CAR T-cell therapy, which engineers a patient’s own immune cells to recognize and attack cancer, has produced extraordinary results in some blood cancers. However, this approach has been far less successful against solid tumors. One major reason is that solid tumors create a harsh environment that gradually weakens the engineered T cells, causing them to become “exhausted” and lose their ability to multiply, survive, and continue fighting the cancer.
Dr. Rafei’s research focuses on a key molecular control system inside T cells called CREM, which helps determine whether T cells remain active or become exhausted. CREM exists in many different forms, known as isoforms, and these forms can have very different effects on immune function. Current gene-editing approaches typically remove CREM broadly, which risks eliminating forms that may help T cells function properly.
Dr. Rafei aims to develop a much more precise strategy by selectively blocking only the harmful CREM isoforms while preserving beneficial ones. To do this, she will use an advanced gene-targeting technology called Cas13, which can precisely target specific RNA molecules inside cells. Her team will first identify which CREM isoforms drive T-cell exhaustion under conditions that mimic solid tumors. They will then engineer CAR T cells with selective Cas13 programs and test whether these enhanced cells survive longer, remain more active, and control tumors more effectively in advanced preclinical models. If successful, this work could lead to a new generation of CAR T-cell therapies capable of treating solid tumors more effectively and establish a broadly applicable strategy for improving immune cell therapies through highly precise genetic control.
Projects and Grants
Splicing isoform-directed Cas13 reprogramming of CAR-T cells for solid tumor immunotherapy
