Health & Medicine
RegMedNet Explains How CAR-T Therapy Can Engineer Patients’ Immune Cells to Treat Their Cancers
Staff Reporter
First Posted: Dec 22, 2021 11:37 AM EST
New studies highlight CAR-T therapy's success in treating acute lymphoblastic leukemia and lymphoma.
20 years ago, virtually all cancer treatments involved surgery, chemotherapy, and radiation. But the past two decades have seen advances in targeted therapies like trastuzumab (Herceptin®) and imatinib (Gleevec®), which target cancer cells by homing in on molecular changes in these cells. Today, targeted therapies like these are now standard treatments for various cancers.
One of the most recent types of therapy is immunotherapy, which strengthens a patient's immune system so they can better attack tumors. The cancer community now widely considers immunotherapy the "fifth pillar" of cancer treatment. Among the various immunotherapies available today, adoptive cell transfer (ACT) is one of the latest approaches. ACT collects and uses patients' immune cells to treat their cancer. There are various types of ACT, but the type that has progressed furthest in clinical development is CAR-T therapy. Researchers are gaining an ever-increasing understanding of how patients respond to this therapy, which is fueling its development and testing procedures.
Here, RegMedNet explains how CAR-T therapy works, introduces studies that test CAR-T therapy's efficacy against acute lymphoblastic leukemia (ALL) and lymphoma, explores new CAR-T cell target antigens, and notes the ways that researchers may be able to use the therapy to treat solid tumors.
As a community site that publishes the latest in regenerative medicine, RegMedNet is an invaluable source of information for the global regenerative medicine research community.
How CAR-T Therapy Works
CAR-T therapy involves drawing blood from a patient and separating the T cells from this blood. (T cells orchestrate our immune responses and kill cells that pathogens have infected.) Researchers then use a disarmed virus to genetically engineer the T cells so they produce receptors on their surfaces. These receptors are called chimeric antigen receptors (CARs), and they help T cells recognize and attach to specific proteins or antigens on tumor cells. Once researchers have engineered the T cells to express the antigen-specific CAR, they can multiply these cells in a laboratory. Having multiplied the CAR-T cells, a practitioner can return the cells to the patient via a drip (although the patient must complete a chemotherapy regimen first). Once the patient has received the CAR-T cells, the cells should reproduce in their body and then recognize and kill cancer cells.
Researchers are currently developing and testing various CAR-T cell therapies. There are important differences among these therapies, but they all share similar components. For example, the CAR on the cell's surface always contains fragments of synthetic antibodies. These fragments affect how well the receptor recognizes or binds to the antigen on the tumor cell. Receptors rely on stimulation signals from the cell. This means that CAR-T cells have signaling and "co-stimulatory" domains that signal the cell from the surface receptor.
Recent progression in the intracellular engineering of CAR-T cells has made it possible for engineered T cells to multiply once they have been returned to the patient. Such advances in the engineering of CAR-T cells also mean that the cells tend to survive longer once the patient has received them. It's also now much faster to produce batches of CAR-T cells than it was previously. Originally, the process took several weeks. Many labs can now produce the engineered cells in under a week.
CAR-T Therapy Studies
Until recently, researchers only used CAR-T therapy in small studies, mostly for patients who have advanced blood cancers. Many of these studies have proven highly successful, achieving positive outcomes for cancer patients whose previous treatments have stopped working. In 2017, the Food and Drug Administration (FDA) approved two CAR-T cell therapies, one for children who have ALL and one for adults who have advanced lymphomas.
Treating Acute Lymphoblastic Leukemia Cancer
Initially, researchers developed CAR-T cell therapy to treat ALL, which is the most common cancer in children. Intensive chemotherapy cures over 80% of children who are diagnosed with ALL that arises in B cells. However, there are very few treatment options for children whose cancer returns after chemotherapy or a stem cell transplant. In fact, relapsed ALL is one of the biggest causes of death from childhood cancer.
That said, CAR-T therapy can be effective for children and young adults whose ALL has returned and for those who aren't responding to alternative therapies. For example, an early study that used CD19-targeted CAR-T cells to treat ALL concluded that the therapy cured all signs of the cancer in 27 out of the 30 patients treated. Many of these patients continued to show no signs of recurrence long after the therapy.
