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Objectives: This meta-analysis was designed to systematically evaluate whether autologous cytokine-induced killer cells (CIK) or dendritic cells and cytokine-induced killer cells (DC-CIK) immunotherapy combined with chemotherapy can improve the therapeutic effect and safety of chemotherapy in esophageal cancer (EC)., Materials and Methods: Randomized controlled trials (RCTs) were electronically searched databases including CNKI, WanFang, WeiPu, CBMDisc, PubMed, Web of Science, EMbase, the Cochrane Library, and Clinical Trials. The databases were searched for articles published until June 2019. Two researchers independently screened the literature, extracted data, and evaluated the quality of the included literature. Meta-analysis was performed using RevMan5.3., Results: Seventeen studies (1416 participants) were included. The differences between CIK/DC-CIK combination chemotherapy and chemotherapy alone were significant. The results displayed that the number of CD3+, CD4+, CD4+/CD8+, and NK cells was significantly increased after 1 to 2 weeks of treatment with CIK/DC-CIK cells in the treatment group (all P < .05). In addition, the results shown that 1-year overall survival was significantly prolonged (P < .0001) and quality of life was improved (P = .001) in EC chemotherapy combined with immunotherapy groups compared with conventional treatment. Furthermore, cytokine expression levels of interleukin 2 (IL-2), tumor necrosis factor α (TNF-α), and interleukin 12 (IL-12) were significantly increased (P = .0003) as well as the levels of immunoglobulins were elevated (P < .00001). Serum levels of tumor marker molecules, carcinoembryonic antigen (CEA), carbohydrate antigen (CA)-199, and CA-125 were lower in treatment groups than that of control groups (P < .00001). No fatal adverse reactions were noted (P = .04)., Conclusions: It is safe and effective for patients to use chemotherapy combined with CIK/DC-CIK immunotherapy. Immunotherapy can simultaneously improve the antitumor immune response. Specifically, DC-CIK cells can increase T lymphocyte subsets, CIK cells, NK cells, and immunoglobulins in peripheral blood to enhance antitumor immunity. Therefore, combination therapy enhances the immune function and improves the therapeutic efficacy of patients with EC., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

SUM-IAP is an aldo-ifosfamide-perhydrothiazine derivative that, under physiological conditions, spontaneously hydrolyzes to SUM-aldo-ifosfamide. In SUM-IAP, one 2-chloroethyl group of the alkylating function of aldo-ifosfamide-perhydrothiazine is substituted by a mesyl-ethyl group. The compound was synthesized to investigate the influence of the alkylating function of aldo-ifosfamide on the antitumor activity of oxazaphosphorine cytostatics. In chemotherapy experiments in CD2F1 mice with advanced subcutaneously growing P388 mice leukemia cells, the primary tumor was reduced below the detection level with two highly dosed injections on days 7 and 8, but after 14 days, the primary tumor was measurable again. The primary tumor and detectable metastases killed the animals 29-30 days after SUM-IAP application. When, however, the animals were treated again with two highly dosed injections on day 14 and 15, a 4-5 times increase in the number of leukocytes was measured and all animals survived the observation period of 100 days. In the high, cancer-reductive dose range, SUM-IAP is not only a cytotoxic but also an immunostimulating oxazaphosphorine cytostatic.

Purpose of Review: The aim of this review is to draw the attention of the physicians and oncologists on the rare side-effects of checkpoint inhibitors not usually reported in clinical trials to treat them quickly and render their prognosis better., Recent Findings: Rare side-effects of checkpoint inhibitors are mainly neurologic, haematologic, rheumatologic, renal, and cardiac. The majority of reported side-effects are consequent of the treatment by ipilimumab in patients diagnosed with melanomas. Neurologic side-effects have poorer prognosis compared with other rare side-effects. There is no relationship between developing rare side-effects and the outcome of the disease., Summary: It is important to be aware, when treating patients with checkpoint inhibitors, to detect as early as possible the unpredictable and uncontrollable rare side-effects of these agents. The large spectrum of these rare side-effects should be well documented and reported to assure to the physicians a road map for the diagnosis and the management of these toxicities.

