Crystal Mackall, MD
Translating SNIP-CAR: A regulatable CAR targeting B7H3
Chimeric antigen receptor (CAR) T cells benefit patients with treatment resistant B-cell leukemia, B-cell lymphoma and multiple myeloma, raising hopes that CAR T cells could be used to treat “solid” cancers, including breast cancer, lung cancer, pancreatic cancer, brain cancer, and sarcomas. Studies show that CAR T cells can work against solid cancers in mouse models, but they also reveal challenges that must be overcome for treating human patients.
One major challenge relates to the fact that the protein targets that CAR T cells recognize in leukemia/lymphoma/myeloma are not expressed on vital normal tissues, whereas CAR T-cell targets for solid cancers are generally expressed on vital tissues as well, albeit at lower levels. Therefore, CAR T cells targeting solid cancers pose greater risk to harming normal tissue.
A related challenge relates to greater suppression and evasion of immune responses by solid cancers, which requires more potent CAR T cells. These competing issues (“increased risk for toxicity combined with a need for greater potency”) have led to limited progress for solid tumors.
The Mackall lab recently developed a new CAR T-cell platform that both increases potency AND increases safety.
SNIP-CARs allow “remote control” of CAR T cells using a drug administered as a pill. SNIP-CARs contain a molecule (called a protease) that continuously “snips” the CAR molecule in half, preventing its function unless a drug is present to inhibit the “snipping protease.” Drugs that inhibit the protease are FDA-approved and well-tolerated. SNIP-CARs are “OFF” at baseline but are able to be activated (they still require the tumor target to be activated) in the presence of the drug.
In mouse models where standard CAR T cells killed the animals due to toxicity, stopping the drug after the animals became ill allowed complete recovery. Surprisingly, in settings where toxicity was not an issue, SNIP-CARs plus daily dosing of the drug resulted in greater tumor control than seen with standard CAR T cells. This is due to the variations in drug levels by drug metabolism, which provided the CAR T cells with periods of activation followed by periods of “rest.” Finally, in situations where tumor and normal vital tissue shared the target and standard CAR T cells killed the animals, a lower dose of the drug allowed the SNIP-CAR T cells to attack the tumor but ignore the normal tissue.
This proposal generates the necessary processes, procedures and materials needed to test SNIP-CARs in patients with solid cancers whose solid cancers are not effectively treated with standard therapies. The proposal will amplify ACGT investment by leveraging substantial infrastructure in place at Stanford University to greatly accelerate clinical testing of a cutting-edge cancer gene therapy platform for patients with critical unmet need.
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Unleashing the hounds.
“Alliance for Cancer Gene Therapy is a very forward-thinking organization. It recognized the potential for new cancer gene therapies very early on and that foresight is paying off. In the next 50 years, I think we’re going to see cell and gene therapy become the part of medicine where the most dramatic advances are made.”