The success of studies like this paved the way for a larger study, which tested a CD19-targeted CAR-T cell therapy called tisagenlecleucel (KymriahTM) on children and teenagers who had ALL. The study was so successful that the FDA approved the therapy in 2017. Other studies of CD19-targeted CAR-T cells have since achieved similar results.
In recent news, the cell therapy research organization Kite Pharma has completed a Phase II "ZUMA-3" study that tested a CAR-T therapy called Tecartus on adult patients who were suffering relapses of ALL. The study achieved a response rate of 71%. Most of these responses were associated with undetectable minimal residual disease. The study also concluded that 97% of patients had deep molecular remission. This means that even sensitive lab tests couldn't identify leukemia cells in the patients' bone marrow once they had undergone therapy. As a result of this study's success, the FDA granted Priority Review designation for Tecartus. If approved, Tecartus will become the first CAR-T therapy for adults who have relapsed or refractory ALL.
Treating Lymphoma
Other studies that investigate CD19-targeted CAR-T cells have revealed that the therapy can also treat patients who have lymphoma. One study, which tested the efficacy of CAR-T therapy on patients who had advanced diffuse large B-cell lymphoma, concluded that over half of the participants had complete responses to the therapy. Kite then launched a larger study, which confirmed the original study's results and laid the foundations for the FDA's approval of the lymphoma treatment axicabtagene ciloleucel (YescartaTM).
New CAR-T Cell Target Antigens
Unfortunately, not all patients who have ALL respond to CD19-targeted therapy. And up to a third of those who do experience a complete response sees their cancer return within 12 months. This is often because the patient's ALL cells stop expressing CD19. Therefore, CAR-T therapy studies are now moving beyond the CD19-targeted CAR-T cells. Now, researchers are testing CAR-T cells that target the CD22 protein in ALL patients. The CD22 protein is often overexpressed by ALL cells. Most patients who took part in the first study involving CD22-targeted CAR-T cells had complete remissions, including those whose cancer had advanced after a complete response to CD19-targeted therapy.
Furthermore, researchers can potentially make CAR-T therapy more durable and forestall antigen loss (if not prevent it altogether) by attacking multiple antigens at the same time. Various research groups are now in the early phases of testing T cells that target both CD19 and CD22. Meanwhile, CHOP researchers are investigating a CAR-T cell that targets both CD19 and CD123, another antigen found on leukemia cells. Early studies in animal models reveal that this dual targeting may prevent antigen loss.
Researchers have also identified antigen targets for CAR-T cell therapy in other blood cancers, like multiple myeloma. The NCI and Kite are collaboratively developing CAR-T cells that target the BCMA protein found on most myeloma cells. Over half of the advanced multiple myeloma patients who took part in an early-phase study of the BCMA-targeted CAR-T cells have seen a complete response to the treatment. Kite has since launched a study that tests the BCMA-targeted T cells on a larger patient population.
Using CAR-T Therapy to Treat Solid Tumors
As research into CAR-T therapy progresses, researchers are now evaluating the therapy's efficacy against solid tumors. So far, most efforts to identify unique antigens on the surface of solid tumors have been ineffective. Some researchers suggest that this inefficacy could be the result of tumor antigens residing within tumor cells, where CARs can't reach them as they can only bind to antigens on the cell surface.
Researchers are also testing how well CAR-T cells can target the protein EGFRvIII, which is present on most tumor cells in patients who have glioblastoma, and the protein mesothelin, which is overexpressed on tumor cells in some of the deadliest cancers (such as pancreatic and lung cancers). That said, early reports from these studies suggest that CAR-T therapy has achieved limited efficacy here.
However, new research from Stanford University (CA, U.S.) has demonstrated that CAR-T therapy can combat tumors by utilizing exhaustion-resistant cells. The research team has demonstrated that overexpressing C-JUN in CAR-T cells allows these cells to stay active and proliferate under laboratory conditions. The team tested both traditional CAR-T and the C-JUN and CAR-T combination on mice that had been injected with human leukemias and saw an increased survival rate in the mice that had received the modified C-JUN + CAR-T treatment. Following this success, the research team then treated mice with human osteosarcoma and managed to achieve a reduction in tumor burden and an extension in lifespan. The team now plans to launch clinical studies against leukemia over the next 18 months and then progress on to studies that examine the effectiveness of the C-JUN + CAR-T therapy against solid tumors.