Purpose of Review: There is currently an unmet need for agents that can prevent the gastrointestinal toxicity (mucositis and enteritis) associated with chemotherapy and radiation therapy of abdominal and pelvic cancers. Herein we provide an overview of how manipulation of the gut microbiota by probiotic administration affects these gastrointestinal symptoms. We focus this review on published human trials and also provide suggestions on how the field can move forward., Recent Findings: Several clinical trials of varying design, patient populations and probiotic products have been reported. Lactobacillus probiotics of adequate dosage demonstrate a potential to reduce gastrointestinal toxicity when administered prophylactically. Common study limitations prevent the widespread adoption of this practice at this point but are informative for rational design of future trials., Summary: No single probiotic strain or product has emerged from human clinical trials for this indication. Further human studies are required to address limitations in the current literature. Preclinical model data should be used to inform the rational design of these new clinical trials to adequately address this important question.

Purpose of Review: Antibody conjugates are a diverse complex class of therapeutics, consisting of a potent cytotoxic agent linked covalently to an antibody or antibody fragment directed toward a specific cell surface target expressed by tumor cells or an extracellular target, that are having impact in the clinic. The notion that antibodies directed toward targets on the surface of malignant cells could be used for drug delivery is not new. The more than 30-year history of antibody conjugates is marked by hurdles that have been identified and overcome., Recent Findings: Technology is continuing to evolve the protein and small molecule components, and it is likely that soon single-chemical entities will be the norm for antibody drug conjugates. More than 20 antibody conjugates are currently in clinical trials., Summary: The time has arrived for this technology to become a major contributor to improving treatment for cancer patients.

A patient with acute lymphoblastic leukemia who was hypersensitive to native Escherichia coli L-asparaginase (L-asp) underwent readministration of the L-asp without serious adverse effects for 11 doses using a desensitization protocol every time. Monitoring of anti-L-asp antibody and L-asp activity levels revealed that the serum L-asp activity was below the effective levels during the administration of first 6 to 7 doses because of extremely high levels of anti-L-asp IgG. Sustained L-asp activity was attained since the eighth dose was administered, when the antibody levels were <5 U/mL. L-asp activity levels in patients with L-asp hypersensitivity should be monitored during the desensitization courses to ensure a sufficient L-asp activity.

Purpose of Review: A lack of effective treatments for advanced cancer remains a major challenge in oncology. Because cancer is a disease associated with aberrant gene expression patterns, transcription factors, which serve as the convergence points of oncogenic signaling and are functionally altered in many cancers, hold great therapeutic promise., Recent Findings: Many human cancers are dependent on the inappropriate activity of oncogenic transcription factors. By contrast, normal cells can often tolerate disruption of these proteins with little toxicity. Direct inhibition of transcription factor expression (e.g., with RNA interference or microRNAs) and DNA binding (e.g., with oligodeoxynucleotide decoys or pyrrole-imidazole polyamides) has demonstrated antitumor responses with minimal side-effects. New strategies of targeting transcription factors include disrupting critical protein-protein interactions, and restricting binding at the epigenetic level by modulating chromatin accessibility. Moreover, targeting transcription factors in tumor-associated immune cells has the potential to overcome tumor immunoresistance., Summary: Transcription factors are an important target for cancer therapy, both through direct anticancer effects and immunomodulatory actions. Newly developed delivery systems that specifically target tumor cells also create opportunities for successes in targeting transcription in cancer.

Objective: The objective was to test a bispecific ligand-directed toxin (BLT), with reduced immunogenicity for enhanced efficacy in targeting orthotopic pancreatic cancer in vivo., Method: A new BLT was created in which both human epidermal growth factor (EGF) and interleukin 4 cytokines were cloned onto the same single chain molecule with deimmunized pseudomonas exotoxin (dEGF4KDEL). Key amino acids dictating B-cell generation of neutralizing antitoxin antibodies were mutated. Bioassays were used to determine whether mutation reduced potency, and enzyme-linked immunosorbent assay studies were performed to determine whether antitoxin antibodies were reduced. A genetically altered luciferase MIA PaCa-2 xenograft model was used to image in real time and determine effects on systemic malignant human cancer. Bispecific ligand-directed toxins targeting B cells were used as specificity controls., Results: Deimmunized EGF4KDEL was significantly effective after systemic injection against established orthotopic MIA PaCa-2 pancreatic cancer and selectively prevented metastasis. Mutagenesis significantly reduced antitoxin levels in vivo with no apparent activity loss in vitro. The drug was effective against 3 human pancreatic cancer lines in vitro, MIA PaCa-2, SW1990, and S2VP10., Conclusions: Despite the metastatic nature of the MIA PaCa-2 orthotopic tumor xenografted in nude mice, high percentages of tumors responded to extended dEGFKDEL treatment resulting in significant anticancer effects and disease-free survivors.

