Lethal toxin–equipped effector cells for the potential treatment of cancer
Abstract
Lethal toxins could become potent therapies against cancer, but their clinical utility is limited by adverse events upon systemic administration. These could be reduced if the toxins were delivered by effector cells that specifically infiltrate cancers, thereby releasing toxins locally into the tumor microenvironment. One of the challenges underlying this strategy is that cells delivering toxins would have to be resistant to them. We address this obstacle by showing that effectors derived from transformed human cell lines genetically engineered for resistance to bacterial adenosine diphosphate ribosylating toxins (ADPRTs), including Pseudomonas aeruginosa exotoxin A (PE), can produce targeted immunotoxins that specifically kill cancer cells expressing cognate tumor-associated antigens. Resistance to immunotoxins was achieved by knockout of genes in the diphthamide biosynthesis pathway ( DPH1-4 ) required for the posttranslational modification of eukaryotic elongation factor 2 (EEF2) that is the target of ADPRTs or by mutation of EEF2 itself. We show that engineering resistance to ADPRTs, one of the most potent toxins acting on human cells, is essential to achieve robust function of armored effector cell lines. This work establishes a critical step on the path to equip effector cells with the ability to deliver powerful toxins to cancer cells and introduces a platform to investigate extension to primary autologous or allogeneic therapeutic cell types.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (16)
Alexander H. Pearlman
Ludwig Center for Cancer Genetics and Therapeutics and Lustgarten Laboratory, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine
Brian J. Mog
Ludwig Center for Cancer Genetics and Therapeutics and Lustgarten Laboratory, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine
Michael S. Hwang
Ludwig Center for Cancer Genetics and Therapeutics and Lustgarten Laboratory, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine
Jordina Rincon-Torroella
Ludwig Center for Cancer Genetics and Therapeutics and Lustgarten Laboratory, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine
Sarah R. DiNapoli
Ludwig Center for Cancer Genetics and Therapeutics and Lustgarten Laboratory, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine
Suman Paul
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
Jacqueline Douglass
Ludwig Center for Cancer Genetics and Therapeutics and Lustgarten Laboratory, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine
Emily Han-Chung Hsiue
Ludwig Center for Cancer Genetics and Therapeutics and Lustgarten Laboratory, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine
Stephanie A. Glavaris
Ludwig Center for Cancer Genetics and Therapeutics and Lustgarten Laboratory, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine
Drew M. Pardoll
Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
Nickolas Papadopoulos
Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
Kenneth W. Kinzler
Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
Chetan Bettegowda
Shibin Zhou
Ludwig Center for Cancer Genetics and Therapeutics and Lustgarten Laboratory, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine
Bert Vogelstein
Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
Maximilian F. Konig
The Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine