Improved chemokine homing enhances CAR T-cell therapy for osteosarcoma

Chimeric antigen receptor (CAR) T–cell immunotherapy re-engineers a patient’s immune cells to target cancer cells. While successful in some types of leukemia, the approach has yet to realize its potential against pediatric solid tumors. Scientists at St. Jude Children’s Research Hospital have identified a way to improve CAR T–cell homing – a T cell’s ability to navigate effectively to a tumor – for osteosarcoma. Improved homing is a necessary step in designing more successful CAR T–cell therapies. The results were published today in Clinical Cancer Research, a journal of the American Association for Cancer Research.  

Osteosarcoma is the most common type of bone cancer in children and teens. It typically starts in the wide ends of long bones, such as the legs, but can also occur in other bones, such as the pelvis and skull. Approximately 15-20% of patients with osteosarcoma already have metastatic disease when they are diagnosed, and less than 20% of those with metastatic or relapsed disease survive beyond three years.  

Treatment for osteosarcoma includes surgery and chemotherapy – approaches that have been a mainstay of care for over 50 years. This underscores the need for novel, more modern therapeutic approaches such as immunotherapy. However, solid tumors present additional challenges that any CAR T–cell technology must overcome to succeed.  

“Solid tumors are just that, solid – these are hard, dense masses which are difficult for immune cells to penetrate,” said first and corresponding author Lindsay Talbot, MD, St. Jude Department of Surgery. “For immunotherapy to work for solid tumors we need to attract T cells to the tumor, help them penetrate it and keep them there to generate a prolonged response.” 

Talbot and her colleagues focused on the first step: homing. 

Unique chemokines help T cells home to cancer 

Imagine a dog that wants to find their favorite bone, lost somewhere in the backyard – they would use their nose to track the scent of the bone to its location. A T cell is like the dog, the bone is like a tumor and the scent the bone emits is like a chemokine. Chemokines are proteins secreted by cells in the body, such as tumor cells, to attract immune cells. Homing happens when the bone’s scent reaches the dog – it will zero in on the bone’s location and go there. However, T cells’ “noses” often cannot pick up the scent of cancer cells, i.e., T cells do not express the receptors, which recognize the chemokines secreted by tumors. T-cell engineering can overcome this chemokine/chemokine receptor mismatch. 

There are approximately 50 chemokines and 20 chemokine receptors in humans. To improve CAR T–cell homing to osteosarcoma, the researchers had to first determine which chemokines are expressed by that particular cancer type.   

“We used patient specimens gathered after surgery to guide us to which chemokines to target in osteosarcoma, agnostically screening for the ones produced by the tumor—that’s as close to what occurs inside a patient as we can get,” explained Talbot, an active surgeon at St. Jude. “When you combine that with gene expression data, you get very robust results about which chemokines are important for a specific type of cancer.” 

Using this approach, the researchers identified two chemokines, CXCL8 and CXCL16, secreted by osteosarcoma. However, CAR T cells do not express the receptors for these chemokines.