Purpose of Review: Giant cell tumor (GCT) of bone is a benign, osteolytic neoplasm of bone. The receptor activator of NF-KB ligand (RANKL) pathway has recently been shown to play a key role in the pathogenesis of GCT., Recent Findings: Treatment for refractory, recurrent, or metastatic GCT remains challenging. The recent development of a monoclonal antibody to RANKL, denosumab, offers promise in the management of these patients. A recent phase 2 study suggested denosumab offers disease and symptom control for patients with advanced or refractory disease. In this population, denosumab appears to be well tolerated. There are key questions which remain to be addressed, including patient selection, optimal scheduling, use as an adjuvant, and application to other giant cell-rich disorders., Summary: Denosumab offers a new treatment option for a subset of patients with previously untreatable GCT. The role of denosumab in curative treatment is the subject of ongoing studies.

Drug resistance in cancer arises from a complex range of biochemical and molecular events, which ultimately result in tumor cell survival. Identifying key genes and signal pathways involved in the molecular mechanisms of drug resistance is essential for establishment of new drug targets for preventing further resistance development and spreading. Epidermal growth factor receptor (EGFR) was the first growth factor receptor proposed as a target for cancer therapy. Significant progress in studying EGFR gene expression and mutation has been made in understanding the molecular events involved in EGFR-targeted agents. Recently, some individual chromosomal features such as EGFR copy number variation were demonstrated as new aspects related to drug sensitivity. Identifying these functional regulators of drug resistance will benefit therapeutic decision-making. In this study, we describe an extensive investigation of the published literature on mutation, amplification, and expression of EGFR and its downstream signaling that directly contribute to EGFR inhibitor resistance, including the gene status of KRAS, BRAF, PIK3CA, PTEN, MEK, and AKT on response to therapy. Analysis of these gene signatures identified reveals general modes of action of multicomponent therapies and the mechanisms of specific drug combinations, highlights the potential value of molecular interaction profiles in the discovery of novel therapies, and provides more information for personalized cancer medicine.

For a long time, anticancer therapies were believed to work (and hence convey a therapeutic benefit) either by killing cancer cells or by inducing a permanent arrest in their cell cycle (senescence). In both scenarios, the efficacy of anticancer regimens was thought to depend on cancer cell-intrinsic features only. More recently, the importance of the tumor microenvironment (including stromal and immune cells) has been recognized, along with the development of therapies that function by modulating tumor cell-extrinsic pathways. In particular, it has been shown that some chemotherapeutic and radiotherapeutic regimens trigger cancer cell death while stimulating an active immune response against the tumor. Such an immunogenic cell death relies on the coordinated emission of specific signals from dying cancer cells and their perception by the host immune system. The resulting tumor-specific immune response is critical for the eradication of tumor cells that may survive therapy. In this review, we discuss the molecular mechanisms that underlie the vaccine-like effects of some chemotherapeutic and radiotherapeutic regimens, with particular attention to the signaling pathways and genetic elements that constitute the prerequisites for immunogenic anticancer therapy.

