Next wave of CAR T cells: Michel Sadelain
CAR T pioneer Michel Sadelain (USA) discussed new directions in CAR T cell engineering, focusing on CAR T cell exhaustion and antigen escape. First, Sadelain discussed so-called TRAC-CAR T cells that were developed in his laboratory. In these cells, the CAR cDNA is specifically integrated into the TRAC locus using CRISPR/Cas9 technology. The cells suffer less from exhaustion in vivo because they down-regulate CAR surface expression upon exposure to antigens. A clinical trial using this approach will start at the end of 2019. “This story, I think, certainly highlights the virtue of genome editing to place transgenes of interest at specific locations in the genome,” said Sadelain.
Second, Sadelain showed how comparing CD28 and 4-1BB CARs may inform the design of better CARs. He explained that CD28 CARs direct high effector function but limited T cell persistence, while 4-1BB CARs yield less potent effectors but longer lasting T cells. Titration of CD28 CAR activation strength (ITAM dosage) augments T cell persistence without compromising anti-tumor function or promoting exhaustion. Balancing effector and memory programs through CAR signaling determines T cell fate and therapeutic potency.
He also presented an effort to combine the CD28 and 4-1BB co-stimulation signal into the same cell, extending the persistence of the cells. The novel CAR T cells are now studied in a trial with DLBCL patients and the results are promising, with high complete remission rates and no severe toxicities. “We think that for now, it supports this idea that if you have better T cells, you should be able to treat with fewer T cells and hopefully with less toxicity,” Sadelain commented.
Turning to the topic of antigen escape, Sadelain presented a series of experiments to confirm that trogocytosis plays a role in CD19 loss. Trogocytosis reversibly decreases antigen density and favors tumor escape. He concluded that antigen-low relapses need to be better defined and managed. He showed that CD28 and 4-1BB CARs differ in sensitivity, with CD28 CARs requiring lower antigen than 4-1BB CARs. Sadelain also discussed combinatorial targeting (i.e., bispecific T cells that recognize both CD19 and CD22) to preempt antigen low tumor escape.