CAR T Cells: Engineering Immune Cells to Treat Cancer – National Cancer Institute

CAR T Cells: Engineering Patients’ Immune Cells to Treat Their Cancers

Co-stimulatory signaling domains have been added to newer generations of CAR T cells to improve their capability to produce more T cells after infusion and sustain longer in the circulation.

For years, the foundations of cancer treatment were surgery, chemotherapy, and radiation therapy. Over the last two decades, targeted therapies like imatinib (Gleevec®) and trastuzumab (Herceptin®)–drugs that target cancer cells by homing in on specific molecular switches seen primarily in those cells–have also cemented themselves as standard treatments for many cancers.

But over the past several years, immunotherapy–therapies that enlist and strengthen the power of a patient`s immune system to attack tumors– has emerged as what many in the cancer community now call the «fifth pole» of cancer treatment.

A rapidly emerging immunotherapy treatment is called adoptive cell transfer (ACT): collecting and using patients` own immune cells to treat their cancer. There are several types of ACT (see «ACT: TILs, TCRs, and CARs»), but the one that is closest to producing a treatment approved by the Food and Drug Administration (FDA) is called CAR T-cell therapy.

Until recently, the use of CAR T-cell therapy has been restricted to petite clinical trials, largely in patients with advanced blood cancers. But these treatments have nevertheless captured the attention of researchers and the public alike because of the remarkable responses they have produced in some patients–both children and adults–for whom all other treatments had stopped working.

One CAR T-cell therapy is expected to be approved in two thousand seventeen for the treatment of children with acute lymphoblastic leukemia (ALL). And a 2nd, for adults with advanced lymphomas, may be close behind. Nevertheless, researchers caution that, in many respects, it`s still early days for CAR T cells and other forms of ACT, including questions about whether they will ever be effective against solid tumors like breast and colorectal cancer.

The different forms of ACT «are still being developed,» said Steven Rosenberg, M.D., Ph.D., chief of the Surgery Branch in NCI`s Center for Cancer Research (CCR), an immunotherapy pioneer whose lab was the very first to report successful cancer treatment with CAR T cells.

But after several decades of painstaking research, the field has reached a tipping point, Dr. Rosenberg continued. In just the last few years, progress with CAR T cells and other ACT approaches has greatly accelerated, with researchers developing a better understanding of how these therapies work in patients and translating that skill into improvements in how they are developed and tested.

«In the next few years,» he said, «I think we`re going to see dramatic progress and shove the boundaries of what many people thought was possible with these adoptive cell transfer–based treatments.»

A «Living Drug»

CAR T cells are the equivalent of «providing patients a living drug,» explained Renier J. Brentjens, M.D., Ph.D., of Memorial Sloan Kettering Cancer Center in Fresh York, another early leader in the CAR T-cell field.

As its name implies, the backbone of CAR T-cell therapy is T cells, which are often called the workhorses of the immune system because of their critical role in orchestrating the immune response and killing cells infected by pathogens. The therapy requires drawing blood from patients and separating out the T cells. Next, using a disarmed virus, the T cells are genetically engineered to produce receptors on their surface called chimeric antigen receptors, or CARs.

These receptors are «synthetic molecules, they don`t exist naturally,» explained Carl June, M.D., of the University of Pennsylvania Abramson Cancer Center, during a latest presentation on CAR T cells at the National Institutes of Health campus. Dr. June has led a series of CAR T cell clinical trials, largely in patients with leukemia.

These special receptors permit the T cells to recognize and link to a specific protein, or antigen, on tumor cells. The CAR T cell therapies furthest along in development target an antigen found on B cells called CD19 (see «The Making of a CAR T Cell»).

Once the collected T cells have been engineered to express the antigen-specific CAR, they are «expanded» in the laboratory into the hundreds of millions.

The final step is the infusion of the CAR T cells into the patient (which is preceded by a «lymphodepleting» chemotherapy regimen). If all goes as planned, the engineered cells further multiply in the patient`s assets and, with guidance from their engineered receptor, recognize and kill cancer cells that harbor the antigen on their surfaces.

The Making of a CAR T Cell

A growing number of CAR T-cell therapies are being developed and tested in clinical studies.

Albeit there are significant differences inbetween these therapies, they all share similar components. The CAR on the cell`s surface is composed of fragments, or domains, of synthetic antibodies. The domains that are used can affect how well the receptor recognizes or ties to the antigen on the tumor cell.

The receptors rely on stimulation signals from inwards the cell to do their job. So each CAR T cell has signaling and «co-stimulatory» domains inwards the cell that signal the cell from the surface receptor. The different domains that are used can affect the cells` overall function.

Over time, advances in the intracellular engineering of CAR T cells have improved the engineered T cells` capability to produce more T cells after infusion into the patient (expansion) and sustain longer in the circulation (persistence).

Advances have also been made in how long it takes to produce a batch of CAR T cells. Albeit it originally took several weeks, many labs have now diminished the time to less than seven days.

A Possible Option Where None Had Existed

The initial development of CAR T-cell therapies has focused largely on ALL, the most common cancer in children.

More than 80% of children diagnosed with ALL that arises in B cells–the predominant type of pediatric ALL–will be cured by intensive chemotherapy. But for patients whose cancers come back after chemotherapy or a stem cell transplant, the treatment options are «close to none,» said Stephan Grupp, M.D., Ph.D., of the Children`s Hospital of Philadelphia (CHOP).

