Cover Story

Driving Killer CARs into Cancer

Automobile pioneer Henry Ford once said of his best-selling Model T, “Any customer can have a car painted any color that he wants so long as its black.” Ford did not mean that all his Model Ts would be one color, but that by selling one model with few customizations on a massive scale, it would bring down the price of each unit to make them more affordable.

If it was an automobile, chimeric antigen receptor T-cell therapy would be a Maserati: exciting, personalized, and very expensive. The Model T was, by comparison, inexpensive and practical. You can make more money per unit if you sell those exotic Italian engineering marvels, but you cannot put one in millions of driveways like Henry Ford did.

In the world of cancer treatment, modified natural killer (NK) cells may serve as the bridge between specifically engineered splendor and mass-produced practicality. The aim of those studying how to use these cells for cancer treatment is to bring them to patients faster, with fewer toxic side effects, and for a wider array of indications.

Patel (left) and Kaufman (right)
Patel (left) and Kaufman (right) enjoy a light-hearted moment before patient Derek Ruff receives the first treatment of FT500.

Source: UC San Diego Health

Alone, or in Combination

Much like a T cell, an NK cell is a type of immune cell. NK cells are a type of white blood cell that have granules with enzymes that can kill tumor or virally infected cells.

There are many strategies currently being tested in clinical trials using NK cells to treat various forms of cancer, including unmodified NK cells, modified NK cells, NK T cells, NK-CARs and NKT CARs.

“NK cells represent an innate pathway that are in hematopoietically derived tissues in the blood, whereas an NKT cell is what’s in the middle of T cells and NK cells before they are assigned a specific function,” William J. Murphy, PhD, a professor of dermatology and vice chair of research at UC Davis School of Medicine, told Cell Therapy Next.

Murphy, who has been researching NK cells for more than 30 years, further explained that NKT cells have some of the properties of an NK cell, but with more of the immunomodulatory and longevity properties of a T cell.

“NK cells, as a rule, do not have the classic memory and a rapid turnover in life, being constantly generated from the bone marrow, whereas NKT cells tend to have longer-lasting function,” he added.

Investigators at Baylor College of Medicine are currently testing the efficacy of CAR-modified NKTs for pediatric neuroblastoma, while researchers at The University of Texas MD Anderson Cancer Center are looking at cord-blood derived CAR-modified NK cells for B-cell malignancies.

Researchers at the University of California San Diego School of Medicine are testing whether induced pluripotent stem cell (iPSC)-derived NK cells can be used to treat cancer and have recently begun a first-in-human clinical trial (NCT0384110) of an investigational NK cell-based therapy (FT500) developed by Fate Therapeutics.

Sandip P. Patel, MD
Sandip Patel

Sandip P. Patel, MD, an oncologist and associate professor of medicine at UC San Diego Moores Cancer Center, is one of the primary investigators of the phase 1 trial for FT500. He told Cell Therapy Next what makes this treatment approach novel compared with CAR T-cell therapy is that these cells come from a different arm of the immune system.

“One of the potential issues with T cells is that you can’t take them from one person and give them to another unedited, or you will end up with a graft-versus-host disease,” Patel said. “An NK cell can be taken from one person and given to another because NK cells do not require matched HLA to recognize and kill a tumor target.”

Patel said one issue with NK cell therapies, such as NK92, is that the cell lines currently being used are more often an exhausted phenotype derived from radiated lymphoma lines that may not be as good at killing cancer. Stem cell-derived NK cells, such as FT500, might circumvent this problem because they come from a clone that was selected for universal and consistent high function.

“The idea behind an induced pluripotent stem cell-derived NK cell product is that it allows both the advantages of a more robust NK cell population but also the ability to engineer these NK cells because there is a master bank of these self-renewing cells. It allows for the development of novel engineered constructs that utilize NK cells as a base,” he said. “NK cells have an advantage because they are amenable to off-the-shelf strategies and can be given to a variety of patients.”

Chasing an ‘Off-the-Shelf’ Option

The research behind FT500 comes from decades of work by Dan Kaufman, MD, PhD, professor of medicine in the division of regenerative medicine and director of cell therapy at UC San Diego School of Medicine, and his long-time colleague Jeffrey Miller, MD, professor of medicine and deputy director of the University of Minnesota’s Masonic Cancer Center. Miller said his lab started administering allogeneic NK cell therapies almost two decades ago and has likely given more NK infusions than any other lab. He explained for Cell Therapy Next the advantages allogeneic NK cell therapy has over CAR T-cell therapy.

