2 was administered as a bolus (5). This was in contrast to patients who received only the vaccine plus adjuvant (5) or boosts with either GM-CSF or IL12, all of which proved ineffective (6) . These findings clearly demonstrate an important role for IL2 as a potent vaccine adjuvant. However, the systemic administration of IL2 as a bolus in clinically effective doses is frequently associated with life-threatening side effects that limit its use in cancer immunotherapy.