Immunotherapy has emerged as an important cancer therapeutics modality and is a significant cancer care advancement. This cancer treatment augments the body’s immune system in attacking cancer cells. While there are different types of cancer immunotherapies, CAR-T cell therapy has shown immense promise in paving the way for more effective cancer treatments.
Saurabh Dahiya, MD, FACP, Stanford Cancer Institute member, associate professor of medicine (blood and marrow transplantation and cellular therapy), and leader of Stanford’s Cancer Cell Therapy Clinical Research Group, shed light on CAR-T cell therapy and ongoing Stanford research and approaches in this space.
Advances in lymphoma treatment with CAR-T cell therapy
Dahiya’s research focuses on treating lymphoma with CAR-T cell therapy, a cutting-edge immunotherapy technique that modifies a patient's T-cells to express artificial receptors that recognize and target cancer cells, leading to their destruction. By harnessing the immune system's power, CAR-T cell therapy offers a promising approach to treating various forms of cancer.
“CAR-T cell therapy is an advanced form of targeted immunotherapy that combines synthetic biology techniques with personalized medicine,” Dahiya said.
In lymphoma, genetically-modified T-cells express the chimeric antigen receptor (CAR) protein, which recognizes proteins on the surface of the lymphoma, with the CD-19 protein being the most common that the T-cell is altered to detect. Like a lock and key, the CD-19 antibody on the T-cell’s surface and CD-19 protein on the lymphoma’s surface unite. Once united, the T-cell gets a signal to attack and kill the lymphoma and a second signal to expand and divide by numbers.
“Generally, when we infuse these cells, they often expand five to ten times on a logarithmic scale within a week of being infused in the patient. These are living drugs,” Dahiya said.
After undergoing single-arm studies, CAR-T cell therapy in lymphoma was originally developed as a third-line treatment, which is given when the first-line, or initial, and second-line, or subsequent, treatments don’t work. Two large trials were conducted in the earlier line of therapy (second line) and compared to standard-of-care treatment. The ZUMA-7 and TRANSFORM trials were large, randomized, controlled trials showing that CAR-T cell therapy can be an effective treatment for patients with relapsed or refractory diffuse large B-cell lymphoma. Patients who received CAR-T cell therapy had a significantly higher rate of complete response than those who received standard-of-care treatments.
Last year, the FDA approved two CAR-T products, axicabtagene ciloleucel (axi-cel) and lisocabtagene ciloleucel (liso-cel), for patients with large B-cell lymphoma who have relapsed after one line of therapy. Most impressively, the ZUMA 7 trial with axi-cel has demonstrated a better overall survival benefit compared to standard-of-care chemotherapy options.
“The study is the first randomized trial to show meaningful survival benefit in a long-running trial in lymphoma,” Dahiya explained.
Among patients with large B-cell lymphoma whose disease returned after initial treatment, 55% of patients given a single administration of axi-cel were still alive four years after treatment compared to 46% of the patients with standard chemotherapy treatment. Stanford Cancer Institute member David Miklos, MD, served as the key investigator for the clinical trial at Stanford and is one of the study's lead authors.
Dahiya notes that identifying targets beyond the CD-19 protein will help expand CAR-T cell treatment to other patients. Ongoing Stanford research led by Stanford Cancer Institute member Matthew Frank, MD, focuses on the CD-22 protein. He cites a successful Stanford trial with the CD-22 protein that will go into a phase 2 study later this summer after a phase 1 with patients who do not do well or progress after CAR-T cell therapy targeting the CD-19 protein.
Identifying patient populations to enhance treatment
The next steps in expanding the treatment possibilities of CAR-T cell therapy include identifying patient populations where providers can better optimize CAR-T cell therapy. At Stanford, high-risk patients are identified and enrolled in novel clinical trials to improve their outcomes. For example, patients with a high tumor burden, defined by having a high tumor marker called LDH, receive higher doses of CAR-T cell therapy separated by time.
“Patients with a high tumor burden tend to have worse outcomes than those with a normal tumor burden. The idea is to optimize these therapies by doing these innovative trials,” Dahiya said.
CAR-T cell therapy is FDA-approved for almost all hematologic malignancies, including leukemia, myeloma, and lymphoma.
“A general theme has emerged in these three fields to identify patient populations who are at risk of poor outcomes and move CAR-T cell therapy to earlier lines of treatment so you don’t expose the patients to the adverse effects of several lines of therapy on T-cell quality, which is what you need to make good CAR-T cells.”
Moving CAR-T cell therapy to solid tumors
Another big theme in the CAR-T field is to go beyond hematologic malignancies and use CAR-T cell therapy to treat solid tumors.
“Solid tumor treatment is a huge space with a large unmet need. To date, the vast majority of patients with metastatic solid tumors are not cured with immunotherapy approaches, so novel approaches and techniques are desperately needed in these patients.”
Dahiya explains that there are ongoing Stanford clinical trials in several metastatic solid tumor settings, including melanoma, ovarian cancer, and sarcoma. Beyond these trials, CAR-T is moving into almost all histologies of solid tumors, including lung and gastrointestinal cancers.
Stanford is partnering with biopharmaceutical and industry companies to find innovative solutions and launch investigator-initiated trials. An example is Stanford Cancer Institute member Crystal Mackall, MD, using GD2-CAR-T to treat diffuse intrinsic pontine glioma (DIPG), a lethal pediatric tumor to the central nervous system that is hard to treat with conventional therapeutics. This approach is now in clinical trials. Mackall developed another novel approach to treat glioblastoma multiforme, a brain tumor (GBM) that is almost always fatal, by injecting B7H-CAR-T cells directly into the brain’s cerebrospinal fluid.
“CAR-T cell therapy represents one of the most innovative frontiers in medicine, as it holds so much promise for treating patients who have historically been incurable. We hope to create effective treatments for these patients through novel approaches and innovative partnerships. With these treatments, there’s a lot of hope for the future.”