Relapsed ALL, in fact, is a leading cause of death from childhood cancer.

Dr. Grupp has led several trials of CAR T cells in children and youthfull adults with ALL that had recurred or was not responding to existing therapies. In one of these earlier trials, which used CD19-targeted CAR T cells, all signs of cancer disappeared (a finish response) in twenty seven of the thirty patients treated in the probe, with many of these patients continuing to showcase no signs of recurrence long after the treatment.

These early successes laid the foundation for a larger trial of a CD19-targeted CAR T-cell therapy, called tisagenlecleucel (Kymriah™), for children and adolescents with ALL. Many of the patients who participated in the trial, funded by Novartis, had finish and long-lasting remissions. Based on the trial results, FDA approved tisagenlecleucel in August 2017.

Similar results have been seen in trials of CD19-targeted CAR T cells led by researchers in CCR`s Pediatric Oncology Branch (POB).

The progress made with CAR T-cell therapy in children with ALL «has been fantastic,» said Terry Fry, M.D., a lead investigator on several POB trials of CAR T cells. CD19-targeted CAR T cells were originally tested in adults. But the fact that the very first approval is for a therapy for children and adolescents with ALL is a watershed moment, Dr. Fry continued.

The agency approving a fresh therapy in children before adults «is almost unheard of in cancer,» he said.

However, there is no shortage of promising data on CAR T cells used to treat adult patients with blood cancers. CD19-targeted CAR T cells have produced strong results not only in patients with ALL but also in patients with lymphomas. For example, in a petite NCI-led trial of CAR T cells primarily in patients with advanced diffuse large B-cell lymphoma, more than half had finish responses to the treatment.

«Our data provide the very first true peek of the potential of this treatment in patients with aggressive lymphomas, who, until this point, were virtually untreatable,» said the trial`s lead investigator, James Kochenderfer, M.D., of the NCI Experimental Transplantation and Immunology Branch.

Since that time, findings from a larger trial funded by Kite Pharmaceuticals (which has a research agreement with NCI to develop ACT-based therapies) have confirmed these earlier results, which are expected to help support the FDA`s approval of Kite`s product for some patients with lymphoma.

The results in lymphoma to date «have been exceptionally successful,» Dr. Kochenderfer said, «and CAR T cells are almost certain to become a frequently-used therapy for several types of lymphoma.»

The rapid advances in and growth of CAR T-cell therapy has exceeded the expectations of even those who were early believers in its potential.

«Did I think it could work? Yes,» Dr. Brentjens said. But he originally thought it would be a «boutique therapy» limited to a very petite, defined patient group. The practice over the past five years, including the entry of the biopharmaceutical industry into the field, has altered his outlook.

«We have cohorts of patients who would have been considered terminal who are now in durable and meaningful remissions with good quality of life for up to five years,» he continued. «So the enthusiasm for this technology is now fairly high.»

Understanding, Managing Side Effects

Like all cancer therapies, CAR T-cell therapy can cause several worrisome, and sometimes fatal, side effects. One of the most frequent is cytokine-release syndrome (CRS).

As part of their immune-related duties, T cells release cytokines, chemical messengers that help to stimulate and direct the immune response. In the case of CRS, there is a rapid and massive release of cytokines into the bloodstream, which can lead to unsafely high fevers and precipitous drops in blood pressure.

Ironically, CRS is considered an «on-target» effect of CAR T-cell therapy–that is, its presence demonstrates that active T cells are at work in the bod. Generally, patients with the most extensive disease prior to receiving CAR T cells are more likely to practice severe CRS, Dr. Kochenderfer explained.

In many patients, both children and adults, CRS can be managed with standard supportive therapies, including steroids. And as researchers have gained more practice with CAR T-cell therapy, they`ve learned how to better manage the more serious cases of CRS.

Several years ago, for example, the research team at CHOP noticed that patients experiencing severe CRS all had particularly high levels of IL-6, a cytokine that is secreted by T cells and macrophages in response to inflammation. So they turned to therapies that are approved to treat inflammatory conditions like juvenile arthritis, including the drug tocilizumab (Actemra®), which blocks IL-6 activity.

The treatment worked, rapidly resolving the problem in most patients. Since that time, tocilizumab has become a standard therapy for managing severe CRS.

«We`ve learned how to grade [CRS], we`ve learned how to treat it,» Dr. Grupp said during an FDA advisory committee meeting on Novartis` CD19-targeted therapy. «And IL-6 blockade was truly the key.»

Another potential side effect of CAR T-cell therapy–an off-target effect–is a mass die off of B cells, known as B-cell aplasia. CD19 is also voiced on normal B cells, which are responsible for producing antibodies that kill pathogens. These normal B cells are also often killed by the infused CAR T cells. To compensate, many patients must receive immunoglobulin therapy, which provides them with the necessary antibodies to fight off infections.

More recently, another serious and potentially fatal side effect–erection in the brain, or cerebral edema–has been seen in some of the larger trials being conducted to support potential FDA approval of CAR T-cell therapies for patients with advanced leukemias. One company, in fact, determined to halt further development of their leading CAR T-cell therapy after several patients in clinical trials died as a result of treatment-induced cerebral edema.

However, the problem emerges to be limited, with the leaders of other trials of CAR T-cell therapies reporting no instances of cerebral edema.

Other so-called neurotoxicities–such as confusion or seizure-like activity–have been seen in most CAR T-cell therapy trials. But in almost all patients the problem is brief lived and reversible, Dr. Brentjens said.

