Spontaneous expectoration of pulmonary metastases in a child with osteogenic sarcoma

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148355/1/pbc27611.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148355/2/pbc27611_am.pd

A phase I trial of the trifunctional anti Her2 × anti CD3 antibody ertumaxomab in patients with advanced solid tumors

Background: Ertumaxomab (ertu) is a bispecific, trifunctional antibody targeting Her2/neu, CD3 and the Fcγ-receptors I, IIa, and III forming a tri-cell complex between tumor cell, T cell and accessory cells. Methods: Patients (pts) with Her2/neu (1+/SISH positive, 2+ and 3+) expressing tumors progressing after standard therapy were treated to investigate safety, tolerability and preliminary efficacy. In this study, ertu was applied i.v. in 2 cycles following a predefined dose escalating scheme. Each cycle consisted of five ascending doses (10–500 μg) applied weekly within 28 days with a 21 day treatment-free interval. If 2 pts experienced a dose limiting toxicity (DLT) at a given dose level, the maximum tolerated dose (MTD) had been exceeded. Results: Fourteen heavily pretreated pts (e.g. breast, rectal, gastric cancer) were enrolled in the four main cohorts. Three (21 %) pts had to be replaced. Two serious adverse events (SAE) with possible relation to the investigational drug were seen, both fully reversible. A DLT was not detected. Consequently, the MTD could not be determined. All adverse events (AE) were transient and completely reversible. Most frequent AEs were fatigue (14/14), pain (13/14), cephalgia (12/14), chills (11/14), nausea (8/14), fever (7/14), emesis (7/14) and diarrhea (5/14). Single doses up to 300 μg were well tolerated (total dose up to 800 μg per cycle). We observed one partial remission and two disease stabilizations after first treatment cycle. Conclusions: Single doses up to 300 μg could be safely administered in an escalating dose scheme. Immunological responses and clinical activity warrant further evaluation in patients with Her2 over expressing tumors. Trial registration EudraCT number: 2011-003201-14; ClinicalTrials.gov identifier: NCT0156941

Immunotherapy with FBTA05 (Bi20), a trifunctional bispecific anti-CD3 x anti-CD20 antibody and donor lymphocyte infusion (DLI) in relapsed or refractory B-cell lymphoma after allogeneic stem cell transplantation: study protocol of an investigator-driven, open-label, non-randomized, uncontrolled, dose-escalating Phase I/II-trial

BACKGROUND: Patients with B cell malignancies refractory to allogeneic stem cell transplantation (SCT) can be treated by subsequent immunotherapy with donor lymphocyte infusions (DLI). But unlike myeloid leukemia, B cell leukemia and lymphoma are less sensitive to allogeneic adoptive immunotherapy. Moreover, the beneficial graft-versus-lymphoma (GVL) effect may be associated with moderate to severe graft-versus-host disease (GVHD). Thus, novel therapeutic approaches augmenting the anti-tumor efficacy of DLI and dissociating the GVL effect from GVHD are needed. The anti-CD20 x anti-CD3 trifunctional bispecific antibody (trAb) FBTA05 may improve the targeting of tumor cells by redirecting immune allogeneic effector cells while reducing the risk of undesirable reactivity against normal host cells. Hence, FBTA05 may maximize GVL effects by simultaneously decreasing the incidence and severity of GVHD. METHODS/DESIGN: Based on this underlying treatment concept and on promising data taken from preclinical results and a small pilot study, an open-label, non-randomized, uncontrolled, dose-escalating phase I/II-study is conducted to evaluate safety and preliminary efficacy of the investigational antibody FBTA05 in combination with DLI for patients suffering from rituximab- and/or alemtuzumab-refractory, CD20-positive low- or high-grade lymphoma after allogeneic SCT. During the first trial phase with emphasis on dose escalation a maximum of 24 patients distributed into 4 cohorts will be enrolled. For the evaluation of preliminary efficacy data a maximum of 12 patients (6 patients with low-grade lymphoma and/or Chronic Lymphocytic Leukemia (CLL) / 6 patients with high-grade or aggressive lymphoma) will attend the second phase of this clinical trial. DISCUSSION: Promising data (e.g. induction of cellular immunity; GVL predominance over GVHD; achievement of partial or complete responses; prolongation of time-to-progression) obtained from this phase I/II trial would represent the first milestone in the clinical evaluation of a novel immunotherapeutic concept for treatment-resistant low- and high-grade lymphoma and NHL patients in relapse. TRIAL REGISTRATION: NCT0113857