Cryotherapy offers a minimally invasive treatment option for the management of both irresectable and localized prostate, liver, pulmonary, and renal tumors. The antineoplastic effects of cryotherapy are mediated by direct tumor lysis and by indirect effects, such as intracellular dehydration, pH changes, and microvascular damage resulting in ischemic necrosis. In this study, we investigated whether percutaneous cryoablation of lung metastasis from renal cell carcinoma (RCC) in combination with aerosolized granulocyte-macrophage colony stimulating factor can induce systemic cellular and humoral immune responses in 6 patients with RCC. Peripheral blood mononuclear cells (PBMCs) were sequentially studied up to 63 days post cryoimmunotherapy (CI). PBMC from pre and post CI were phenotyped for lymphocyte subsets and tested for cytotoxicity and interferon-γ EliSpots directed at RCC cells. Humoral responses were measured by in vitro antibody synthesis assay directed at RCC cells. The immune monitoring data showed that CI induced tumor specific cytotoxic T lymphocyte, specific in vitro antitumor antibody responses, and enhanced Th1 cytokine production in 4 of 6 patients. More importantly, the magnitude of cellular and humoral antitumor response seems to be associated with clinical responses. These pilot data show that CI can induce robust and brisk cellular and humoral immune responses in patients with metastatic RCC, but requires further evaluation in optimized protocols.

We have earlier demonstrated T-cell-independent antitumor effects of a combination of anti-CD40 monoclonal antibody (mAb) and CpG oligodeoxynucleotides (CpG) which involved macrophages. As some immunotherapeutic treatments can be potentiated by chemotherapy, we tested if cyclophosphamide (CY) would enhance the antitumor effect of anti-CD40 mAb+CpG. Treatment of B16 melanoma-bearing mice with CY and anti-CD40 mAb+CpG resulted in a significant reduction in tumor growth in immunocompetent mice compared with either CY alone or anti-CD40 mAb with CpG. This enhanced antitumor effect was maintained in severe combined immunodeficiency mice, as measured by both tumor growth and overall survival. Natural killer cells were not required for this antitumor effect as it was also observed in severe combined immunodeficiency/beige mice. Moreover, although CY treatment of immunocompetent mice suppressed natural killer cell activity, it did not negatively affect the antitumor activity of their macrophages when assayed in vitro. Depletion of macrophages in vivo reduced the antitumor effect of CY and anti-CD40 mAb+CpG. These results suggest that therapeutic strategies to activate macrophages may have potential for clinical application in cancer patients receiving chemotherapy.

Multidrug resistance is a common problem in the treatment of childhood rhabdomyosarcoma (RMS). Therefore, novel treatment regimes such as immunotherapy have to be evaluated. The aim of this study was to detect possible targets on RMS cells and to investigate whether corresponding humanized antibodies could be used to treat RMS. Screening for potential targets common for different subtypes of RMS was carried out with Affymetrix mRNA expression arrays on 12 primary RMS samples. Subsequent pathway analysis revealed the epidermal growth factor receptor (EGFR) as a potential target for antibody therapy. Expression of EGFR and binding of its specific antibody Cetuximab to embryonal RMS cell lines RD and A-204 and alveolar RMS Rh30 were monitored by flow cytometry. Cetuximab activity was quantified by proliferation assay on RMS cells, and by antibody dependent cellular cytotoxicity assay with peripheral blood mononuclear cells (PBMCs). Gene expression analysis revealed a high expression of EGFR in all embryonal RMS compared with alveolar RMS. The EGFR specific antibody, Cetuximab binds to Rh30 and to RD but not to A-204 cells. Proliferation of these cells was influenced neither by Cetuximab nor by the growth factor EGF. However, cell dependent cytotoxicity of PBMCs to RMS cells such as Rh30 and RD was enhanced specifically by Cetuximab. These promising Cetuximab effects justify analysis under in vivo conditions using suitable models.

Nearly all chemotherapy and biotherapy drugs used in cancer treatment today can cause hypersensitivity reactions. Certain groups of drugs frequently associated with these reactions include the asparaginases, taxanes, platinum compounds, epipodophyllotoxins, and the monoclonal antibodies. Recognizing and managing hypersensitivity reactions are critical when caring for patients receiving these drugs because the reactions are potentially life-threatening. A thorough understanding of the drugs is necessary to assist the nurse in prevention, early recognition, and timely management.