There was speculation early on that these neurotoxicities might be related to CRS. But albeit researchers are still attempting to get their palms around the mechanisms, he added, «I think most investigators [in the field] would agree that they`re distinct from CRS.»

CAR T cells and TCR T cells are engineered to produce special receptors on their surfaces. They are then expanded in the laboratory and returned to the patient.

Fresh Target Antigens for CAR T Cells

Research on CAR T cells is continuing at a swift rhythm, mostly in patients with blood cancers, but also in patients with solid tumors. As the biopharmaceutical industry has become more involved in the field, for example, the number of clinical trials testing CAR T cells has expanded dramatically, from just a handful five years ago to more than one hundred eighty and counting.

Most of the trials conducted to date have used CD19-targeted CAR T cells. But that`s switching quickly, in part out of necessity.

Some patients with ALL, for example, don`t react to the CD19-targeted therapy. And even in those who practice a accomplish response, up to a third will see their disease come back within a year, Dr. Fry said. Many of these disease recurrences have been linked to ALL cells` no longer voicing CD19, a phenomenon known as antigen loss.

So in children and youthful adults with advanced ALL, researchers in NCI`s POB are testing CAR T cells that target the CD22 protein, which is also often overexpressed by ALL cells. In the very first trial of CD22-targeted CAR T cells, most treated patients had finish remissions, including patients whose cancer had progressed after primarily having a finish response to CD19-targeted therapy.

Similar to the case with the CD19-targeted CAR T cells, however, relapses after CD22-targeted treatment are not uncommon, Dr. Fry explained.

«There is undoubtedly room to improve from the standpoint of the durability of remissions,» he said.

One potential way to improve durability and perhaps at least forestall antigen loss, if not prevent it altogether, is to at the same time attack numerous antigens. NCI researchers, for example, are developing T cells that target both CD19 and CD22. They hope to open a trial to test this fresh treatment before the end of 2017, Dr. Fry said.

CHOP researchers are also testing a CAR T cell that targets both CD19 and CD123, another antigen commonly found on leukemia cells. Early studies in animal models have suggested that this dual targeting may prevent antigen loss.

Antigen targets for CAR T-cell therapy have been identified in other blood cancers as well, including numerous myeloma.

Dr. Kochenderfer and his colleagues at NCI, as part of the collaboration with Kite, have developed CAR T cells that target the BCMA protein, which is found on almost all myeloma cells. Early results from a trial of the BCMA-targeted CAR T cells were positive, and Kite is moving ahead with testing the BCMA-targeted cells in a larger trial.

Expanding CAR T Cells to Solid Tumors?

There is some skepticism that CAR T cells will have the same success in solid tumors. Dr. Rosenberg believes that finding suitable antigens to target on solid tumors–which has been a major challenge–may prove to be too difficult in most cases.

«Efforts to identify unique antigens on the surface of solid tumors have largely been unsuccessful,» he said.

Researchers estimate that the breathtaking majority of tumor antigens reside inwards tumor cells, out of the reach of CARs, which can only truss to antigens on the cell surface.

As a result, as has already been shown in melanoma, Dr. Rosenberg said that he believes other forms of ACT may be better suited for solid tumors.

But that doesn`t mean that researchers aren`t attempting with CAR T cells.

For example, investigators are conducting trials of CAR T cells that target the protein mesothelin, which is overexpressed on tumor cells in some of the most deadly cancers, including pancreatic and lung cancers, and the protein EGFRvIII, which is present on almost all tumor cells in patients with the aggressive brain cancer glioblastoma.

Early reports from these trials, however, have not reported the same success that`s been seen with blood cancers.

«As far as targeting antigens on solid tumors the same way we go after CD19, I don`t think that`s going to work in most cases,» Dr. Brentjens acknowledged.

Another key obstacle with solid tumors, he explained, is that components of the microenvironment that surrounds them conspire to blunt the immune response.

So success against solid tumors may require a «super T cell,» he said, that has been engineered to overcome the immune-suppressing environment of many advanced solid tumors. Work on a CAR T cell with these properties–an «armored» CAR T cell–is ongoing at Memorial Sloan Kettering, he said.

CAR T cells have garnered the lion`s share of the attention when it comes to the cellular therapies that fall under the ACT umbrella. But other forms of ACT have also shown promise in puny clinical trials, including in patients with solid tumors.

One treatment uses immune cells that have penetrated the environment in and around the tumor, known as tumor-infiltrating lymphocytes (TILs). Researchers at NCI were the very first to use TILs to successfully treat patients with advanced cancer–primarily in melanoma and later in several other cancers, including cervical cancer. More recently, NCI researchers have developed a mechanism for identifying TILs that recognize cancer cells with mutations specific to that cancer. In several cases, this treatment has led to tumor regressions in patients with advanced colorectal and liver cancer.

The other primary treatment to ACT involves engineering patients` T cells to express a specific T-cell receptor (TCR). CARs use portions of synthetic antibodies that can recognize specific antigens only on the surface of cells. TCRs, on the other forearm, use naturally occurring receptors that can also recognize antigens that are inwards tumor cells. Puny chunks these antigens are shuttled to the cell surface and «introduced» to the immune system as part of a collection of proteins called the MHC sophisticated.

To date, TCR T cells have been tested in patients with a multiplicity of solid tumors, showcasing promise in melanoma and sarcoma.

