The accident occurred shortly after noon near the Van Buren Boulevard exit. The semi-truck was towing a trailer and heading northbound in the No. 2 lane on the freeway.
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For an unknown reason, the car veered left into the center median, collided with a guardrail and overturned. The trailer then went into the southbound lanes of the freeway.
As cars passed the southbound lanes, the trailer went through and struck four cars. One of the drivers in one of the cars suffered minor injuries. It was unclear if anyone else was injured.
Emergency officials said the driver of the semi was successfully extricated from the wreckage. A female passenger was also with him. The driver suffered major injuries and was taken to a nearby hospital. The woman suffered moderate injuries, authorities said.
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The southbound 215 Freeway was closed between Van Buren Boulevard and Harley Knox Boulevard.
Most lanes on the freeway reopened in the evening hours, with only one lane closed.
The cause of the crash was not immediately known.