Shakeel Modak

Orally administered β-glucans enhance anti-tumor effects of monoclonal antibodies

Abstract. β-Glucan primes leukocyte CR3 for enhanced cytotoxicity and synergizes with anti-tumor monoclonal antibodies (mAb). We studied readily available (1→3)-β-D-glucan using the immune deficient xenograft tumor models, and examined the relationship of its anti-tumor effect and physico-chemical properties. Established subcutaneous (s.c.) human xenografts were treated for 29 days orally with daily β-glucan by intragastric injection and mAb intravenously (i.v.) twice weekly. Control mice received either mAb alone or β-glucan alone. Tumor sizes were monitored over time. β-Glucans were studied by carbohydrate linkage analysis, and high performance size-exclusion chromatography with multiple angle laser scattering detection. Orally administered β-D-glucan greatly enhanced the anti-tumor effects of mAb against established tumors in mice. We observed this β-glucan effect irrespective of antigen (GD2, GD3, CD20, epidermal growth factor-receptor, HER-2), human tumor type (neuroblastoma, melanoma, lymphoma, epidermoid carcinoma and breast carcinoma) or tumor sites (s.c. versus systemic). This effect correlated with the molecular size of the (1→3),(1→4)-β-D-glucan. Orally administered (1→3),(1→6)-β-D-glucans also synergized with mAb, although the effect was generally less marked. Given the favorable efficacy and toxicity profile of oral β-D-glucan treatment, the role of natural products that contain β-glucan in cancer treatment as an enhancer of the effect of mAb therapy deserves further study.

Neuroblastoma: Therapeutic strategies for a clinical enigma

Neuroblastoma, the most common extracranial pediatric solid tumor remains a clinical enigma with outcomes ranging from cure in >90% of patients with locoregional tumors with little to no cytotoxic therapy, to <30% for those >18months of age at diagnosis with metastatic disease despite aggressive multimodality therapy. Age, stage and amplification of the MYCN oncogene are the most validated prognostic markers. Recent research has shed light on the biology of neuroblastoma allowing more accurate stratification of patients which has permitted reducing or withholding cytotoxic therapy without affecting outcome for low-risk patients. However, for children with high-risk disease, the development of newer therapeutic strategies is necessary. Current surgery and radiotherapy techniques in conjunction with induction chemotherapy have greatly reduced the risk of local relapse. However, refractory or recurrent osteomedullary disease occurs in most patients with high-risk neuroblastoma. Toxicity limits for high-dose chemotherapy appear to have been reached without further clinical benefit. Neuroblastoma is the first pediatric cancer for which monoclonal-antibody-based immunotherapy has been shown to be effective, particularly for metastatic osteomedullary disease. Radioimmunotherapy appears to be a critical component of a recent, successful regimen for treating patients who relapse in the central nervous system, a possible sanctuary site. Efforts are under way to refine and enhance antibody-based immunotherapy and to determine its optimal use. The identification of newer tumor targets and the harnessing of cell-mediated immunotherapy may generate novel therapeutic approaches. It is likely that a combination of therapeutic modalities will be required to improve survival and cure rates.

Murine Anti-GD2 Monoclonal Antibody 3F8 Combined With Granulocyte-Macrophage Colony-Stimulating Factor and 13-Cis-Retinoic Acid in High-Risk Patients With Stage 4 Neuroblastoma in First Remission

PURPOSE Anti-GD2 monoclonal antibody (MoAb) combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) has shown efficacy against neuroblastoma (NB). Prognostic variables that could influence clinical outcome were explored. PATIENTS AND METHODS One hundred sixty-nine children diagnosed with stage 4 NB (1988 to 2008) were enrolled onto consecutive anti-GD2 murine MoAb 3F8 ± GM-CSF ± 13-cis-retinoic acid (CRA) protocols after achieving first remission (complete remission/very good partial remission). Patients enrolled in regimen A (n = 43 high-risk [HR] patients) received 3F8 alone; regimen B (n = 41 HR patients), 3F8 + intravenous GM-CSF + CRA, after stem-cell transplantation (SCT); and regimen C (n = 85), 3F8 + subcutaneous GM-CSF + CRA, 46 of 85 after SCT, whereas 28 of 85 required additional induction therapy and were deemed ultra high risk (UHR). Marrow minimal residual disease (MRD) was measured by quantitative reverse transcription polymerase chain reaction. Survival probability was calculated by the Kaplan-Meier method, and prognostic variables were analyzed by multivariate Cox regression model. RESULTS At 5 years from the start of immunotherapy, progression-free survival (PFS) improved from 44% for HR patients receiving regimen A to 56% and 62% for those receiving regimens B and C, respectively. Overall survival (OS) was 49%, 61%, and 81%, respectively. PFS and OS of UHR patients were 36% and 75%, respectively. Relapse was mostly at isolated sites. Independent adverse prognostic factors included UHR (PFS) and post-cycle two MRD (PFS and OS), whereas the prognostic factors for improved outcome were missing killer immunoglobulin-like receptor ligand (PFS and OS), human antimouse antibody response (OS), and regimen C (OS). CONCLUSION Retrospective analysis of consecutive trials from a single center demonstrated that MoAb 3F8 + GM-CSF + CRA is effective against chemotherapy-resistant marrow MRD. Its positive impact on long-term survival can only be confirmed definitively by randomized studies.