“The biggest difference, when compared with iPSC-derived NK cells, is we are talking about a truly off-the-shelf allogeneic product.” Much like CAR T-cell therapy, iPSC-derived NK cells are a living drug, but it has advantages that allow for multiple dosing strategies that are likely unattainable by current CAR T-cell technology.

“It’s very, very different from CAR T, which we know is roughly a half million dollars per dose,” Miller said. “CAR T has both economic and portability issues to deal with,” he added.

“iPSC-derived NK cells can be cryopreserved, and you can manufacture hundreds of doses, right now, in a single manufacturing run.”

Dan Kaufman, MD, PhD
Dan Kaufman

There is one caveat to all these alleged advantages: it is provided that the cells work as an effective treatment for cancer, and Miller reminded us that data on its safety and effectiveness are still preliminary.

“The main difference between NK cells and T cells is that NK cells can normally function as allogeneic cells — they don’t have to be matched to a specific patient,” Kaufman, a faculty member of both the Sanford Consortium for Regenerative Medicine and the Sandford Stem Cell Clinical Center at UC San Diego Health, told Cell Therapy Next. Conversely, he explained, the CAR T-cell process can take 3 or more weeks, and only a small fraction of patients will qualify for the treatment.

Kaufman reiterated that NK cells have been used as a successful immunotherapy to treat AML for almost 2 decades and that NK cells do not have to be matched to a specific patient.

“We can make these in the lab,” he said, adding that “they can be a standardized, off-the-shelf product.”

Murphy, however, warned that there are trade-off issues to consider when comparing allogenic and autologous cell therapies.

“First, if you are doing it autologously, which will always be the best because there won’t be rejection by the patient, it is problematic because by the time patients receive these therapies, they are usually older and more immunosuppressed, and their immune activity will be much more limited. If you do them at the source, like an off-the-shelf allogeneic type, that gives you a lot more flexibility on time and cost, but you will need to immune suppress the patient to allow those cells to graft and that represents a problem.”

Then there is an issue of sustainable responses, Murphy added. CAR T-cell therapy has been a game changer because it allows for the continuous triggering of a receptor and a response that keeps the T cell alive to attack tumors.

“The biggest challenge to off-the-shelf cell therapy will always be sustainability because no matter how they are engineered, cells from another source will elicit an immune response,” Murphy said.

“The immune system seems to be exquisitely sensitive to cells from another individual, and that represents a real hurdle. The balance between off-the-shelf and autologous is that for off the shelf, it needs to produce its anti-tumor effects over a short period of time, whereas autologous T-cell therapies like CAR T have been successful because they are allowed to remain for a longer period of time and the tumor does not have a chance to escape.”

William J. Murphy, PhD
William J. Murphy

Less Toxic CARs

A new anti-cancer agent must balance its ability to fight the disease with its potential toxic side effects. It is in this area that NK cells may have a potential advantage over current CAR T-cell therapies. It may be that switching out T cells for NK cells and engineering them with modified CARs could produce less of the neurotoxicity and cytokine release syndrome that has been observed with CAR T-cell therapy.

“While there are some key advantages for T-cell immunotherapy, CAR-directed NK cells offer an alternative treatment modality that could overcome some of the challenges associated with T-cell CARs, most prominent among them is the manifestation of life-threatening toxicities which have led to the termination of clinical trials and drug development programs,” Murphy and colleagues wrote in a 2017 review in Immunotherapy.

“The fact that, unlike T cells, NK cells are generally perceived to be short-lived effector cells, which do not undergo clonal expansion, may allow CAR-directed NK cells to be utilized with less fear for the development of autoimmunity or adverse toxicities associated with rampant T-cell expansion that can occur in patients receiving CAR-T,” they added.

Murphy told Cell Therapy Next that not enough is known about the biology of NK or NKT cells, but the research continues. He said that what makes NK cells attractive as an anti-cancer therapy is, they can limit the activity of T cells and associated toxicities, which lends itself to combining CARs with NK cells and the potential for less toxic cell-based therapies.

“One of the problems with T cells is that they release so many cytokines when they are stimulated,” Miller said. “This is based on preclinical data, but the speculation is that there will be a better safety profile for allogeneic NK cell therapy then we are currently seeing with CAR T.”

Alternate or Replacement Therapy?