Evolution of CAR T-Cell Therapies

Other refinements or reconfigurations of CAR T cells are being tested. One treatment is the development of CAR T-cell therapies that use immune cells collected not from patients, but from healthy donors. The idea is to create so-called off-the-shelf CAR T-cell therapies that are instantaneously available for use and don`t have to be manufactured for each patient.

The French company Cellectis, in fact, has already launched a phase I trial of its off-the-shelf CD19-targeted CAR T-cell product in the United States for patients with advanced acute myeloid leukemia. The company`s product–which is made using a gene-editing technology known as TALEN–has already been used in Europe, including in two infants with ALL who had fatigued all other treatment options. In both cases, the treatment was effective.

Numerous other approaches are under investigation. Researchers, for example, are using nanotechnology to create CAR T cells inwards the assets, developing CAR T cells with «off switches» as a means of preventing or limiting side effects like CRS, and using the gene-editing technology CRISPR/Cas9 to more precisely engineer the T cells.

But there is still more to do with existing CAR T-cell therapies, Dr. Fry said.

He is particularly enthusiastic about the potential to use CAR T cells earlier in the treatment process for children with ALL, specifically those who are at high risk (based on specific clinical factors) of their disease returning after their initial chemotherapy, which typically is given for approximately two and a half years.

In this screenplay, he explained, if early indicators suggested that these high-risk patients weren`t having an optimal response to chemotherapy, it could be stopped and the patients could be treated with CAR T cells.

For patients who react well, «they could be spared two more years of chemotherapy,» Dr. Fry said. «That`s amazing to think about.»

CAR T Cells: Engineering Immune Cells to Treat Cancer – National Cancer Institute

CAR T Cells: Engineering Patients’ Immune Cells to Treat Their Cancers

Co-stimulatory signaling domains have been added to newer generations of CAR T cells to improve their capability to produce more T cells after infusion and get through longer in the circulation.

A «Living Drug»

Once the collected T cells have been engineered to express the antigen-specific CAR, they are «expanded» in the laboratory into the hundreds of millions.

The final step is the infusion of the CAR T cells into the patient (which is preceded by a «lymphodepleting» chemotherapy regimen). If all goes as planned, the engineered cells further multiply in the patient`s figure and, with guidance from their engineered receptor, recognize and kill cancer cells that harbor the antigen on their surfaces.

The Making of a CAR T Cell

A growing number of CAR T-cell therapies are being developed and tested in clinical studies.

Advances have also been made in how long it takes to produce a batch of CAR T cells. Albeit it originally took several weeks, many labs have now diminished the time to less than seven days.

A Possible Option Where None Had Existed

The initial development of CAR T-cell therapies has focused largely on ALL, the most common cancer in children.

Relapsed ALL, in fact, is a leading cause of death from childhood cancer.

Dr. Grupp has led several trials of CAR T cells in children and youthfull adults with ALL that had recurred or was not responding to existing therapies. In one of these earlier trials, which used CD19-targeted CAR T cells, all signs of cancer disappeared (a accomplish response) in twenty seven of the thirty patients treated in the probe, with many of these patients continuing to showcase no signs of recurrence long after the treatment.

These early successes laid the foundation for a larger trial of a CD19-targeted CAR T-cell therapy, called tisagenlecleucel (Kymriah™), for children and adolescents with ALL. Many of the patients who participated in the trial, funded by Novartis, had accomplish and long-lasting remissions. Based on the trial results, FDA approved tisagenlecleucel in August 2017.

Similar results have been seen in trials of CD19-targeted CAR T cells led by researchers in CCR`s Pediatric Oncology Branch (POB).

The agency approving a fresh therapy in children before adults «is almost unheard of in cancer,» he said.

However, there is no shortage of promising data on CAR T cells used to treat adult patients with blood cancers. CD19-targeted CAR T cells have produced strong results not only in patients with ALL but also in patients with lymphomas. For example, in a puny NCI-led trial of CAR T cells primarily in patients with advanced diffuse large B-cell lymphoma, more than half had accomplish responses to the treatment.

The rapid advances in and growth of CAR T-cell therapy has exceeded the expectations of even those who were early believers in its potential.

«Did I think it could work? Yes,» Dr. Brentjens said. But he primarily thought it would be a «boutique therapy» limited to a very puny, defined patient group. The practice over the past five years, including the entry of the biopharmaceutical industry into the field, has altered his outlook.

Understanding, Managing Side Effects

Like all cancer therapies, CAR T-cell therapy can cause several worrisome, and sometimes fatal, side effects. One of the most frequent is cytokine-release syndrome (CRS).

As part of their immune-related duties, T cells release cytokines, chemical messengers that help to stimulate and direct the immune response. In the case of CRS, there is a rapid and massive release of cytokines into the bloodstream, which can lead to riskily high fevers and precipitous drops in blood pressure.

Ironically, CRS is considered an «on-target» effect of CAR T-cell therapy–that is, its presence demonstrates that active T cells are at work in the assets. Generally, patients with the most extensive disease prior to receiving CAR T cells are more likely to practice severe CRS, Dr. Kochenderfer explained.

The treatment worked, rapidly resolving the problem in most patients. Since that time, tocilizumab has become a standard therapy for managing severe CRS.

However, the problem shows up to be limited, with the leaders of other trials of CAR T-cell therapies reporting no instances of cerebral edema.

