Two decades ago, cancer treatments virtually always meant chemotherapy, radiation, and surgery. But, over the years, scientists have developed therapies that target cancer cells by homing in on molecular changes in these cells. Today, one of the most prominent types of therapy is immunotherapy, which strengthens patients’ immune systems so they can attack tumors more effectively. In fact, the cancer community often refers to immunotherapy as the “fifth pillar” of cancer treatment.
Out of the several immunotherapies now available, adoptive cell transfer (ACT), which collects patients’ immune cells and uses these to treat their cancers, is one of the latest to take shape in the treatment space. There are various types of ACT, but the type that has achieved most success in clinical development so far is CAR-T therapy.
Studies into this therapy demonstrate its success in treating lymphoma and acute lymphoblastic leukemia (ALL). As research continues to guide scientists in their understanding of how patients respond to this therapy, its development and testing procedures continue to emerge.
When new findings come to light, research professionals can rely on RegMedNet to share insightful articles and videos on its informative website. RegMedNet publishes a wealth of information on how CAR-T therapy works, the studies that have tested (and are testing) the therapy’s effectiveness against lymphoma and ALL, new CAR-T cell target antigens, and emerging methods that scientists may employ to treat solid tumors.
CAR-T Therapy: How the Process Works
Put simply, CAR-T therapy involves taking blood from a patient and separating the T cells from the blood. (T cells arrange our immune responses and eliminate cells that pathogens have infected.) Once the T cells have been removed, scientists can genetically engineer these cells with a disarmed virus so the T cells produce receptors on their surfaces. These receptors, chimeric antigen receptors (CARs), help T cells identify and attach to specific proteins or antigens on tumor cells.
When the scientists have engineered the T cells so they express an antigen-specific CAR, turning them into CAR-T cells, they multiply the cells in a laboratory. Once the scientists have multiplied the CAR-T cells, the patient receives these via a drip. (They should complete a chemotherapy regimen first). When the patient has received the CAR-T cells, these cells continue to multiply in the body, where they identify and eliminate cancer cells.
Testing Different CAR-T Therapies
Today, scientists are developing and testing a variety of CAR-T cell therapies. Although these differ in several ways, they all share similar components. For example, the CAR on each cell surface always contains fragments of synthetic antibodies. The fragments dictate how effectively the receptor identifies and binds to the antigen on the tumor cell. Receptors rely on the cell’s stimulation signals, meaning that CAR-T cells have signaling and “co-stimulatory” domains. These domains signal the cell from the surface receptor.
New developments in the intracellular engineering of CAR-T cells have enabled engineered T cells to multiply when they have been returned to the patient. This development in CAR-T cell engineering allows cells to survive longer once in the patient’s body. It’s also now possible for laboratories to produce CAR-T cell batches within a week, a process that previously took several weeks.
Studies That Have Led to New CAR-T Therapy Treatments
Until recently, scientists only utilized CAR-T therapy in small studies, usually to test the therapy’s efficacy against advanced blood cancers. However, lots of these studies proved successful and led to positive outcomes for patients whose previous cancer treatments had been ineffective. As a result, in 2017, the Food and Drug Administration (FDA) approved two CAR-T cell products, one for adults who have advanced lymphomas and one for children who have ALL.
Treatments for Acute Lymphoblastic Leukemia
Originally, scientists developed CAR-T therapy to treat ALL, the most common cancer in children. Although intensive chemotherapy cures more than 80% of children whose ALL arises in B cells, there are very few treatment options for children whose cancer returns after a stem cell transplant or chemotherapy. Relapsed ALL is one of the biggest causes of death related to childhood cancer.
CAR-T therapy marks a major step forward in cancer treatments for children and young adults who aren’t responding to alternative therapies or whose ALL has returned. An early study that utilized CD-19 targeted CAR-T cells to target ALL demonstrated that the therapy cured all signs of cancer in 27 out of the 30 patients who received the treatment.
Many of these patients demonstrated no signs of recurrence long after the therapy. The success of small studies like this led to a larger study, which tested tisagenlecleucel (Kymriah™), a CD-19-targeted CAR-T cell therapy, on children and teenagers who had ALL. This study also proved successful, and the FDA approved the therapy in 2017.
Since then, studies of other CD19-targeted CAR-T cells have achieved similar results. For example, in 2021, Kite Pharma, a cell therapy research organization, completed a Phase II “ZUMA-3” study that tested the Tecartus CAR-T therapy on adult patients whose ALL had relapsed. The study achieved a response rate of 71%, and many of these responses were associated with minimal residual disease.
The study also demonstrated that 97% of the patients had deep molecular remission, which means that even sensitive lab tests couldn’t identify leukemia cells in the patients’ bone marrow post-therapy. Given the study’s success, the FDA granted Priority Review designation for Tecartus. Now, if approved, Tecartus, will become the first CAR-T treatment for adults who have refractory or relapsed ALL.
