Engineering Chimeric Antigen Receptor T Cells to Activate Only When Ultrasound Energy is Applied
Providing a patient's T cells with a receptor to match the surface characteristics of the patient's cancer cells is proving to work quite well for some types of cancer. Unfortunately the match is never perfectly specific for cancerous cells, and chimeric antigen receptor T cells (CAR-T cells) can do a lot of damage to healthy tissue in many of the desired scenarios for treatment. Researchers here report on one of a number of presently explored approaches to limit the activation of CAR-T cells to only the cancerous tissue of interest, thereby making the therapy more viable.
New work addresses a longstanding problem in the field of cancer immunotherapy: how to make chimeric antigen receptor (CAR) T-cell therapy safe and effective at treating solid tumors. CAR T-cell therapy is a promising new approach to treat cancer. It involves collecting a patient's T cells and genetically engineering them to express special receptors, called CAR, on their surface that recognize specific antigens on cancer cells. The resulting CAR T cells are then infused back into the patient to find and attack cells that have the cancer antigens on their surface.
This therapy has worked well for the treatment of some blood cancers and lymphoma, but not against solid tumors. That's because many of the target antigens on these tumors are also expressed on normal tissues and organs. This can cause toxic side effects that can kills cells - these effects are known as on-target, off-tumor toxicity. To combat this issue, the team took standard CAR T cells and re-engineered them so that they only express the CAR protein when ultrasound energy is applied. This allowed the researchers to choose where and when the genes of CAR T cells get switched on. Ultrasound can penetrate tens of centimeters beneath the skin, so this type of therapy has the potential to non-invasively treat tumors that are buried deep inside the body.
The team's approach involves injecting the re-engineered CAR T cells into tumors in mice and then placing a small ultrasound transducer on an area of the skin that's on top of the tumor to activate the CAR T cells. The transducer uses focused ultrasound beams to focus or concentrate short pulses of ultrasound energy at the tumor. This causes the tumor to heat up moderately - in this case, to a temperature of 43 degrees Celsius (109 degrees Fahrenheit) - without affecting the surrounding tissue. The CAR T cells in this study are equipped with a gene that produces the CAR protein only when exposed to heat. As a result, the CAR T cells only switch on where ultrasound is applied.
My gut take on this type of approach is that the tool itself, ultrasound pulses to heat up the tumor, is more useful than the engineered CAR-Ts. 109 degrees is pretty firmly in heat-shock territory which is likely to be toxic to many cells, and especially so in cancer cells. Hyperthermia treatments for breast cancer (and other superficial tumors) has been moderately well studied to increase the sensitivity of the tumor to standard chemotherapeutics, and I imagine this kind of localized heating of a tumor may be a way to reproduce those results in less superficial tumors.
The model in breast cancer has usually been heat stress -> misfolded proteins -> impaired cellular repair mechanisms -> increased toxicity to chemotherapeutics in the locally heated environment.
I will have to do some research to see if this is something being investigated by this group or others.
IIRC, some time ago researchers claimed to have used ultrasound to 'break off' tiny bits (proteins) of solid tumors which then entered the blood stream where they were exposed to immune cells which recognized the tumor proteins as foreign invaders and startet attacking the proteins and the tumor as well. No CAR-T involvement needed.
And then there is High-Intensity Focused Ultrasound Ablation: https://www.ajronline.org/doi/pdf/10.2214/AJR.09.3321