Long-term complications in survivors of advanced stage neuroblastoma†

Few studies have assessed late effects in neuroblastoma (NB) survivors, particularly those with advanced stage disease.

Ototoxicity from high‐dose use of platinum compounds in patients with neuroblastoma

The young age of neuroblastoma patients makes them especially prone to the ototoxic effects of widely used treatments that feature aggressive use of platinum compounds. We present data defining the extent of the problem in a large series of neuroblastoma patients whose induction included high‐dose cisplatin/etoposide (HD‐P/E) as used in both the Memorial Sloan‐Kettering Cancer Center N7 regimen and the Childrens Oncology Group A3973 study.

Irinotecan Plus Temozolomide for Relapsed or Refractory Neuroblastoma

PURPOSE To report on an irinotecan and temozolomide regimen for neuroblastoma (NB). Quality of life and minimizing toxicity were major considerations. PATIENTS AND METHODS The plan stipulated 5-day courses of irinotecan 50 mg/m2 (1-hour infusion) and temozolomide 150 mg/m2 (oral) every 3 to 4 weeks, with a pretreatment platelet count more than 30,000/microL. Granulocyte colony-stimulating factor was used when the absolute neutrophil count was less than 1,000/microL. RESULTS Forty-nine NB patients received 1 to 15 courses (median, 5). Gastrointestinal and myelosuppressive toxicities were readily managed. Lymphocyte responses to phytohemagglutinin after 2 to 10 courses (median, 3.5) were normal in 10 of 10 patients treated after nonimmunosuppressive therapy, and normalized in five of seven patients first treated less than 2 months after high-dose alkylators. Of 19 patients treated for refractory NB and assessable for response, nine showed evidence of disease regression, including two complete responses and seven objective responses. Of 17 patients treated for progressive disease, three showed evidence of disease regression, including one partial response and two objective responses. Multiple courses entailed no cumulative toxicity and controlled disease for prolonged periods in many patients, including some who were unable to complete prior treatments because of hematologic, infectious, cardiac, or renal problems. CONCLUSION This regimen has anti-NB activity, spares vital organs, is feasible with poor bone marrow reserve, causes limited immunosuppression, and allows good quality of life.

Thiotepa-Based High-Dose Chemotherapy With Autologous Stem-Cell Rescue in Patients With Recurrent or Progressive CNS Germ Cell Tumors

PURPOSE To evaluate the efficacy and toxicity of high-dose chemotherapy (HDC) followed by autologous stem-cell rescue (ASCR) in patients with relapsed or progressive CNS germ cell tumors (GCTs). PATIENTS AND METHODS Twenty-one patients with CNS GCTs who experienced relapse or progression despite having received initial chemotherapy and/or radiotherapy were treated with thiotepa-based HDC regimens followed by ASCR. RESULTS Estimated overall survival (OS) and event-free survival (EFS) rates for the entire group 4 years after HDC were 57% +/- 12% and 52% +/- 14%, respectively. Seven of nine (78%) patients with germinoma survived disease-free after HDC with a median survival of 48 months. One patient died as a result of progressive disease (PD) 39 months after HDC, and another died as a result of pulmonary fibrosis unrelated to HDC 78 months after ASCR without assessable disease. However, only four of 12 patients (33%) with nongerminomatous germ cell tumors (NGGCTs) survived without evidence of disease, with a median survival of 35 months. Eight patients with NGGCTs died as a result of PD, with a median survival of 4 months after HDC (range, 2 to 17 months). Patients with germinoma fared better than those with NGGCTs (P =.016 and.014 for OS and EFS, respectively). Patients with complete response to HDC also had significantly better outcome (P <.001 for OS and EFS) compared with patients with only a partial response or stable disease. There were no toxic deaths because of HDC. CONCLUSION Dose escalation of chemotherapy followed by ASCR is effective therapy for patients with recurrent CNS germinomas and might be effective in patients with recurrent NGGCTs with a low tumor burden.

Reduction From Seven to Five Cycles of Intensive Induction Chemotherapy in Children With High-Risk Neuroblastoma