Tumor-induced immune suppression is one of the most difficult obstacles to the success of tumor immunotherapy. Here, we show that established tumors suppress CD8 T cell clonal expansion in vivo, which is normally observed in tumor-free mice upon antigen-specific glycoprotein (gp) 96-chaperone vaccination. Suppression of CD8 T-cell expansion by established tumors is independent of tumor-associated expression of the antigen that is recognized by the CD8-T-cell receptor. Vaccination of tumor-bearing mice is associated with increased cellular recruitment to the vaccine site compared with tumor-free mice. However, rejection of established, suppressive tumors required frequent (daily) gp96 vaccination. B cells are known to attenuate T helper cell-1 responses. We found that in B-cell deficient mice, tumor rejection of established tumors can be achieved by a single vaccination. Accordingly, in tumor-free B-cell deficient mice, cognate CD8 cytotoxic T lymphocyte clonal expansion is enhanced in response to gp96-chaperone vaccination. The data have implications for the study of tumor-induced immune suppression and for translation of tumor immunotherapy into the clinical setting. Frequent vaccination with cellular vaccines and concurrent B-cell depletion may greatly enhance the activity of anticancer vaccine therapy in patients.

The induction of effective immune responses to tumor vaccines requires the preferential activation of effector T cells relative to regulatory or suppressive T cells. Glial tumors commonly overexpress the epidermal growth factor receptor (EGFR), which can be targeted by monoclonal antibodies. Here we show that the coating of glial tumor cells with a clinical grade anti-EGFR antibody, cetuximab, leads to enhanced tumor-specific, interferon-gamma producing CD8+ T cells by dendritic cells (DCs). The selective targeting of monoclonal antibody coated glioma cells to activating Fcgamma receptors (FcgammaRs) on DCs, which is achieved with a blocking antibody to the inhibitory form of FcgammaR, leads to the induction of antitumor immunity without the need for an exogenous maturation stimulus. Importantly, this approach reduces the concurrent induction of regulatory T cells, which can also be depleted to further enhance immunity. These data suggest that immunity to EGFR expressing tumors, including glioma, can be enhanced through the concerted function of antitumor monoclonal antibodies, activating FcgammaR, and DCs.

The International Society for Biologic Therapy of Cancer held a mini-symposium on October 26, 2006 in Los Angeles to review current information regarding the biologic effects of both standard and targeted therapies. The purpose of the mini-symposium was to describe the existing knowledge regarding various biologic effects of current therapies, identify the most relevant issues and gaps in the knowledge base and discuss the optimal means of obtaining necessary missing information. Topics discussed included: (1) The impact of antitumor monoclonal antibody therapy on antigen presentation and adaptive immunity; (2) the effects of antiangiogenic/targeted therapy of the immune system; (3) the impact of chemotherapy on angiogenesis and immune function; (4) combination of antiangiogenic and immunotherapy at the clinical level; (5) the effects of tyrosine kinase inhibitors on TH1/TH2 response and T-regulatory cells; (6) the impact of farnesyltransferase inhibitors and other targeted agents on T-cell activation; (7) the impact of epigenetic modulators on biologic properties, and (8) the impact of the nature of cell death on the immune system. The ultimate goals of this mini-symposium were to use the above information to inform and influence basic science efforts and discussions, rationally design combination treatment regimens and optimally employ correlative studies in the context of ongoing and future clinical investigations.

The objective of this study was to investigate the ability of the anti-CD20 antibody, Rituximab (RTX), to inhibit the activity of P-glycoprotein (P-gp), and reverse multidrug resistance (MDR) in 2 P-gp/CD20 lymphoma cell lines. We determined whether RTX would chemosensitize the 2 P-gp cell lines in vitro, and inhibit the ability of the cells to efflux Rhodamine 123. One cell line was infected with an MDR1 vector and the other was generated by drug selection. We also determined whether RTX induced P-gp to translocate out of lipid rafts. RTX chemosensitized 2 different MDR cell lines, inhibited the activity of P-gp in both, and induced P-gp to translocate out of lipid rafts in the 1 cell line that was studied in greater detail. In contrast, 3 other anti-CD20 antibodies did not chemosensitize, inhibit the activity of P-gp, or induce it to translocate out of rafts, despite the fact that 1 antibody recognized the same epitope on CD20. Our results suggest that RTX can chemosensitize 2 CD20/P-gp cell lines in vitro by inhibiting the activity of the P-gp pump. The inhibition of P-gp activity correlated with the ability of RTX to induce P-gp to translocate out of lipid rafts. Although the mechanisms by which RTX effects P-gp translocation and activity are not yet known, they are not associated with acid-sphingomyelinase activation in raft microdomains, as described for the antiproliferative activity of RTX.