CAR T cells and TCR T cells are engineered to produce special receptors on their surfaces. They are then expanded in the laboratory and returned to the patient.

Fresh Target Antigens for CAR T Cells

Research on CAR T cells is continuing at a swift tempo, mostly in patients with blood cancers, but also in patients with solid tumors. As the biopharmaceutical industry has become more involved in the field, for example, the number of clinical trials testing CAR T cells has expanded dramatically, from just a handful five years ago to more than one hundred eighty and counting.

Most of the trials conducted to date have used CD19-targeted CAR T cells. But that`s switching quickly, in part out of necessity.

So in children and youthfull adults with advanced ALL, researchers in NCI`s POB are testing CAR T cells that target the CD22 protein, which is also often overexpressed by ALL cells. In the very first trial of CD22-targeted CAR T cells, most treated patients had accomplish remissions, including patients whose cancer had progressed after originally having a accomplish response to CD19-targeted therapy.

Similar to the case with the CD19-targeted CAR T cells, however, relapses after CD22-targeted treatment are not uncommon, Dr. Fry explained.

«There is certainly room to improve from the standpoint of the durability of remissions,» he said.

Antigen targets for CAR T-cell therapy have been identified in other blood cancers as well, including numerous myeloma.

Expanding CAR T Cells to Solid Tumors?

«Efforts to identify unique antigens on the surface of solid tumors have largely been unsuccessful,» he said.

Researchers estimate that the tremendous majority of tumor antigens reside inwards tumor cells, out of the reach of CARs, which can only truss to antigens on the cell surface.

As a result, as has already been shown in melanoma, Dr. Rosenberg said that he believes other forms of ACT may be better suited for solid tumors.

But that doesn`t mean that researchers aren`t attempting with CAR T cells.

Early reports from these trials, however, have not reported the same success that`s been seen with blood cancers.

«As far as targeting antigens on solid tumors the same way we go after CD19, I don`t think that`s going to work in most cases,» Dr. Brentjens acknowledged.

Another key obstacle with solid tumors, he explained, is that components of the microenvironment that surrounds them conspire to blunt the immune response.

CAR T cells have garnered the lion`s share of the attention when it comes to the cellular therapies that fall under the ACT umbrella. But other forms of ACT have also shown promise in petite clinical trials, including in patients with solid tumors.

The other primary treatment to ACT involves engineering patients` T cells to express a specific T-cell receptor (TCR). CARs use portions of synthetic antibodies that can recognize specific antigens only on the surface of cells. TCRs, on the other palm, use naturally occurring receptors that can also recognize antigens that are inwards tumor cells. Petite chunks these antigens are shuttled to the cell surface and «introduced» to the immune system as part of a collection of proteins called the MHC complicated.

To date, TCR T cells have been tested in patients with a multitude of solid tumors, demonstrating promise in melanoma and sarcoma.

Evolution of CAR T-Cell Therapies

Other refinements or reconfigurations of CAR T cells are being tested. One treatment is the development of CAR T-cell therapies that use immune cells collected not from patients, but from healthy donors. The idea is to create so-called off-the-shelf CAR T-cell therapies that are instantly available for use and don`t have to be manufactured for each patient.

The French company Cellectis, in fact, has already launched a phase I trial of its off-the-shelf CD19-targeted CAR T-cell product in the United States for patients with advanced acute myeloid leukemia. The company`s product–which is made using a gene-editing technology known as TALEN–has already been used in Europe, including in two infants with ALL who had tired all other treatment options. In both cases, the treatment was effective.

Numerous other approaches are under investigation. Researchers, for example, are using nanotechnology to create CAR T cells inwards the figure, developing CAR T cells with «off switches» as a means of preventing or limiting side effects like CRS, and using the gene-editing technology CRISPR/Cas9 to more precisely engineer the T cells.

But there is still more to do with existing CAR T-cell therapies, Dr. Fry said.

For patients who react well, «they could be spared two more years of chemotherapy,» Dr. Fry said. «That`s amazing to think about.»

CAR T Cells: Engineering Immune Cells to Treat Cancer – National Cancer Institute

CAR T Cells: Engineering Patients’ Immune Cells to Treat Their Cancers

Co-stimulatory signaling domains have been added to newer generations of CAR T cells to improve their capability to produce more T cells after infusion and get through longer in the circulation.

Until recently, the use of CAR T-cell therapy has been restricted to puny clinical trials, largely in patients with advanced blood cancers. But these treatments have nevertheless captured the attention of researchers and the public alike because of the remarkable responses they have produced in some patients–both children and adults–for whom all other treatments had stopped working.

One CAR T-cell therapy was approved in August two thousand seventeen for the treatment of children with acute lymphoblastic leukemia (ALL). And a 2nd, for adults with advanced lymphomas, may be close behind. Nevertheless, researchers caution that, in many respects, it`s still early days for CAR T cells and other forms of ACT, including questions about whether they will ever be effective against solid tumors like breast and colorectal cancer.

«In the next few years,» he said, «I think we`re going to see dramatic progress and thrust the boundaries of what many people thought was possible with these adoptive cell transfer–based treatments.»

A «Living Drug»

Once the collected T cells have been engineered to express the antigen-specific CAR, they are «expanded» in the laboratory into the hundreds of millions.

The final step is the infusion of the CAR T cells into the patient (which is preceded by a «lymphodepleting» chemotherapy regimen). If all goes as planned, the engineered cells further multiply in the patient`s bod and, with guidance from their engineered receptor, recognize and kill cancer cells that harbor the antigen on their surfaces.

