Remote-controlled CAR T cells fighting cancer.

Crystal Mackall, MD (Stanford University), was awarded her first research grant from Alliance for Cancer Gene Therapy (ACGT) in 2016. At the time, CAR T-cell therapy was emerging as an effective treatment option for certain types of blood cancer. 

“It was already established that with genetic engineering, T cells could be successfully trained to find and destroy cancers that express the protein biomarker CD19, which is expressed by leukemia and lymphoma, for example,” Dr. Mackall says. 

Dr. Mackall’s focus – like many other scientists in the field of cancer cell and gene therapy – was on developing an effective CAR T-cell therapy for solid tumors such as lung cancer, ovarian cancer, brain cancer and sarcomas.

“To use a patient’s own immune system to fight solid tumors, we need to turn that patient’s CAR T cells into bloodhounds,” says Dr. Mackall, who is the founding director of the Stanford Center for Cancer Cell Therapy and director of the Parker Institute for Cancer Immunotherapy at Stanford University. “We need to train them to sniff out and kill cancer cells.” 

What she has learned along the way is the immune system’s “bloodhounds” may need to be reined in at times to make them more effective against tumors.

How solid tumors evade CAR T cells. 

Dr. Mackall’s first ACGT research grant was to develop a CAR T-cell therapy for osteosarcoma (bone cancer) and neuroblastoma (nerve cell cancer), which both express the protein GD2. In the process of advancing this CAR T-cell therapy into clinical trials, Dr. Mackall discovered that a devastating pediatric brain tumor known as diffuse midline glioma (DMG) also expresses GD2, and she helped run a clinical trial testing the CAR T-cell therapy for children with this brain cancer. 

Finding valuable protein targets such as GD2 is rare for solid tumors. Many good targets are unfortunately expressed by healthy tissue as well. This can lead to the CAR T cells attacking noncancerous cells and causing toxicities for patients. Even if the CAR T cells are trying to attack tumors, scientists still see resistance due to the immunosuppressive environment around the tumor, and T cells often become exhausted after prolonged battles with cancer. 

These competing issues – increased risk for toxicity combined with a need for greater potency – have made progress more challenging in developing an effective CAR T-cell therapy for solid tumors. 

These issues also led Dr. Mackall to her second ACGT-funded research project: the development of remote-controlled CAR T cells. 

Controlling CAR T cells to be more effective against solid tumors. 

ACGT awarded a second research grant to Dr. Mackall in 2023 to support the development of a remote-controlled CAR T-cell therapy. Funding from ACGT is supporting a phase 1 clinical trial testing the therapy – called “SNIP-CAR” – in patients with B7H3-expressing tumors.

The remote-control feature is intended to provide more command of how the engineered cells operate in the patient’s body. First, the cells can be switched “on” and “off” as needed to reduce toxicities for patients. 

“It’s something everyone can understand,” Dr. Mackall said. “If you’re creating a machine – and these engineered CAR T cells are really machines – you need an on/off switch. If you have a machine with only an on switch and no off switch, you’ll get in trouble.” 

Scientists can also regulate the CAR T cells where they only attack cancer cells and ignore healthy tissue expressing the protein target. The B7H3 protein target is expressed by numerous tumors at higher levels than healthy tissue. 

“One person’s T cells are not the same as another person’s T cells,” Dr. Mackall said. “Our immune systems are very different. So, the amount of activity these cells need to have may differ from patient to patient. This creates a personalized therapy tailored to each individual patient.” 

Lastly, the “off” state serves as “rest” time for the CAR T cells. This can give the cells more energy to attack the tumor when turned back on. 

“At first, we thought, ‘Hit the cancer hard with CAR T cells, and if it doesn’t work, hit it again,’” Dr. Mackall says. “What we found is that sometimes less is more.” 

The “less-is-more” approach might be the next evolution of CAR T-cell therapy for cancer. If the remote-controlled CAR T cells work as intended, they will limit toxicities while attacking the tumor with the necessary potency to persist in an immunosuppressive environment. 

“You might take a small hit in the short-term by not constantly having the T cells attack cancer,” Dr. Mackall says, “but you are setting yourself up to win the war.” 

This Alliance for Cancer Gene Therapy Research Fellow is funded in part by Swim Across America and Wendy Walk.

Note: Dr. Mackall is a three-time ACGT grant recipient. She is part of a multidisciplinary, cross-institution collaboration that received an ACGT-Barbara Netter Collaboration Challenge Award grant in 2024. Dr. Mackall and scientists at Stanford are working with scientists at St. Jude Children’s Research Hospital and McMaster University Cancer Research Centre (Canada) to develop a synthetic T-cell therapy for children with brain tumors.