NBI-3001 is a novel immunotoxin of attenuated Pseudomonas exotoxin fused to circularly permutated IL-4, which has shown some antitumor effects in glioblastoma multiforme with intratumoral administration. The authors evaluated the safety and tolerability of NBI-3001 administered intravenously in a dose-escalation design to patients with renal cell and non-small cell lung carcinoma whose tumors showed at least 10% IL-4 receptor expression. Cohorts of three to six patients were treated at dose levels of 0.008, 0.016, and 0.027 mg/m2 daily x 5 days every 28 days. Neutralizing antibody (NAB) titers, plasma levels of NBI-3001, and patient tolerability were monitored sequentially. 14 patients received a total of 36 cycles of NBI-3001 (range 1-6). No dose-limiting toxicities were noted at dose levels 0.008 and 0.016 mg/m2. At 0.027 mg/m2, two patients developed self-limiting, grade 3 or 4 transaminase elevation during cycle 1. NAB titers of more than 1:100 were detected in five of the seven patients treated with at least two cycles; the median titer after cycle 1 and the median maximum titer in subsequent cycles were 1:50 and approximately 1:1,710, respectively. No objective tumor responses were noted. Eight of 12 evaluable patients with renal cell carcinoma had stable disease; four patients had disease progression. High NAB titers resulted in four patients being withdrawn from the study. The dose-limiting toxicity for intravenous NBI-3001 was transaminase elevation at 0.027 mg/m2. NBI-3001 at 0.016 mg/m2 was well tolerated. Low circulating levels of NBI-3001, coupled with rising NAB titers, may have contributed to the lack of response in tumors that express IL-4R.

Despite new treatment options, including autologous and allogeneic stem cell transplants, multiple myeloma remains an incurable disease. The authors developed and characterized a murine anti-human ICAM-1 (CD54) monoclonal antibody, UV3, which is highly effective in SCID mice with advanced human myeloma xenografts (SCID/ARH-77). To improve the effector functions and pharmacokinetic parameters and to reduce its immunogenicity in humans, the authors engineered this monoclonal antibody into a mouse/human IgG1kappa chimeric (c) antibody, cUV3. Following coexpression and purification of the genetically spliced heavy and light chain constructs, the authors compared cUV3 and UV3 in various in vitro assays, including relative cell-binding affinities and effector functions, namely antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. The authors compared their in vivo retention times and biodistribution patterns in normal mice. In each assay, the authors found that cUV3 was essentially equivalent to UV3. Finally, these antibodies were tested in a SCID/ARH-77 model of advanced myeloma, with daily treatments of 4 mug/g for 4 consecutive days commencing 14 days after tumor cell inoculation. cUV3 was at least as effective as UV3; 40% and 20% of the mice, respectively, were cured, with no sign of disease at day 150. The authors intend to evaluate the efficacy of cUV3 further in SCID/ARH-77 mice using other doses and dosing schedules to try to improve the cure rate. Eventually, they hope to test the efficacy of cUV3 in patients with multiple myeloma.

We investigated the anti-asparaginase antibody (Ab) and asparaginase enzymatic activity in the sera of 1,001 patients (CCG-1961) with high-risk acute lymphoblastic leukemia (HR-ALL). Patients received nine doses of native Escherichia coli asparaginase during induction. Half of rapid early responders (RER) were randomly assigned to standard intensity arms and continued to receive native asparaginase. The other RER patients and all slow early responders received 6 or 10 doses of PEG-asparaginase. Serum samples (n = 3,193) were assayed for determination of asparaginase Ab titers and enzymatic activity. Three hundred ninety of 1,001 patients (39%) had no elevation of Ab among multiple evaluations-that is, were Ab-negative (<1.1 over negative control)-and 611 patients (61%) had an elevated Ab titer (>1.1). Among these 611 patients, 447 had no measurable asparaginase activity during therapy. Patients who were Ab-positive but had no clinical allergies continued to receive E. coli asparaginase, the activity of which declined precipitately. No detectable asparaginase activity was found in 81 of 88 Ab-positive patients shortly after asparaginase injections (94% neutralizing Ab). The Ab-positive patients with clinical allergies subsequently were given Erwinase and achieved substantial activity (0.1-0.4 IU/ml). An interim analysis of 280 patients who were followed for 30 months from induction demonstrated that the Ab-positive titers during interim maintenance-1 and in delayed intensification-1 were associated with an increased rate of events. The CCG-1961 treatment schedule was very immunogenic, plausibly due to initially administrated native asparaginase. Anti-asparaginase Ab was associated with undetectable asparaginase activity and may be correlated with adverse outcomes in HR ALL.

