Scientists at St. John’s Children’s Research HospitalJude report identifying a way to target CAR-T cells for osteosarcoma. They examine “Redirection of B7-H3. CAR T cells to chemokines expressed in osteosarcoma basal and antitumor activity in preclinical models. ” appears in Clinical Cancer Research, a journal of the American Association for Cancer Research.
Treatment for osteosarcoma includes surgery and chemotherapy, approaches that have been the mainstay of care for more than 50 years. This underscores the need for new and more modern curative approaches, such as immunotherapy. However, sham tumors provide more demanding situations than any CAR-T. The mobile generation will have to succeed to succeed.
“Solid tumors are just that, falsified. These are hard, dense masses that immune cells have difficulty penetrating,” Dr. Kelly said. Lindsay Talbot, MD, of the Department of Surgery at St. Louis. Jude. ” For immunotherapy to work in artificial tumors, we need to attract T cells to the tumor, help them enter, and keep them there to generate a sustained response. »
Talbot and his colleagues on the first step: SEO.
In humans, there are about 50 chemokines and 20 chemokine receptors. To target CAR T cells toward osteosarcoma, the researchers first had to determine which chemokines are expressed in this specific type of cancer.
“We used patient samples collected after surgery to ask us what chemokines to target in osteosarcoma, independent of those produced through the tumor. It’s the closest you can get to what happens in a patient,” Talbot said. , surgeon of St. . John’s. Jude. ” When you mix this with gene expression data, you get strong effects on chemokines that are vital for a specific type of cancer. “
Ashley Chabot (left), laboratory operations manager, Department of Surgery, and Lindsay Talbot, MD, associate member of the Department of Surgery, have shown that increased chemokine localization improves CAR T-cell treatment for osteosarcoma. Jude Children’s Research Hospital] Use In this way, the researchers identified two chemokines, CXCL8 and CXCL16, secreted by osteosarcoma. However, CAR T cells have specific receptors for these chemokines.
After identifying this discrepancy between chemokine and chemokine receptor, the researchers changed the CAR T cells that target the osteosarcoma antigen B7-H3 to specify the receptors (CXCR2 or CXCR6) for known chemokines. They evaluated the return kinetics (movement) and potency of the modified cells. , testing its ability to infiltrate osteosarcoma.
The researchers found that the changed cells behaved differently. Those expressing CXCR2 temporarily moved to the tumor, but their activity stalled at first. Those expressing CXCR6 took a little longer to return home, but they also reached a plateau. In particular, the researchers observed extended survival in a metastatic disease style changed CXCR2 or CXCR6 B7-H3-CAR T cells compared to unchanged B7-H3-CAR T cells.
“When expressed in B7-H3. CAR T cells, CXCR2 and CXCR6 modifications confer improved OS [osteosarcoma] targeting in vitro and in vivo. Mice treated with CXCR2 and CXCR6-B7-H3. CAR experienced longer metastatic survival than mice treated with B7-H3. CAR T cells,” the researchers write.
“Our patient-based project has known goals for the modification of mobile CAR T chemokine receptors targeting the operating system. The expression of CXCR2 and CXCR6 improved the localization and anti-OS activity of B7-H3 mobiles. CAR T. These effects help the clinical evaluation of CXCR-modified CAR T mobiles for adoptive mobile treatment for patients with OS.
“We haven’t replaced anything about how T cells kill tumor cells; what we replace is how they manage to penetrate the tumor, and that has implications in terms of specificity and toxicity,” Talbot continued. “But the paintings are not finished and I am excited about the opportunity to continue advancing toward robust tumor immunotherapy through this platform. “
“Immunotherapy has great potential as a cancer treatment, but much remains to be done to achieve this potential in pediatric artificial tumors,” added Christopher DeRenzo, MD, Department of Medicine. St. Jude Bone Marrow Transplant and Mobile Therapy. “Improving CAR T mobiles for patients with larger osteosarcoma is an exciting development, so we are working to link laboratory findings like this with what we can do for patients through clinical trials. “
“By devising a strategy to increase the movement of CAR T cells to osteosarcoma sites, Dr. Talbot and his team were able to show that these cells enhanced their antitumor activity in preclinical models,” said Stephen Gottschalk, M. D. , of the study. Article and Director of the Department of Bone Marrow Transplantation and Cell Therapy. “Based on those results, we are committed to translating those ‘enhanced osteosarcoma detector’ CAR T cells into early-phase clinical trials. “