Not all vehicles run on gasoline. Some use diesel, others use electricity, and some are still tinkering with hydrogen-based fuels. Just as the automobile has undergone continuous development, perhaps research on the usefulness of NK cells is not about replacing CAR-T, but rather widening the fleet of available vehicles to treat cancer. Perhaps given NK cells’ ability to avoid the immune response that causes the toxic side effects of CAR T-cell therapy, research may lead us to one day strap CARs on NK cells and drive killer CARs into solid tumors.

Kaufman does not see NK cells as a complete replacement for CAR T-cell therapy. Instead, he predicted that different cell-based products will have different roles in treating various forms of cancer.

FT500 is just one product that Fate Therapeutics is working on in the area of NK cells. While FT500 is an unmodified cell therapy, another investigational therapy, called FT516, is a genetically modified product designed to express CD16 in a stabilized fashion. A third product under development, FT596, is an NK cell therapy with an anti-CD19 CAR combined with a CD16 molecule and an IL-15 fusion protein to provide further anti-tumor activity and persistence.

“It’s likely that different products will be used to target certain tumors with different receptors,” Kaufman said.

Patel said it is hard to predict whether NK cells will be an alternative or a replacement for CAR T-cell therapy until some NK cell therapies are approved and comparison studies are conducted.

“My sense is there will be situations where a CAR T approach is more effective, or other situations where an NK approach or CAR NK approach is more efficacious,” he said.

“We will have to see where the data lead us, and determine which modality is best for treating a particular type of cancer, and which one has the best risk–benefit ratio for treating the disease. Cell therapies have major toxicities, both medical and financial, so anything that reduces both is attractive.”

Murphy pointed to the financial issues that surround autologous CAR T-cell therapy and says whatever direction the field takes, the issue of cost must be addressed.

“We need to either figure out ways to have a universal donor to avoid rejection, or the field will have to develop a way to do more cost-effective autologous CARs in humans. The cost issues not only revolve around manufacturing, but the large amount of toxicities that result in the need for acute post-treatment care,” Murphy noted.

“In the end, we need a product that is both durable and sustainable in the body, with an acceptable amount of toxicity.”

Kaufman took pause and reflected on the reality of the situation — cell therapy is not a new frontier, but rather a maturing field. “People tend to think that cell therapy is a new thing, but we have been doing bone marrow transplants as a form of cell therapy for over 40 to 50 years,” he said with a laugh.

The only difference is that CAR T cells have popularized the field of cell therapy, and captivated a public looking for lab coat-wearing heroes who can cure cancer. CAR T-cell therapy was not the invention of cell therapy, but it has ushered in an era where it may have more widespread application.

“We are still in the first stages of these new targeted cell therapies. However, the way we are doing it now, I can almost guarantee we won’t be doing it the same way 10 or 20 years from now,” Kaufman said.

“CAR T cells were a great first step in the right direction, but people are coming up with different versions — whether they be NK cells or other modified cell therapies — so there will be many more strategies to choose from going forward.” – by Drew Amorosi

Disclosures: Miller reports a consulting role and research funding from Fate Therapeutics and GT Biopharma. Kaufman reports consulting/advisory roles, research funding and income, stock options and royalties from Fate Therapeutics. Murphy and Patel report no relevant financial disclosures.

Click here to read Cell Therapy Next’s interview with Yu-Wayne “Wayne” Chu, VP of clinical development for Fate Therapeutics.

Automobile pioneer Henry Ford once said of his best-selling Model T, “Any customer can have a car painted any color that he wants so long as its black.” Ford did not mean that all his Model Ts would be one color, but that by selling one model with few customizations on a massive scale, it would bring down the price of each unit to make them more affordable.

If it was an automobile, chimeric antigen receptor T-cell therapy would be a Maserati: exciting, personalized, and very expensive. The Model T was, by comparison, inexpensive and practical. You can make more money per unit if you sell those exotic Italian engineering marvels, but you cannot put one in millions of driveways like Henry Ford did.

In the world of cancer treatment, modified natural killer (NK) cells may serve as the bridge between specifically engineered splendor and mass-produced practicality. The aim of those studying how to use these cells for cancer treatment is to bring them to patients faster, with fewer toxic side effects, and for a wider array of indications.

Patel (left) and Kaufman (right)
Patel (left) and Kaufman (right) enjoy a light-hearted moment before patient Derek Ruff receives the first treatment of FT500.

Source: UC San Diego Health

Alone, or in Combination

Much like a T cell, an NK cell is a type of immune cell. NK cells are a type of white blood cell that have granules with enzymes that can kill tumor or virally infected cells.