Treatments for Lymphoma
Other studies that test CD19-targeted CAR-T cells have concluded that the therapy can also treat lymphoma. One study investigated the effectiveness of a CAR-T therapy against advanced diffuse large B-cell lymphoma and demonstrated that more than half of the participants had complete responses to the therapy. From here, Kite Pharma launched a bigger study, which backed up the original study’s results and led to the FDA’s approval of lymphoma treatment, axicabtagene ciloleucel (Yescarta™).
Testing Other CAR-T Cell Target Antigens
However, some ALL patients don’t respond to CD19-targeted therapy, and up to a third of patients who do see a complete response to the treatment also see their cancer return within a year, often because the patient’s ALL cells stop expressing CD19. As a result, scientists are moving beyond CD19-targeted cells and are now testing CAR-T cells that target the CD22 protein, which is often overexpressed by ALL cells in ALL patients. The majority of patients who took part in the first study of CD22-targeted CAR-T cells saw complete remissions, including patients whose cancer had advanced after a complete response to CD19-targeted therapy.
Scientists have also demonstrated that they can potentially make CAR-T therapy more robust and stunt antigen loss, if not prevent it altogether, by tackling multiple antigens simultaneously. Research groups are in the early phases of studies that investigate T cells that target both CD19 and CD22. Meanwhile, CHOP researchers are testing a CAR-T cell that targets both CD19 and CD123, another antigen in leukemia cells. Early studies in animal models suggest that this dual targeting could prevent antigen loss.
Furthermore, scientists have recognized antigen targets for CAR-T therapy in other blood cancers, such as multiple myeloma. Kite Pharma and the NCI are working together to develop CAR-T cells that target the BCMA protein that is present in most myeloma cells. More than half of the multiple myeloma patients who took part in an early-phase study of the BCMA-targeted CAR-T cells experienced a complete response to the treatment, and Kite Pharma has since launched a study that investigates the BCMA-targeted T cells on a larger patient population.
The Possibility of Treating Solid Tumors With CAR-T Therapy
The latest research into CAR-T therapy is also seeing scientists investigate the therapy’s effectiveness against solid tumors. However, most efforts to locate unique antigens on the surfaces of tumors haven’t proven effective. Some scientists believe this could be because tumor antigens reside within tumor cells where CARs can’t reach as they only bind to antigens on the cell surface.
That said, new research from Stanford University has concluded that CAR-T therapy can tackle tumors by utilizing exhaustion-resistant cells. Researchers have demonstrated that overexpressing C-JUN in CAR-T cells enables these cells to both stay active and proliferate under lab conditions. The researchers tested CAR-T and combined C-JUN and CAR-T cells on mice that had been injected with human leukemias. The mice that received the modified C-JUN and CAR-T therapy saw an improved survival rate.
The researchers then treated the mice with human osteosarcoma, which achieved an extension in lifespan and a reduction in tumor burden. The researchers are now launching clinical studies against leukemia over the next 18 months. From here, they will progress on to studies that investigate the efficacy of the C-JUN and CAR-T therapy against solid tumors.
Upcoming CAR-T Therapy Developments
As CAR-T therapy continues to prove its efficacy against various cancers, researchers are developing further reconfigurations and refinements of CAR-T cells. Currently, scientists are utilizing nanotechnology to develop CAR-T cells within the body, leveraging CRISPR gene editing techniques to engineer T cells more precisely, and producing CAR-T cells that have “off switches” to reduce and possibly prevent the therapy’s side effects.
Other research teams have demonstrated the possibilities of developing CAR-T therapies using cells from healthy donors instead of patients. This approach could lead to the development of off-the-shelf CAR-T therapy products that would be available for instant use. Cellectis, a French biopharmaceutical company, has launched the first phase of a study to test its off-the-shelf CD19-targeted CAR-T cell product for advanced acute myeloid leukemia patients in the U.S. Cellectis has already tested this product on two infants in Europe. The therapy proved effective in both cases, and both children had exhausted all other treatment options.
Furthermore, scientists may be able to improve the effectiveness of existing CAR-T therapies by employing these therapies earlier in the treatment process for children who have ALL. This could prove especially beneficial for children who are at a high risk of cancer returning after their initial chemotherapy. If early indicators suggest that the chemotherapy isn’t stimulating optimum responses, the best approach may be to stop the chemotherapy and progress with CAR-T therapy instead, sparing children two years of invasive chemotherapy.
Over the past five years alone, the number of CAR-T therapy studies in progress has grown from a handful to more than 180. This number will only grow further. As CAR-T therapies and technologies accelerate and improve, these therapies and technologies should become standard cancer care practices.
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