The Future of CAR-T Therapy
Now, scientists are exploring even more refinements and reconfigurations of CAR-T cells. For example, researchers are using nanotechnology to produce CAR-T cells inside the body, developing CAR-T cells that have "off switches" to minimize (or even prevent) side effects, and employing CRISPR gene editing techniques to engineer T cells more precisely.
Meanwhile, other researchers have found that it may be possible to develop CAR-T therapies using cells from healthy donors instead of patients. This could open doors to off-the-shelf CAR-T therapies that would be available for instant use and wouldn't have to be manufactured for each patient. The French company Cellectis has already launched the first phase of a study of its off-the-shelf CD19-targeted CAR-T-cell product for patients who have advanced acute myeloid leukemia in the U.S. Cellectis has also tested this product on two infants in Europe who had ALL and had exhausted all other treatment options. The therapy was effective in both cases.
On top of this, researchers may be able to improve the efficacy of existing CAR-T therapies by implementing these therapies earlier in the treatment process for children who have ALL, especially for those who are at a higher risk of their cancer returning after their initial chemotherapy. If early indicators suggest that chemotherapy isn't triggering optimal responses, practitioners may stop the chemotherapy and move forward with CAR-T therapy instead - potentially sparing young patients two years of chemotherapy.
Five years ago, there were only a handful of CAR-T therapy studies in progress. Today, there are over 180. And this number is only set to grow. As these therapies and their associated technologies develop, we can expect to see CAR-T therapy become a standard practice in cancer care.
About RegMedNet
RegMedNet covers the latest developments in the investigation, development, manufacture and provision of the treatments that are becoming today's mainstream medicines. A global community of scientific professionals follows the website, where scientists, researchers, and other professionals can read, watch, and listen to content that examines the development, trialing, manufacture, regulation, and commercialization of cell therapies. Meanwhile, RegMedNet's sister journal Regenerative Medicine publishes reviews and papers that examine regenerative medicine approaches like small molecule drugs, biomaterials, biologics, cell and gene therapies, and tissue engineering.
See Now:
NASA's Juno Spacecraft's Rendezvous With Jupiter's Mammoth Cyclone
©2024 ScienceWorldReport.com All rights reserved. Do not reproduce without permission. The window to the world of science news.
* This is a contributed article and this content does not necessarily represent the views of scienceworldreport.com
More on SCIENCEwr
First Posted: Dec 22, 2021 11:37 AM EST
New studies highlight CAR-T therapy's success in treating acute lymphoblastic leukemia and lymphoma.
20 years ago, virtually all cancer treatments involved surgery, chemotherapy, and radiation. But the past two decades have seen advances in targeted therapies like trastuzumab (Herceptin®) and imatinib (Gleevec®), which target cancer cells by homing in on molecular changes in these cells. Today, targeted therapies like these are now standard treatments for various cancers.
One of the most recent types of therapy is immunotherapy, which strengthens a patient's immune system so they can better attack tumors. The cancer community now widely considers immunotherapy the "fifth pillar" of cancer treatment. Among the various immunotherapies available today, adoptive cell transfer (ACT) is one of the latest approaches. ACT collects and uses patients' immune cells to treat their cancer. There are various types of ACT, but the type that has progressed furthest in clinical development is CAR-T therapy. Researchers are gaining an ever-increasing understanding of how patients respond to this therapy, which is fueling its development and testing procedures.
Here, RegMedNet explains how CAR-T therapy works, introduces studies that test CAR-T therapy's efficacy against acute lymphoblastic leukemia (ALL) and lymphoma, explores new CAR-T cell target antigens, and notes the ways that researchers may be able to use the therapy to treat solid tumors.
As a community site that publishes the latest in regenerative medicine, RegMedNet is an invaluable source of information for the global regenerative medicine research community.
How CAR-T Therapy Works
CAR-T therapy involves drawing blood from a patient and separating the T cells from this blood. (T cells orchestrate our immune responses and kill cells that pathogens have infected.) Researchers then use a disarmed virus to genetically engineer the T cells so they produce receptors on their surfaces. These receptors are called chimeric antigen receptors (CARs), and they help T cells recognize and attach to specific proteins or antigens on tumor cells. Once researchers have engineered the T cells to express the antigen-specific CAR, they can multiply these cells in a laboratory. Having multiplied the CAR-T cells, a practitioner can return the cells to the patient via a drip (although the patient must complete a chemotherapy regimen first). Once the patient has received the CAR-T cells, the cells should reproduce in their body and then recognize and kill cancer cells.