Psychology and aggression

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68264/2/10.1177_002200275900300301.pd

Rupture process of large earthquakes in the northern Mexico subduction zone

The Cocos plate subducts beneath North America at the Mexico trench. The northernmost segment of this trench, between the Orozco and Rivera fracture zones, has ruptured in a sequence of five large earthquakes from 1973 to 1985; the Jan. 30, 1973 Colima event ( M s 7.5) at the northern end of the segment near Rivera fracture zone; the Mar. 14, 1979 Petatlan event ( M s 7.6) at the southern end of the segment on the Orozco fracture zone; the Oct. 25, 1981 Playa Azul event ( M s 7.3) in the middle of the Michoacan “gap”; the Sept. 19, 1985 Michoacan mainshock ( M s 8.1); and the Sept. 21, 1985 Michoacan aftershock ( M s 7.6) that reruptured part of the Petatlan zone. Body wave inversion for the rupture process of these earthquakes finds the best: earthquake depth; focal mechanism; overall source time function; and seismic moment, for each earthquake. In addition, we have determined spatial concentrations of seismic moment release for the Colima earthquake, and the Michoacan mainshock and aftershock. These spatial concentrations of slip are interpreted as asperities; and the resultant asperity distribution for Mexico is compared to other subduction zones. The body wave inversion technique also determines the Moment Tensor Rate Functions ; but there is no evidence for statistically significant changes in the moment tensor during rupture for any of the five earthquakes. An appendix describes the Moment Tensor Rate Functions methodology in detail.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43169/1/24_2004_Article_BF00875970.pd

Trifunctional bispecific antibodies induce tumor-specific T cells and elicit a vaccination effect.

A major goal of tumor immunotherapy is the induction of long-lasting systemic T-cell immunity. Bispecific antibodies (bsAbs) that lack the immunoglobulin Fc region confer T-cell-mediated killing of tumor cells but do not induce long-term memory. In contrast, trifunctional bsAbs comprise an appropriate Fc region and, therefore, not only recruit T cells but also accessory cells that bear activating Fc gamma receptors (Fc gamma R), providing additional T-cell-activating signals and securing presentation of tumor-derived antigens to T cells. In this study, we show that trifunctional bsAbs induce a polyvalent T-cell response and, therefore, a vaccination effect. Mice were treated with melanoma cells and with a trifunctional bsAb directed against the melanoma target antigen ganglioside GD2 in addition to murine CD3. The trifunctional bsAb activated dendritic cells and induced a systemic immune response that was not replicated by treatment with the F(ab')(2)-counterpart lacking the Fc region. Restimulation of spleen and lymph node cells in vitro yielded T-cell lines that specifically produced interferon-gamma in response to tumor. In addition, trifunctional bsAb-induced T cells recognized various specific peptides derived from melanoma-associated antigens. Moreover, these polyvalent responses proved to be tumor-suppressive and could not be induced by the corresponding bsF(ab')(2)-fragment. Taken together, our findings provide preclinical proof of concept that trifunctional bsAbs can induce tumor-specific T cells with defined antigen specificity

Potential of the trifunctional bispecific antibody Surek depends on dendritic cells: Rationale for a new approach of tumor immunotherapy.

Trifunctional bispecific antibodies (trAbs) used in tumor immunotherapy have the unique ability to recruit T cells toward antigens on the tumor cell surface and, moreover, to activate accessory cells through their immunoglobulin Fc region interacting with activating Fcγ receptors. This scenario gives rise to additional costimulatory signals required for T cell–mediated tumor cell destruction and induction of an immunologic memory. Here we show in an in vitro system that most effective trAb-dependent T-cell activation and tumor cell elimination are achieved in the presence of dendritic cells (DCs). On the basis of these findings, we devise a novel approach of cancer immunotherapy that combines the specific advantages of trAbs with those of DC-based vaccination. Simultaneous delivery of trAbs and in vitro differentiated DCs resulted in a markedly improved tumor rejection in a murine melanoma model compared with monotherapy