Improved Chemokine Homing Enhances CAR T-Cell Therapy in Preclinicals for Osteosarcoma

Scientists at St. Jude Children’s Research Hospital report that they have identified a way to improve CAR T-cell homing for osteosarcoma. Their study “Redirecting B7-H3.CAR T cells to chemokines expressed in osteosarcoma enhances homing 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 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

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, a surgeon at St. Jude. “When you combine that with gene expression data, you get 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.

Having identified this chemokine/chemokine receptor mismatch, the researchers modified CAR T cells targeting the osteosarcoma antigen B7-H3 to express the receptors (CXCR2 or CXCR6) for the identified chemokines. They evaluated the homing kinetics (movement) and efficiency of the modified cells, testing their ability to find and infiltrate osteosarcoma.

The researchers found that the engineered cells behaved differently. Those expressing CXCR2 quickly homed and arrived at the tumor but plateaued in their activity early. Those expressing CXCR6 took a little longer to home, but similarly plateaued. Notably, the researchers observed prolonged survival in a model of metastatic disease using the CXCR2 or CXCR6 modified B7-H3-CAR T cells compared to unmodified B7-H3-CAR T cells.

Findings support clinical evaluation of CXCR-modified CAR T cells

“When expressed in B7-H3.CAR T cells, CXCR2- and CXCR6 modification conferred enhanced homing towards OS [osteosarcoma] in vitro and in vivo. CXCR2- and CXCR6-B7-H3.CAR treated mice experienced prolonged survival in a metastatic model compared to B7-H3.CAR T cell treated mice,” write the investigators.

“Our patient-based pipeline identified targets for chemokine receptor modification of CAR T cells targeting OS. CXCR2 and CXCR6 expression enhanced homing and anti-OS activity of B7-H3.CAR T cells. These findings support clinical evaluation of CXCR-modified CAR T cells to improve adoptive cell therapy for OS patients.”

“We haven’t changed anything about how the T cells kill the tumor cells; what we’ve changed is how well they get to the tumor, and that has implications for specificity and toxicity,” continued Talbot. “But the work isn’t over, and I’m excited about the opportunity to continue making strides toward solid tumor immunotherapy with this platform.”

“Immunotherapy has tremendous potential as a treatment for cancer, but there is still a lot of work to be done to realize that potential in pediatric solid tumors,” added Christopher DeRenzo, MD, paper author, St. Jude department of bone marrow transplantation and cellular therapy. “Improving CAR T cells to better home to osteosarcoma is an exciting advance, so we are working on connecting laboratory discoveries like this with what we can do for patients through clinical trials.”

“By devising a strategy to increase the homing of CAR T cells to osteosarcoma sites, Dr. Talbot and her team were able to demonstrate that these cells have improved anti-tumor activity in preclinical models,” noted Stephen Gottschalk, MD, author on the paper and chair of department of bone marrow transplantation and cellular therapy. “Based on these findings, we are committed to translating these ‘improved osteosarcoma finder’ CAR T cells into early phase clinical testing.”