Researchers are currently developing and testing various CAR-T cell therapies. There are important differences among these therapies, but they all share similar components. For example, the CAR on the cell's surface always contains fragments of synthetic antibodies. These fragments affect how well the receptor recognizes or binds to the antigen on the tumor cell. Receptors rely on stimulation signals from the cell. This means that CAR-T cells have signaling and "co-stimulatory" domains that signal the cell from the surface receptor.
Recent progression in the intracellular engineering of CAR-T cells has made it possible for engineered T cells to multiply once they have been returned to the patient. Such advances in the engineering of CAR-T cells also mean that the cells tend to survive longer once the patient has received them. It's also now much faster to produce batches of CAR-T cells than it was previously. Originally, the process took several weeks. Many labs can now produce the engineered cells in under a week.
CAR-T Therapy Studies
Until recently, researchers only used CAR-T therapy in small studies, mostly for patients who have advanced blood cancers. Many of these studies have proven highly successful, achieving positive outcomes for cancer patients whose previous treatments have stopped working. In 2017, the Food and Drug Administration (FDA) approved two CAR-T cell therapies, one for children who have ALL and one for adults who have advanced lymphomas.
Treating Acute Lymphoblastic Leukemia Cancer
Initially, researchers developed CAR-T cell therapy to treat ALL, which is the most common cancer in children. Intensive chemotherapy cures over 80% of children who are diagnosed with ALL that arises in B cells. However, there are very few treatment options for children whose cancer returns after chemotherapy or a stem cell transplant. In fact, relapsed ALL is one of the biggest causes of death from childhood cancer.
That said, CAR-T therapy can be effective for children and young adults whose ALL has returned and for those who aren't responding to alternative therapies. For example, an early study that used CD19-targeted CAR-T cells to treat ALL concluded that the therapy cured all signs of the cancer in 27 out of the 30 patients treated. Many of these patients continued to show no signs of recurrence long after the therapy.
The success of studies like this paved the way for a larger study, which tested a CD19-targeted CAR-T cell therapy called tisagenlecleucel (KymriahTM) on children and teenagers who had ALL. The study was so successful that the FDA approved the therapy in 2017. Other studies of CD19-targeted CAR-T cells have since achieved similar results.
In recent news, the cell therapy research organization Kite Pharma has completed a Phase II "ZUMA-3" study that tested a CAR-T therapy called Tecartus on adult patients who were suffering relapses of ALL. The study achieved a response rate of 71%. Most of these responses were associated with undetectable minimal residual disease. The study also concluded that 97% of patients had deep molecular remission. This means that even sensitive lab tests couldn't identify leukemia cells in the patients' bone marrow once they had undergone therapy. As a result of this study's success, the FDA granted Priority Review designation for Tecartus. If approved, Tecartus will become the first CAR-T therapy for adults who have relapsed or refractory ALL.
Treating Lymphoma
Other studies that investigate CD19-targeted CAR-T cells have revealed that the therapy can also treat patients who have lymphoma. One study, which tested the efficacy of CAR-T therapy on patients who had advanced diffuse large B-cell lymphoma, concluded that over half of the participants had complete responses to the therapy. Kite then launched a larger study, which confirmed the original study's results and laid the foundations for the FDA's approval of the lymphoma treatment axicabtagene ciloleucel (YescartaTM).
New CAR-T Cell Target Antigens
Unfortunately, not all patients who have ALL respond to CD19-targeted therapy. And up to a third of those who do experience a complete response sees their cancer return within 12 months. This is often because the patient's ALL cells stop expressing CD19. Therefore, CAR-T therapy studies are now moving beyond the CD19-targeted CAR-T cells. Now, researchers are testing CAR-T cells that target the CD22 protein in ALL patients. The CD22 protein is often overexpressed by ALL cells. Most patients who took part in the first study involving CD22-targeted CAR-T cells had complete remissions, including those whose cancer had advanced after a complete response to CD19-targeted therapy.