The Making of a CAR T Cell

A growing number of CAR T-cell therapies are being developed and tested in clinical studies.

Advances have also been made in how long it takes to produce a batch of CAR T cells. Albeit it primarily took several weeks, many labs have now diminished the time to less than seven days.

A Possible Option Where None Had Existed

The initial development of CAR T-cell therapies has focused largely on ALL, the most common cancer in children.

More than 80% of children diagnosed with ALL that arises in B cells–the predominant type of pediatric ALL–will be cured by intensive chemotherapy. But for patients whose cancers comeback after chemotherapy or a stem cell transplant, the treatment options are «close to none,» said Stephan Grupp, M.D., Ph.D., of the Children`s Hospital of Philadelphia (CHOP).

Relapsed ALL, in fact, is a leading cause of death from childhood cancer.

Dr. Grupp has led several trials of CAR T cells in children and youthfull adults with ALL that had recurred or was not responding to existing therapies. In one of these earlier trials, which used CD19-targeted CAR T cells, all signs of cancer disappeared (a accomplish response) in twenty seven of the thirty patients treated in the probe, with many of these patients continuing to demonstrate no signs of recurrence long after the treatment.

These early successes laid the foundation for a larger trial of a CD19-targeted CAR T-cell therapy, called tisagenlecleucel (Kymriah™), for children and adolescents with ALL. Many of the patients who participated in the trial, funded by Novartis, had accomplish and long-lasting remissions. Based on the trial results, FDA approved tisagenlecleucel in August 2017.

Similar results have been seen in trials of CD19-targeted CAR T cells led by researchers in CCR`s Pediatric Oncology Branch (POB).

The progress made with CAR T-cell therapy in children with ALL «has been fantastic,» said Terry Fry, M.D., a lead investigator on several POB trials of CAR T cells. CD19-targeted CAR T cells were primarily tested in adults. But the fact that the very first approval is for a therapy for children and adolescents with ALL is a watershed moment, Dr. Fry continued.

The agency approving a fresh therapy in children before adults «is almost unheard of in cancer,» he said.

The rapid advances in and growth of CAR T-cell therapy has exceeded the expectations of even those who were early believers in its potential.

«Did I think it could work? Yes,» Dr. Brentjens said. But he primarily thought it would be a «boutique therapy» limited to a very petite, defined patient group. The practice over the past five years, including the entry of the biopharmaceutical industry into the field, has altered his outlook.

Understanding, Managing Side Effects

Like all cancer therapies, CAR T-cell therapy can cause several worrisome, and sometimes fatal, side effects. One of the most frequent is cytokine-release syndrome (CRS).

Ironically, CRS is considered an «on-target» effect of CAR T-cell therapy–that is, its presence demonstrates that active T cells are at work in the figure. Generally, patients with the most extensive disease prior to receiving CAR T cells are more likely to practice severe CRS, Dr. Kochenderfer explained.

The treatment worked, rapidly resolving the problem in most patients. Since that time, tocilizumab has become a standard therapy for managing severe CRS.

However, the problem emerges to be limited, with the leaders of other trials of CAR T-cell therapies reporting no instances of cerebral edema.

There was speculation early on that these neurotoxicities might be related to CRS. But albeit researchers are still attempting to get their arms around the mechanisms, he added, «I think most investigators [in the field] would agree that they`re distinct from CRS.»

CAR T cells and TCR T cells are engineered to produce special receptors on their surfaces. They are then expanded in the laboratory and returned to the patient.

Fresh Target Antigens for CAR T Cells

Most of the trials conducted to date have used CD19-targeted CAR T cells. But that`s switching quickly, in part out of necessity.

Some patients with ALL, for example, don`t react to the CD19-targeted therapy. And even in those who practice a finish response, up to a third will see their disease come back within a year, Dr. Fry said. Many of these disease recurrences have been linked to ALL cells` no longer voicing CD19, a phenomenon known as antigen loss.

Similar to the case with the CD19-targeted CAR T cells, however, relapses after CD22-targeted treatment are not uncommon, Dr. Fry explained.

«There is certainly room to improve from the standpoint of the durability of remissions,» he said.

Antigen targets for CAR T-cell therapy have been identified in other blood cancers as well, including numerous myeloma.

Expanding CAR T Cells to Solid Tumors?

«Efforts to identify unique antigens on the surface of solid tumors have largely been unsuccessful,» he said.

Researchers estimate that the staggering majority of tumor antigens reside inwards tumor cells, out of the reach of CARs, which can only tie to antigens on the cell surface.

As a result, as has already been shown in melanoma, Dr. Rosenberg said that he believes other forms of ACT may be better suited for solid tumors.

But that doesn`t mean that researchers aren`t attempting with CAR T cells.

Early reports from these trials, however, have not reported the same success that`s been seen with blood cancers.

«As far as targeting antigens on solid tumors the same way we go after CD19, I don`t think that`s going to work in most cases,» Dr. Brentjens acknowledged.

Another key obstacle with solid tumors, he explained, is that components of the microenvironment that surrounds them conspire to blunt the immune response.

