Revisiting CD28 Superagonist TGN1412 as Potential Therapeutic for Pediatric B Cell Leukemia: A Review.

Katelyn Brown

doi:10.3390/diseases6020041

Abstract

Pediatric acute lymphoblastic leukemia (ALL) represents the most common pediatric cancer diagnosis, with numbers rising gradually every year. This paper proposes a novel therapeutic agent for pediatric ALL on the basis of a failed clinical drug trial in 2006. TGN1412 was a promising therapeutic agent that yielded outstanding results in both in vitro studies and animal trials. It is a CD28 superagonist monoclonal antibody that activates T regulatory (TReg) cells in the absence of costimulation of the T cell receptor (TCR) by an antigen-presenting cell. This drug was intended as a solution to T cell deficient diseases such as B cell leukemia and autoimmune diseases such as rheumatoid arthritis. When phase I clinical trials were conducted, all volunteers that received the drug experienced severe cytokine release syndrome (CRS) and faced multiple-organ failure within hours. TGN1412 was reassessed and re-entered clinical trials as a therapeutic for rheumatoid arthritis. A new assay was developed to better quantify T cell response, and volunteers in this trial experienced no pro-inflammatory cytokine release. This essay analyzes how misinformation contributed to the failure of TGN1412 in clinical trials and how revisiting this therapeutic could yield a novel treatment for pediatric B cell leukemia.

Highlights

Pediatric B cell leukemia is a serious issue, with case numbers rising annually [1]
This essay analyzes how misinformation contributed to the failure of TGN1412 in clinical trials and how revisiting this therapeutic could yield a novel treatment for pediatric B cell leukemia
The causation of the cytokine storm remained largely unknown; there was speculation of contamination or other incidences of foul play, but these were quickly disproven by the Medicines and Healthcare products Regulatory Agency (MHRA); the drug was pure and correctly formulated [10]

Summary

Introduction

Pediatric B cell leukemia is a serious issue, with case numbers rising annually [1]. Approximately. The health of the volunteers continued to decline over the 5 h Because this was a novel therapeutic, the medical team did not administer additional drugs to try to relieve the symptoms. In the first phase of CRS, pro-inflammatory cytokines are released that stimulate activation and differentiation of lymphocytes These cytokines promote vasodilation and increase the expression of adhesion molecules on the surface of endothelial cells. The second phase of CRS begins; both neutrophils and cytotoxic T lymphocytes (CTLs) are recruited, and their actions result in endothelial damage This creates a positive feedback loop; as more inflammation is caused by these cells, more cytokines are released to facilitate the activation of additional leukocytes. It is theorized that TGN1412 initiated this response by preferentially binding and over-activating TReg cells [6]

Discussion

Findings

Regulation of Drug Development and Clinical Trials

Conclusions