CD20-Targeted T Cells after Stem Cell Transplantation for High Risk and Refractory Non-Hodgkin's Lymphoma

Clinical Cancer Research

Al-Kadhimi

et al. 2015

Self Cite

113

PURPOSE This study reports a phase I immunotherapy (IT) trial in 23 women with metastatic breast cancer consisting of eight infusions of anti-CD3 × anti-HER2 bispecific antibody (HER2Bi) armed anti-CD3 activated T cells (ATC) in combination with low dose interleukin 2 (IL-2) and granulocyte-macrophage-colony stimulating factor to determine safety, maximum tolerated dose (MTD), technical feasibility, T cell trafficking, immune responses, time to progression, and overall survival (OS). EXPERIMENTAL DESIGN ATC were expanded from leukapheresis product using IL-2 and anti-CD3 monoclonal antibody and armed with HER2Bi. In 3+3 dose escalation design, groups of 3 patients received 5, 10, 20, or 40 × 109 armed ATC (aATC) per infusion. RESULTS There were no dose limiting toxicities and the MTD was not defined. It was technically feasible to grow 160 × 109 ATC from a single leukapheresis. aATC persisted in the blood for weeks and trafficked to tumors. Infusions of aATC induced anti-breast cancer responses and increases in immunokines. At 14.5 weeks after enrollment, 13 of 22 (59.1%) evaluable patients had stable disease and 9 of 22 (40.9%) had progressive disease. The median OS was 36.2 months for all patients, 57.4 months for HER2 3+ patients, and 27.4 months for HER2 0–2+ patients. CONCLUSIONS Targeting HER2 positive and negative tumors with aATC infusions induced anti-tumor responses, increases in Th1 cytokines and IL-12 serum levels that suggest that aATC infusions vaccinated patients against their own tumors. These results provide a strong rationale for conducting phase II trials.

Section: Discussionmentioning

confidence: 99%

“…ATC were produced as described (18). After 10–14 days, ATC were harvested and armed with 50 ng of HER2Bi/10 6 ATC, and cryopreserved (18).…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…Serum cytokines were detected by multiplex cytokine array as described previously (18) using the Bio-Plex system (Bio-Rad Lab., Hercules, CA).…”

Section: Methodsmentioning

confidence: 99%

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Targeted T-cell Therapy in Stage IV Breast Cancer: A Phase I Clinical Trial

Clinical Cancer Research

Al-Kadhimi

et al. 2015

Self Cite

113

“…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. 31 It is likely that 15 infusions induced comparable or more persistence levels of these cytokines and chemokines.…”

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

Pray

et al. 2013

Bone Marrow Transplant

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.

Bispecific Antibody Armed T Cells to Target Cancer Cells

Methods in Molecular Biology

Mittal

2017

The common strategy for making bispecific antibodies (BsAbs) involves combining the variable domains of the desired monoclonal antibodies (mAbs) into a single bispecific structure. Bispecific immunotherapeutics has generated many different formats of BsAbs including chemical heteroconjugation of two complete molecules or fragments of monoclonal antibodies, quadroma, F(ab), diabodies, tandem diabodies, and single-chain antibodies (scFv). This chapter describes the process of generating activated T cells and arming T cells with heteroconjugated BsAbs to target cancer cells.