One treatment uses immune cells that have penetrated the environment in and around the tumor, known as tumor-infiltrating lymphocytes (TILs). Researchers at NCI were the very first to use TILs to successfully treat patients with advanced cancer–originally in melanoma and later in several other cancers, including cervical cancer. More recently, NCI researchers have developed a technology for identifying TILs that recognize cancer cells with mutations specific to that cancer. In several cases, this treatment has led to tumor regressions in patients with advanced colorectal and liver cancer.

The other primary treatment to ACT involves engineering patients` T cells to express a specific T-cell receptor (TCR). CARs use portions of synthetic antibodies that can recognize specific antigens only on the surface of cells. TCRs, on the other mitt, use naturally occurring receptors that can also recognize antigens that are inwards tumor cells. Puny lumps these antigens are shuttled to the cell surface and «introduced» to the immune system as part of a collection of proteins called the MHC complicated.

To date, TCR T cells have been tested in patients with a multitude of solid tumors, displaying promise in melanoma and sarcoma.

Evolution of CAR T-Cell Therapies

The French company Cellectis, in fact, has already launched a phase I trial of its off-the-shelf CD19-targeted CAR T-cell product in the United States for patients with advanced acute myeloid leukemia. The company`s product–which is made using a gene-editing technology known as TALEN–has already been used in Europe, including in two infants with ALL who had weary all other treatment options. In both cases, the treatment was effective.

But there is still more to do with existing CAR T-cell therapies, Dr. Fry said.

In this script, he explained, if early indicators suggested that these high-risk patients weren`t having an optimal response to chemotherapy, it could be stopped and the patients could be treated with CAR T cells.

For patients who react well, «they could be spared two more years of chemotherapy,» Dr. Fry said. «That`s amazing to think about.»

CAR T Cells: Engineering Immune Cells to Treat Cancer – National Cancer Institute

CAR T Cells: Engineering Patients’ Immune Cells to Treat Their Cancers

Co-stimulatory signaling domains have been added to newer generations of CAR T cells to improve their capability to produce more T cells after infusion and sustain longer in the circulation.

A «Living Drug»

Once the collected T cells have been engineered to express the antigen-specific CAR, they are «expanded» in the laboratory into the hundreds of millions.

The Making of a CAR T Cell

A growing number of CAR T-cell therapies are being developed and tested in clinical studies.

Advances have also been made in how long it takes to produce a batch of CAR T cells. Albeit it originally took several weeks, many labs have now diminished the time to less than seven days.

A Possible Option Where None Had Existed

The initial development of CAR T-cell therapies has focused largely on ALL, the most common cancer in children.

Relapsed ALL, in fact, is a leading cause of death from childhood cancer.

Dr. Grupp has led several trials of CAR T cells in children and youthful adults with ALL that had recurred or was not responding to existing therapies. In one of these earlier trials, which used CD19-targeted CAR T cells, all signs of cancer disappeared (a finish response) in twenty seven of the thirty patients treated in the examine, with many of these patients continuing to showcase no signs of recurrence long after the treatment.

These early successes laid the foundation for a larger trial of a CD19-targeted CAR T-cell therapy, called tisagenlecleucel (Kymriah™), for children and adolescents with ALL. Many of the patients who participated in the trial, funded by Novartis, had accomplish and long-lasting remissions. Based on the trial results, FDA approved tisagenlecleucel in August 2017.

Similar results have been seen in trials of CD19-targeted CAR T cells led by researchers in CCR`s Pediatric Oncology Branch (POB).

The agency approving a fresh therapy in children before adults «is almost unheard of in cancer,» he said.

However, there is no shortage of promising data on CAR T cells used to treat adult patients with blood cancers. CD19-targeted CAR T cells have produced strong results not only in patients with ALL but also in patients with lymphomas. For example, in a puny NCI-led trial of CAR T cells primarily in patients with advanced diffuse large B-cell lymphoma, more than half had accomplish responses to the treatment.

The results in lymphoma to date «have been amazingly successful,» Dr. Kochenderfer said, «and CAR T cells are almost certain to become a frequently-used therapy for several types of lymphoma.»

The rapid advances in and growth of CAR T-cell therapy has exceeded the expectations of even those who were early believers in its potential.

«Did I think it could work? Yes,» Dr. Brentjens said. But he originally thought it would be a «boutique therapy» limited to a very puny, defined patient group. The practice over the past five years, including the entry of the biopharmaceutical industry into the field, has altered his outlook.

Understanding, Managing Side Effects

Like all cancer therapies, CAR T-cell therapy can cause several worrisome, and sometimes fatal, side effects. One of the most frequent is cytokine-release syndrome (CRS).

As part of their immune-related duties, T cells release cytokines, chemical messengers that help to stimulate and direct the immune response. In the case of CRS, there is a rapid and massive release of cytokines into the bloodstream, which can lead to riskily high fevers and precipitous drops in blood pressure.

The treatment worked, rapidly resolving the problem in most patients. Since that time, tocilizumab has become a standard therapy for managing severe CRS.

More recently, another serious and potentially fatal side effect–full salute in the brain, or cerebral edema–has been seen in some of the larger trials being conducted to support potential FDA approval of CAR T-cell therapies for patients with advanced leukemias. One company, in fact, determined to halt further development of their leading CAR T-cell therapy after several patients in clinical trials died as a result of treatment-induced cerebral edema.

However, the problem shows up to be limited, with the leaders of other trials of CAR T-cell therapies reporting no instances of cerebral edema.

There was speculation early on that these neurotoxicities might be related to CRS. But albeit researchers are still attempting to get their mitts around the mechanisms, he added, «I think most investigators [in the field] would agree that they`re distinct from CRS.»