Furthermore, researchers can potentially make CAR-T therapy more durable and forestall antigen loss (if not prevent it altogether) by attacking multiple antigens at the same time. Various research groups are now in the early phases of testing T cells that target both CD19 and CD22. Meanwhile, CHOP researchers are investigating a CAR-T cell that targets both CD19 and CD123, another antigen found on leukemia cells. Early studies in animal models reveal that this dual targeting may prevent antigen loss.
Researchers have also identified antigen targets for CAR-T cell therapy in other blood cancers, like multiple myeloma. The NCI and Kite are collaboratively developing CAR-T cells that target the BCMA protein found on most myeloma cells. Over half of the advanced multiple myeloma patients who took part in an early-phase study of the BCMA-targeted CAR-T cells have seen a complete response to the treatment. Kite has since launched a study that tests the BCMA-targeted T cells on a larger patient population.
Using CAR-T Therapy to Treat Solid Tumors
As research into CAR-T therapy progresses, researchers are now evaluating the therapy's efficacy against solid tumors. So far, most efforts to identify unique antigens on the surface of solid tumors have been ineffective. Some researchers suggest that this inefficacy could be the result of tumor antigens residing within tumor cells, where CARs can't reach them as they can only bind to antigens on the cell surface.
Researchers are also testing how well CAR-T cells can target the protein EGFRvIII, which is present on most tumor cells in patients who have glioblastoma, and the protein mesothelin, which is overexpressed on tumor cells in some of the deadliest cancers (such as pancreatic and lung cancers). That said, early reports from these studies suggest that CAR-T therapy has achieved limited efficacy here.
However, new research from Stanford University (CA, U.S.) has demonstrated that CAR-T therapy can combat tumors by utilizing exhaustion-resistant cells. The research team has demonstrated that overexpressing C-JUN in CAR-T cells allows these cells to stay active and proliferate under laboratory conditions. The team tested both traditional CAR-T and the C-JUN and CAR-T combination on mice that had been injected with human leukemias and saw an increased survival rate in the mice that had received the modified C-JUN + CAR-T treatment. Following this success, the research team then treated mice with human osteosarcoma and managed to achieve a reduction in tumor burden and an extension in lifespan. The team now plans to launch clinical studies against leukemia over the next 18 months and then progress on to studies that examine the effectiveness of the C-JUN + CAR-T therapy against solid tumors.
The Future of CAR-T Therapy
Now, scientists are exploring even more refinements and reconfigurations of CAR-T cells. For example, researchers are using nanotechnology to produce CAR-T cells inside the body, developing CAR-T cells that have "off switches" to minimize (or even prevent) side effects, and employing CRISPR gene editing techniques to engineer T cells more precisely.
Meanwhile, other researchers have found that it may be possible to develop CAR-T therapies using cells from healthy donors instead of patients. This could open doors to off-the-shelf CAR-T therapies that would be available for instant use and wouldn't have to be manufactured for each patient. The French company Cellectis has already launched the first phase of a study of its off-the-shelf CD19-targeted CAR-T-cell product for patients who have advanced acute myeloid leukemia in the U.S. Cellectis has also tested this product on two infants in Europe who had ALL and had exhausted all other treatment options. The therapy was effective in both cases.
On top of this, researchers may be able to improve the efficacy of existing CAR-T therapies by implementing these therapies earlier in the treatment process for children who have ALL, especially for those who are at a higher risk of their cancer returning after their initial chemotherapy. If early indicators suggest that chemotherapy isn't triggering optimal responses, practitioners may stop the chemotherapy and move forward with CAR-T therapy instead - potentially sparing young patients two years of chemotherapy.
Five years ago, there were only a handful of CAR-T therapy studies in progress. Today, there are over 180. And this number is only set to grow. As these therapies and their associated technologies develop, we can expect to see CAR-T therapy become a standard practice in cancer care.
About RegMedNet
RegMedNet covers the latest developments in the investigation, development, manufacture and provision of the treatments that are becoming today's mainstream medicines. A global community of scientific professionals follows the website, where scientists, researchers, and other professionals can read, watch, and listen to content that examines the development, trialing, manufacture, regulation, and commercialization of cell therapies. Meanwhile, RegMedNet's sister journal Regenerative Medicine publishes reviews and papers that examine regenerative medicine approaches like small molecule drugs, biomaterials, biologics, cell and gene therapies, and tissue engineering.
See Now: NASA's Juno Spacecraft's Rendezvous With Jupiter's Mammoth Cyclone