Bispecific Antibodies for Arming Activated T Cells and Other Effector Cells for Tumor Therapy

Lum, Lawrence G.; Thakur, Archana

doi:10.1007/978-3-642-20910-9_14

Cited by 2 publications

(2 citation statements)

References 128 publications

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“…These women experience grade 3 chills and hypotension, grade 1–2 fevers, headaches and fatique. 28 The cytokine responses to armed ATC infusions were more like ‘flurries’ as opposed to the ‘storm’ seen with direct infusions of bispecific antibodies 29,30 or infusions of anti-CD3/anti-CD28 costimulated T cells transduced with scFv anti-CD19 chimeric Ab receptor. 26,27 In a separate study using 4 weekly infusions of CD20Bi-armed ATC given without IL-2 supplementation starting 4 days after SCT, infusions induced a Th1 pattern and levels of IL-2R, IL-12, CXCL10 and CXCL9 increased during the first 3 months after SCT.…”

Section: Discussionmentioning

confidence: 99%

Multiple infusions of CD20-targeted T cells and low-dose IL-2 after SCT for high-risk non-Hodgkin's lymphoma: A pilot study

Lum

Thakur

Pray

et al. 2013

Bone Marrow Transplant

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A pilot phase I clinical trial involving 15 infusions of anti-CD3 × anti-CD20 bispecific Ab (CD20Bi)-armed anti-CD3-activated T cells (aATC) and low-dose IL-2 was conducted in three non-Hodgkin’s lymphoma (NHL) patients (two high-risk and one refractory) after autologous SCT. The feasibility of T-cell expansion, safety of aATC infusions, cytotoxic immune responses and trafficking of aATC were evaluated. Three NHL patients received 15 infusions of 5 × 109 aATC (three infusions/week for 3 weeks and one infusion/week for 6 weeks) between days 1 and 65 after SCT with IL-2. There were no dose-limiting toxicities. Chills, fever, hypotension and malaise were the common side effects. Engraftment was delayed in one patient with a low stem cell dose. CD20Bi aATC infusions induced specific cytotoxicity directed at lymphoma targets. Endogenous peripheral blood mononuclear cells from two patients mediated anti-lymphoma cytotoxicity above preSCT background (P <0.001). 111In labeled aATC trafficked to the lungs at 1 h and accumulated in the liver and bone marrow after 24 h. aATC infusions given over 69 days in combination with IL-2 were safe, did not inhibit engraftment, and induced endogenous cytotoxic responses directed at lymphoma targets.

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Section: Discussionmentioning

confidence: 99%

Multiple infusions of CD20-targeted T cells and low-dose IL-2 after SCT for high-risk non-Hodgkin's lymphoma: A pilot study

Lum

Thakur

Pray

et al. 2013

Bone Marrow Transplant

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“…There are ongoing phase I/II clinical trials that are promising using a number of different BiAb that target solid tumor and hematologic malignancies (reviewed in [21]). Studies from our group have used BiAb armed ATCs to increase cytotoxicity directed at both solid tumors and hematologic malignancies [16,17,21,27]. However, none of our studies have targeted neuroblastoma cells.…”

Section: Discussionmentioning

confidence: 99%

Anti‐CD3 × anti‐GD2 bispecific antibody redirects T‐cell cytolytic activity to neuroblastoma targets

Yankelevich

Kondadasula

Thakur

et al. 2012

Pediatric Blood & Cancer

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Background The ganglioside GD2 is an attractive target for immunotherapy of neuroectodermal tumors. We tested a unique bispecific antibody anti-CD3 × anti-GD2 (3F8BiAb) for its ability to redirect activated T cells (ATC) to target GD2-positive neuroblastomas. Procedure ATC were generated from normal human peripheral blood mononuclear cells (PBMC) by stimulating the PBMC with OKT3 and expanding the T cells in the presence of interleukin 2 (IL-2) for 14 days. ATC were armed with 3F8BiAb (100 ng/106 cells) or Her2BiAb (50 ng/106 cells) prior to use. 3F8 BiAb were tested for its dual-binding specificity to GD2 expressed on cancer cell lines and CD3 expressed on ATC. 3F8BiAb-armed ATC were further tested ex vivo for their cytotoxicity against GD2 positive tumor targets and its ability to induce cytokine response upon binding to targets. Results GD2 expression in neuroblastoma cells was confirmed by FACS analysis. Specific binding of 3F8BiAb to the tumor targets as well as to ATC was confirmed by FACS analysis. 3F8BiAb-armed ATC exhibited specific killing of GD2 positive neuroblastoma cell lines significantly above unarmed ATC (P < 0.001). GD2BiAb-armed ATC secreted significantly higher levels of Th1 cytokines and chemokines compared to unarmed ATC (P < 0.001). Conclusions These preclinical findings support the potential of a novel immunotherapeutic approach to target T cells to neuroblastoma.

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Bispecific Antibodies for Arming Activated T Cells and Other Effector Cells for Tumor Therapy

Cited by 2 publications

References 128 publications

Multiple infusions of CD20-targeted T cells and low-dose IL-2 after SCT for high-risk non-Hodgkin's lymphoma: A pilot study

Multiple infusions of CD20-targeted T cells and low-dose IL-2 after SCT for high-risk non-Hodgkin's lymphoma: A pilot study

Anti‐CD3 × anti‐GD2 bispecific antibody redirects T‐cell cytolytic activity to neuroblastoma targets

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