CAR T cells and TCR T cells are engineered to produce special receptors on their surfaces. They are then expanded in the laboratory and returned to the patient.

Fresh Target Antigens for CAR T Cells

Most of the trials conducted to date have used CD19-targeted CAR T cells. But that`s switching quickly, in part out of necessity.

Some patients with ALL, for example, don`t react to the CD19-targeted therapy. And even in those who practice a finish response, up to a third will see their disease comeback within a year, Dr. Fry said. Many of these disease recurrences have been linked to ALL cells` no longer voicing CD19, a phenomenon known as antigen loss.

So in children and youthful adults with advanced ALL, researchers in NCI`s POB are testing CAR T cells that target the CD22 protein, which is also often overexpressed by ALL cells. In the very first trial of CD22-targeted CAR T cells, most treated patients had accomplish remissions, including patients whose cancer had progressed after originally having a accomplish response to CD19-targeted therapy.

Similar to the case with the CD19-targeted CAR T cells, however, relapses after CD22-targeted treatment are not uncommon, Dr. Fry explained.

«There is undoubtedly room to improve from the standpoint of the durability of remissions,» he said.

Antigen targets for CAR T-cell therapy have been identified in other blood cancers as well, including numerous myeloma.

Expanding CAR T Cells to Solid Tumors?

«Efforts to identify unique antigens on the surface of solid tumors have largely been unsuccessful,» he said.

Researchers estimate that the breathtaking majority of tumor antigens reside inwards tumor cells, out of the reach of CARs, which can only tie to antigens on the cell surface.

As a result, as has already been shown in melanoma, Dr. Rosenberg said that he believes other forms of ACT may be better suited for solid tumors.

But that doesn`t mean that researchers aren`t attempting with CAR T cells.

Early reports from these trials, however, have not reported the same success that`s been seen with blood cancers.

«As far as targeting antigens on solid tumors the same way we go after CD19, I don`t think that`s going to work in most cases,» Dr. Brentjens acknowledged.

Another key obstacle with solid tumors, he explained, is that components of the microenvironment that surrounds them conspire to blunt the immune response.

The other primary treatment to ACT involves engineering patients` T cells to express a specific T-cell receptor (TCR). CARs use portions of synthetic antibodies that can recognize specific antigens only on the surface of cells. TCRs, on the other mitt, use naturally occurring receptors that can also recognize antigens that are inwards tumor cells. Puny lumps these antigens are shuttled to the cell surface and «introduced» to the immune system as part of a collection of proteins called the MHC sophisticated.

To date, TCR T cells have been tested in patients with a multitude of solid tumors, showcasing promise in melanoma and sarcoma.

Evolution of CAR T-Cell Therapies

Other refinements or reconfigurations of CAR T cells are being tested. One treatment is the development of CAR T-cell therapies that use immune cells collected not from patients, but from healthy donors. The idea is to create so-called off-the-shelf CAR T-cell therapies that are instantly available for use and don`t have to be manufactured for each patient.

The French company Cellectis, in fact, has already launched a phase I trial of its off-the-shelf CD19-targeted CAR T-cell product in the United States for patients with advanced acute myeloid leukemia. The company`s product–which is made using a gene-editing technology known as TALEN–has already been used in Europe, including in two infants with ALL who had weary all other treatment options. In both cases, the treatment was effective.

But there is still more to do with existing CAR T-cell therapies, Dr. Fry said.

For patients who react well, «they could be spared two more years of chemotherapy,» Dr. Fry said. «That`s amazing to think about.»

CAR T Cells: Engineering Immune Cells to Treat Cancer – National Cancer Institute

CAR T Cells: Engineering Patients’ Immune Cells to Treat Their Cancers

Co-stimulatory signaling domains have been added to newer generations of CAR T cells to improve their capability to produce more T cells after infusion and get through longer in the circulation.

A «Living Drug»

These special receptors permit the T cells to recognize and fasten to a specific protein, or antigen, on tumor cells. The CAR T cell therapies furthest along in development target an antigen found on B cells called CD19 (see «The Making of a CAR T Cell»).

Once the collected T cells have been engineered to express the antigen-specific CAR, they are «expanded» in the laboratory into the hundreds of millions.

The Making of a CAR T Cell

A growing number of CAR T-cell therapies are being developed and tested in clinical studies.

Advances have also been made in how long it takes to produce a batch of CAR T cells. Albeit it primarily took several weeks, many labs have now diminished the time to less than seven days.

A Possible Option Where None Had Existed

The initial development of CAR T-cell therapies has focused largely on ALL, the most common cancer in children.

More than 80% of children diagnosed with ALL that arises in B cells–the predominant type of pediatric ALL–will be cured by intensive chemotherapy. But for patients whose cancers comeback after chemotherapy or a stem cell transplant, the treatment options are «close to none,» said Stephan Grupp, M.D., Ph.D., of the Children`s Hospital of Philadelphia (CHOP).

Relapsed ALL, in fact, is a leading cause of death from childhood cancer.

Dr. Grupp has led several trials of CAR T cells in children and youthfull adults with ALL that had recurred or was not responding to existing therapies. In one of these earlier trials, which used CD19-targeted CAR T cells, all signs of cancer disappeared (a finish response) in twenty seven of the thirty patients treated in the examine, with many of these patients continuing to demonstrate no signs of recurrence long after the treatment.