It happened late Saturday morning in the northbound lanes of the Northeast Extension (I-476) in Worcester Twp. between the Mid-County and Lansdale exits.
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Police say a vehicle was stopped in the right lane of the multi-lane highway due to a flat tire. Another driver stopped to help and pulled up behind the car with its hazard lights on.
Police say a tanker truck carrying jet fuel was unable to stop in time and slammed into both vehicles, which caused a large fire.
Video of fiery scene after truck crash on Pa. Turnpike
The driver of the tanker truck and the driver and passenger of the second vehicle died from their injuries.
The driver of the first vehicle with a flat tire remains hospitalized.
Footage captured by passing motorist Hector Lucena shows the scene soon after the crash, as emergency services were arriving.
"My God, debris all over the place. What happened here?" Lucena says aloud in the video, before passing the burning tanker.
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An aerial view shows the extent of the blaze as firefighters on ladder trucks worked to put out the blaze.
Drivers were stranded for hours as crews worked to clear the scene.
Further details on the crash have not been released.
Chopper 6 video of tanker truck crash on Pa. Turnpike