Monoclonal antibodies, specific for antigens expressed on lymphoid malignancies, which have been conjugated to toxins such as ricin, hold promise in the therapy of childhood leukemia and lymphoma. Anti-B4-blocked ricin (anti-B4-bR) is such an agent, and a phase I study of this agent was conducted in children with relapsed or refractory B-lineage leukemia and lymphoma. Anti-B4-bR was given as two 7-day continuous infusions separated by 7 days. Twenty patients were enrolled and 19 received the drug. Two dosage levels (30 and 40 microg/kg per day) were evaluated. Forty micrograms per kilogram per day was the maximally tolerated dose. Dose-limiting toxicity was capillary leak syndrome. Grade 3 reversible elevation in transaminases was also encountered. Human antimouse antibodies or human antiricin antibodies were detected in five patients. No complete remissions or partial remissions were seen.

Background: Carboplatin (CBDCA) has been used increasingly to treat pediatric low-grade gliomas. Allergic reactions to CBDCA have been reported in 2% to 30% of children. The reason for this high incidence of allergy is unclear., Methods: To determine the risk factors for CBDCA allergy, an historic cohort study was conducted for all children who received the drug during a 6-year period at the Lucile Salter Packard Children's Hospital at Stanford. The patients' medical records were reviewed for data on age, tumor type, CBDCA dose schedule, total number of doses, cumulative dosage, dose per treatment, other chemotherapy administered, and allergic reaction., Results: Fifty-four children (mean age 7.2 years, 35 boys) were identified. Six children (11.1%) had an allergic reaction to CBDCA. All reactors had low-grade gliomas treated with weekly CBDCA and vincristine, with a dosage per treatment <500 mg/m2. Overall, six (75%) of eight children administered weekly CBDCA, 6 (46.2%) of 13 children with brain tumors, and 6 (40%) of 15 administered CBDCA dosage <500 mg/m2 manifested allergic reactions. Patients receiving more than five doses had significant risk for CBDCA allergy (relative risk [RR] = 11.8; 95% confidence interval [CI]: 1.5-94.1). Using logistic regression with multiple variables, weekly dose schedule was the most predictive covariate for allergic reaction (P < 0.000 1), and other factors were unrelated or redundant., Conclusions: Children with low-grade gliomas receiving CBDCA weekly are at significantly increased risk for CBDCA allergy. The repetitive, weekly dosing schedule of CBDCA appears to be a key risk factor for allergic reaction in brain tumor patients. The high frequency of allergy with weekly CBDCA warrants further consideration when planning future trials.

WHI-P131 is a novel dimethoxyquinazoline compound that is a potent inhibitor of Janus kinase-3-(JAK3)-dependent mast cell responses. In the present study, the authors investigated the anti-anaphylactic activity and pharmacokinetics of WHI-P131 in mice. After intraperitoneal (i.p.) administration of two consecutive bolus doses of 25 mg/kg injected 30 min apart at dose level of 25 mg/kg, WHI-P131 was rapidly absorbed with an observed C(max) of 82.6 microM, which is higher than the target concentration of 30 microM, at which WHI-P131 abrogates mast cell responses in vitro and the time to reach the maximum plasma concentration (t(max)) was 10.0+/-2.9 min. At a nontoxic 50 mg/kg dose level, WHI-P131 prevented compound 48/80-induced mast cell histamine release and fatal anaphylaxis in mice. Further development of WHI-P131 may provide the basis for new and effective treatment as well as prevention programs for mast cell mediated allergic reactions in clinical settings.

