CAR T cells: Are they on the horizon for treatment of solid tumors?
Chimeric antigen receptor T-cell therapy, better known as CAR T-cell therapy, made headlines in 2017 when the federal Food and Drug Administration approved the first two CAR T-cell products. The therapy has been heralded by some as a miracle cure based on the dramatic response reported in several patients. Both products use CD19-CAR T cells for select treatment of acute lymphoblastic leukemia (ALL) in children and young adults as well as adults with large B-cell lymphoma, including non-Hodgkin lymphoma.
But as excitement and questions continue to swirl around CAR T-cell therapies for lymphoid tumors, where are CAR T-cell therapies for solid tumors, including brain tumors? Novel, specific therapies are urgently needed for these patients, whose long-term survival rates often lag behind outcomes for children with leukemia and other blood disorders. For some, treatment-related complications are severe and lifelong.
Stephen Gottschalk, MD, joined St. Jude in 2017 as chair of the Department of Bone Marrow Transplantation and Cellular Therapy. A native of Germany, he has spent his career in the clinic and the laboratory working to harness the immune system to fight cancer. His arrival at St. Jude marked a push to accelerate development of cell-based immunotherapies, including CAR T-cell therapies.
“The realization that the immune system can destroy cancer cells remains the biggest driver of my research,” Gottschalk said. “The specificity of cell-based immunotherapies holds the promise of improving outcomes for children with cancers who do not respond to current therapies, but also reducing long-term, treatment-related complications that all pediatric cancer survivors still endure.”
Before joining St. Jude, Gottschalk was a professor at the Center for Cell and Gene Therapy at Baylor College of Medicine in Houston, and served as director of Texas Children’s Cancer Center Basic and Translational Research Division.
He will provide an update on CAR T-cell therapy for solid tumors at the annual meeting of the American Society of Clinical Oncology in Chicago. The June 4 educational session is titled, “Advances in Immunotherapy for Solid Tumors in Pediatric Oncology.”
Gottschalk took time recently to answer questions and preview his talk.
St. Jude Progress: Please provide some background on the research that led to FDA approval of the first CAR T-cell therapies and how approval has affected the field of cell therapy.
Stephen Gottschalk: The first description of how to engineer T cells with chimeric antigen receptors was published in 1993 by Zelig Eshhar. He called the resulting T cells “T bodies” to highlight that these cells combine the specificity of monoclonal antibodies with the effector function of T cells.
Since then the field has moved rapidly. Numerous investigators have contributed to the development of these receptors, including Dario Campana, MD, PhD, who, as a St. Jude faculty member, oversaw creation of the chimeric antigen receptor that was the centerpiece of the first CAR T-cell therapy to receive FDA approval. The product is Kymriah or tisagenlecleucel.
Kymriah uses CD19-CAR T cells to treat children and young adults with B-cell acute lymphoblastic leukemia. CD19-CAR T cells are also used in the second FDA-approved CAR T-cell therapy. The treatment is Yescarta, or axicabtagene ciloleucel.
St. Jude has also developed its own CD19-CAR T-cell product based on Dr. Campana’s work. The first St. Jude clinical study will start enrolling patients by the end of June.
The success of CD19-CAR T-cell therapies has galvanized the field and drawn in investigators from many different areas of research, including basic scientists in disciplines ranging from immunology and structural biology to nanotechnology and bioengineering. Bringing these scientists into the field is critical for moving the technology forward.
In addition to the scientific challenges, the costs and regulatory requirements associated with clinical testing of CAR T cells have the potential to impede clinical progress.
SJP: What is the status of CAR T-cell therapy for childhood solid tumors?
Gottschalk: Clinical trials to date suggest that CAR T cells are safe for the treatment of solid tumors, including brain tumors, but so far, they have not been very effective.
This lack of efficacy is likely multi-factorial. The lack of tumor-specific antigens to target with CAR T cells is one of the roadblocks. In addition, many of the antigens that have been targeted so far show variable expression within tumors. Other roadblocks include the limited ability of CAR T cells to home to tumor sites and penetrate them, and the hostile immunosuppressive environment that brain and solid tumors create.
- Finding more targets
Most CARs developed so far recognize cell surface proteins that were originally discovered as targets for monoclonal antibodies. Using data from gene expression arrays and proteomics, work has begun to identify new cell surface antigens to target. For example, this approach recently led to identification of an antigen that is expressed at high levels on neuroblastoma. CAR T cells are also being developed to recognize antigen patterns. This approach might involve developing CARs that recognize two antigens or engineering T cells that express multiple CARs. The resulting T cells would become fully activated only in the presence of all targeted antigens.
- Enhancing CAR T-cell homing to tumor sites
Several preclinical studies have highlighted strategies to enhance the homing and antitumor activity of CAR T cells for solid tumors. For example, solid tumors secrete chemokines that CAR T cells "do not recognize." In preclinical models, transgenic expression of receptors for these chemokines on CAR T cells has enhanced their homing to tumor sites and anti-tumor activity.
- Rendering CAR T cells resistant to the hostile tumor microenvironment
Immune cells, including CAR T cells, are sensitive to immunosuppressive factors produced by tumors. Genetic engineering can now be used to render CAR T cells resistant to these factors. For example, expressing immune stimulatory cytokines or cytokine receptors in CAR T cells has increased their anti-tumor activity in preclinical models.
SJP: What’s next for CAR T cells?
Gottschalk: Several things:
- Novel CAR generation
The majority of clinical studies so far have used retroviral or lentiviral vectors to generate clinical grade CAR T-cell products. It is a lengthy, costly process that comes with a significant regulatory burden, which is why alternative solutions are being explored. For example, robust non-viral DNA delivery systems, combined with gene-editing technology, have the potential to address these limitations. Off-the-shelf CAR T-cell products also hold the promise of streamlining CAR T-cell production and distribution so these therapies can be seamlessly integrated into clinical care.
- Combination therapy
There is significant interest to combine CAR T cells with other treatment methods. For example, there have been encouraging reports from preclinical models that combined CAR T-cell therapy with other therapies, including checkpoint blockade, oncolytic viruses, chemotherapy, radiation and small molecules.
- Safety enhancements
Enhanced safety goes hand-in-hand with enhancing CAR T cell effectiveness. Safety switches are being tested as a way to switch off CAR T cells if patients develop severe side effects. The switches tested so far include inducible suicide switches based on viral or human proteins or antibody-based approaches.
We also need to improve our ability to evaluate CAR T-cell therapies in preclinical models and track CAR T cells noninvasively in patients. This will improve our understanding of why therapy fails and help us devise evidence-based approaches to overcome roadblocks as they are identified.
SJP: How hopeful are you that solid tumor patients will benefit from CAR T cells?
Gottschalk: Many approaches have been developed that dramatically improve the anti-tumor activity of CAR T cells in preclinical models for solid tumors. The methods now await early phase clinical testing in humans. So, I remain very hopeful that within the next decade, solid tumor patients will benefit from CAR T-cell therapies to the same degree patients with B-cell malignancies are today.
Gottschalk will provide more details about efforts to develop CAR T cells for solid tumors at ASCO. The educational session begins at 11:30 a.m. in S504 of McCormick Place.
St. Jude Research Collaboratives program reaches across institutional boundaries to multiply impactNov 9, 2023