PURPOSE We previously reported a high response rate with a dose-intensive chemotherapy regimen in 24 children with high-risk neuroblastoma (NB). We now describe similar results with changes that reduce toxicity (fewer cycles, less vincristine, use of granulocyte colony-stimulating factor). PATIENTS AND METHODS Eighty-seven consecutive newly diagnosed children with high-risk NB underwent induction that initially had seven cycles (57 patients) but was later limited to five (30 patients). Cycles 1, 2, 4, and 6 used cyclophosphamide (140 mg/kg)/doxorubicin (75 mg/m(2))/vincristine (0.15 mg/kg in the first 27 patients, 0.067 mg/kg subsequently). Cycles 3, 5, and 7 used cisplatin (200 mg/m(2))/etoposide (600 mg/m(2)). Tumor resection followed a minimum of three cycles. The induction was eventually modified to include anti-G(D2) immunotherapy after each of the last three cycles (38 patients). RESULTS Bone marrow disease resolved in 70 (91%) of 77 patients and was not detected pre- and postinduction in 10 patients. After cycle 3 or 4, 86% of primary tumors were more than 50% smaller. Postinduction metaiodobenzylguanidine scans showed normal radiotracer distribution in metastatic sites in 74 (87%) of 85 patients. Overall results were: 68 (79%) complete/very good partial responses (CR/VGPR); 14 (16%) partial responses (PR); three (3%) less than PR; one (1%) death from infection; and one patient not assessable for response. Five cycles yielded a CR/VGPR rate of 83%, compared with a 77% rate from seven cycles. Side effects were myelosuppression, mucositis, and hearing deficits; neurotoxicity was insignificant with the lower vincristine dosage. Four patients (each received seven cycles) developed myelodysplasia/leukemia. CONCLUSION Five cycles of this induction regimen, plus surgery, suffice to achieve CR/VGPR in approximately 80% of children with high-risk NB.

Sensitivity of Surveillance Studies for Detecting Asymptomatic and Unsuspected Relapse of High-Risk Neuroblastoma

PURPOSE Relapse-free survival (RFS) is a powerful measure of treatment efficacy. We describe the sensitivity of standard surveillance studies for detecting relapse of neuroblastoma (NB). PATIENTS AND METHODS The patients were in complete/very good partial remission of high-risk NB; routine monitoring revealed asymptomatic and, therefore, unsuspected relapses in 113 patients, whereas 41 patients had symptoms prompting urgent evaluations. Assessments every 2 to 4 months included computed tomography, iodine-131-metaiodobenzylguanidine (131)I-MIBG; through November 1999) or iodine-123-metaiodobenzylguanidine ((123)I-MIBG) scan, urine catecholamines, and bone marrow (BM) histology. Bone scan was routine through 2002. RESULTS (123)I-MIBG scan was the most reliable study for revealing unsuspected relapse; it had an 82% detection rate, which was superior to the rates with (131)I-MIBG scan (64%; P = .1), bone scan (36%; P < .001), and BM histology (34%; P < .001). Among asymptomatic patients, (123)I-MIBG scan was the sole positive study indicating relapse in 25 (27%) of 91 patients compared with one (4.5%) of 22 patients for (131)I-MIBG scan (P = .04) and 0% to 6% of patients for each of the other studies (P < .001). Patients whose monitoring included (123)I-MIBG scan were significantly less likely than patients monitored by (131)I-MIBG scan to have an extensive osteomedullary relapse and had a significantly longer survival from relapse (P < .001) and from diagnosis (P = .002). They also had significantly longer survival than patients with symptomatic relapses (P = .002). CONCLUSION (123)I-MIBG scan is essential for valid estimation of the duration of RFS of patients with high-risk NB. Without monitoring that includes (123)I-MIBG scan, caution should be used when comparing RFS between institutions and protocols.

Camptothecin Analogs (Irinotecan or Topotecan) plus High-Dose Cyclophosphamide as Preparative Regimens for Antibody-Based Immunotherapy in Resistant Neuroblastoma

Purpose: We used high-dose cyclophosphamide plus topotecan/vincristine (CTV) or irinotecan (C/I) in patients with resistant neuroblastoma. The aim was to use a regimen with little risk to major organs to (a) achieve or consolidate remission in heavily treated patients and to (b) induce an immunological state conducive to passive immunotherapy with the murine 3F8 antibody. Experimental Design: CTV and C/I included cyclophosphamide 140 mg/kg (∼4200 mg/m2). With CTV, topotecan 2 mg/m2 was infused i.v. (30 min) on days 1–4 (total, 8 mg/m2), and vincristine 0.067 mg/kg was injected on day 1. With C/I, irinotecan, 50 mg/m2 was infused i.v. (1 h) on days 1–5 (total, 250 mg/m2). Mesna and granulocyte colony-stimulating factor were used. Results: Twenty-nine patients received 38 courses of CTV, and 26 patients received 38 courses of C/I. All patients had previously received topotecan, a hemopoietic stem-cell transplant, and/or high-dose cyclophosphamide. CTV and C/I caused myelosuppression of comparably prolonged duration as follows: absolute neutrophil counts <500/μl lasted 5–12 days in patients who had not previously received transplant and 7–21 days in patients who were post-transplant. Other significant toxicities included typhlitis (two CTV-treated patients, one C/I-treated patient) and hemorrhagic cystitis (one C/I-treated patient). Major responses were seen in 4 (15%) of 26 CTV and 4 (17%) of 24 C/I-treated patients with assessable disease. Bone marrow disease resolved in 5 (28%) of 18 CTV-treated patients and in 4 (27%) of 15 C/I-treated patients. 3F8 after CTV or C/I was not blocked by neutralizing antibodies, consistent with the desired immunosuppressive effect of high-dose cyclophosphamide. Conclusions: CTV and C/I require transfusional and antibiotic support but otherwise entail tolerable morbidity. They have modest antineuroblastoma activity in heavily treated patients and are good preparative regimens for passive immunotherapy with monoclonal antibodies.