Interleukin-18 (IL-18) exhibits antitumor activity in various laboratory models. In the current study, brain tumors in naive mice regressed after an intratumoral injection of a single dose of recombinant IL-18 (rIL-18). Intraperitoneal rIL-18 substantially delayed the growth of subcutaneously inoculated gliomas but not gliomas located in the brain. Efficacy was reduced when studies were performed in mice depleted of natural killer cells. Although intracerebral administration of rIL-18 increased the serum interferon-gamma concentration, the antitumor effect of IL-18 was not mediated by interferon-gamma. These data suggest the therapeutic potential for control of tumor growth by intratumoral administration of rIL-18 in patients with glioma.

Background: Posttransplant lymphoproliferative (PT-LPD) disorder is a life-threatening complication with an incidence of 1-10%. Uniform treatment, so far, does not exist., Methods: In December 1996, 5 months after a liver transplant, a 43-year-old patient developed a PT-LPD with para-aortal lymphomas and splenomegaly. Histological investigations revealed a PT-LPD of a diffuse large B-cell type of the centroblastic variant. The patient received three cycles of a modified cyclophosphamide, doxorubicin, vincristine, and prednisone-regimen, resulting in complete remission but the patient withdrew from further treatment. In February 1998, the patient had a recurrence of PT-LPD with gastric involvement and parasplenic lymphomas. The patient rejected cytotoxic treatment because of her fear of drug-induced progressive myopathy, so we conducted treatment with the monoclonal antibody--directed against CD20-rituximab., Results and Conclusions: After 2 doses of rituximab, clinical symptoms had disappeared and after 6 doses, gastroscopy revealed no residual disease. At this time, the patient remains in remission, with a follow up of > or =6 months. Anti-CD20 monoclonal antibody rituximab is a new, well-tolerated drug for the treatment of lymphomas. In addition, this drug may offer an additional treatment option for patients with PT-LPDs.

To develop a T-cell-based therapy for carcinomas, the superantigen staphylococcal enterotoxin A (SEA) was supplied with tumor specificity by means of a recombinant fusion of the Fab fragment of the monoclonal antibody C242 recognizing human colorectal (CRC) and pancreatic carcinomas (PC). Using this Fab-SEA fusion protein (PNU-214565), potent cytotoxicity by activation of T cells can be obtained in the targeted area. Twenty-one patients with CRC and 3 with PC were treated with single, escalating doses of PNU-214565 to establish the maximum tolerated dose (MTD) and to define toxicities. The doses ranged from 0.01 ng/kg to 4.0 ng/kg with three patients at each dose level, except for the dose of 1.5 ng/kg with which six patients were treated because of dose-limiting toxicity. Adverse events (AE) were transient: 13 patients experienced mild to moderate fever. In one patient, a grade 3 fever was followed by a grade 2 hypotension. Other mild or moderate AEs were fatigue, nausea, vomiting, diarrhea, and abdominal pain. No significant hematological toxicity occurred. Immune activation was highly variable with strong activity in peripheral blood seen only in two patients at the dosage level 1.5 ng/kg. They showed pronounced elevations of interleukin-2 (IL-2), IL-6, tumor necrosis factor-alpha, and interferon-gamma, 3-5 hours after the start of infusion. In one patient, IL-2 and IL-6 increased substantially (2,925 U/mL and 32,000 U/mL) concomitantly with grade 3 fever and transient grade 2 neutropenia, grade 2 lymphopenia, and grade 2 monocytopenia. In conclusion, a single 3-hour infusion of PNU-214565 could be safely administered up to 4 ng/kg. MTD was not determined. Instead, a repeat-dose trial was initiated starting at 0.5 ng/kg, considered safe in this trial, with the objective of defining the MTD.

[3H]Navelbine (NVB) was administered orally to two patients. Drug levels in biological fluids were monitored by radioimmunoassay (RIA) and direct radioactivity (RA) determinations. NVB absorption was rapid: maximum plasma concentrations appeared in the first 2 h after oral administrations. Pharmacokinetic parameters estimated from RIA data were in complete accordance with those obtained from i.v. injections. Bioavailability (i.v./po) estimated from RIA and RA data averaged 40.6 and 93.0%, respectively. NVB urine excretion was low. Fecal excretion remained its main elimination route. Moreover, large differences were observed in area under NVB plasma concentration-time curve (AUC) values obtained by the two methods, implying intense drug bio-transformations.