There are many strategies currently being tested in clinical trials using NK cells to treat various forms of cancer, including unmodified NK cells, modified NK cells, NK T cells, NK-CARs and NKT CARs.

“NK cells represent an innate pathway that are in hematopoietically derived tissues in the blood, whereas an NKT cell is what’s in the middle of T cells and NK cells before they are assigned a specific function,” William J. Murphy, PhD, a professor of dermatology and vice chair of research at UC Davis School of Medicine, told Cell Therapy Next.

Murphy, who has been researching NK cells for more than 30 years, further explained that NKT cells have some of the properties of an NK cell, but with more of the immunomodulatory and longevity properties of a T cell.

“NK cells, as a rule, do not have the classic memory and a rapid turnover in life, being constantly generated from the bone marrow, whereas NKT cells tend to have longer-lasting function,” he added.

PAGE BREAK

Investigators at Baylor College of Medicine are currently testing the efficacy of CAR-modified NKTs for pediatric neuroblastoma, while researchers at The University of Texas MD Anderson Cancer Center are looking at cord-blood derived CAR-modified NK cells for B-cell malignancies.

Researchers at the University of California San Diego School of Medicine are testing whether induced pluripotent stem cell (iPSC)-derived NK cells can be used to treat cancer and have recently begun a first-in-human clinical trial (NCT0384110) of an investigational NK cell-based therapy (FT500) developed by Fate Therapeutics.

Sandip P. Patel, MD
Sandip Patel

Sandip P. Patel, MD, an oncologist and associate professor of medicine at UC San Diego Moores Cancer Center, is one of the primary investigators of the phase 1 trial for FT500. He told Cell Therapy Next what makes this treatment approach novel compared with CAR T-cell therapy is that these cells come from a different arm of the immune system.

“One of the potential issues with T cells is that you can’t take them from one person and give them to another unedited, or you will end up with a graft-versus-host disease,” Patel said. “An NK cell can be taken from one person and given to another because NK cells do not require matched HLA to recognize and kill a tumor target.”

Patel said one issue with NK cell therapies, such as NK92, is that the cell lines currently being used are more often an exhausted phenotype derived from radiated lymphoma lines that may not be as good at killing cancer. Stem cell-derived NK cells, such as FT500, might circumvent this problem because they come from a clone that was selected for universal and consistent high function.

“The idea behind an induced pluripotent stem cell-derived NK cell product is that it allows both the advantages of a more robust NK cell population but also the ability to engineer these NK cells because there is a master bank of these self-renewing cells. It allows for the development of novel engineered constructs that utilize NK cells as a base,” he said. “NK cells have an advantage because they are amenable to off-the-shelf strategies and can be given to a variety of patients.”

Chasing an ‘Off-the-Shelf’ Option

The research behind FT500 comes from decades of work by Dan Kaufman, MD, PhD, professor of medicine in the division of regenerative medicine and director of cell therapy at UC San Diego School of Medicine, and his long-time colleague Jeffrey Miller, MD, professor of medicine and deputy director of the University of Minnesota’s Masonic Cancer Center. Miller said his lab started administering allogeneic NK cell therapies almost two decades ago and has likely given more NK infusions than any other lab. He explained for Cell Therapy Next the advantages allogeneic NK cell therapy has over CAR T-cell therapy.

PAGE BREAK

“The biggest difference, when compared with iPSC-derived NK cells, is we are talking about a truly off-the-shelf allogeneic product.” Much like CAR T-cell therapy, iPSC-derived NK cells are a living drug, but it has advantages that allow for multiple dosing strategies that are likely unattainable by current CAR T-cell technology.

“It’s very, very different from CAR T, which we know is roughly a half million dollars per dose,” Miller said. “CAR T has both economic and portability issues to deal with,” he added.

“iPSC-derived NK cells can be cryopreserved, and you can manufacture hundreds of doses, right now, in a single manufacturing run.”

Dan Kaufman, MD, PhD
Dan Kaufman

There is one caveat to all these alleged advantages: it is provided that the cells work as an effective treatment for cancer, and Miller reminded us that data on its safety and effectiveness are still preliminary.

“The main difference between NK cells and T cells is that NK cells can normally function as allogeneic cells — they don’t have to be matched to a specific patient,” Kaufman, a faculty member of both the Sanford Consortium for Regenerative Medicine and the Sandford Stem Cell Clinical Center at UC San Diego Health, told Cell Therapy Next. Conversely, he explained, the CAR T-cell process can take 3 or more weeks, and only a small fraction of patients will qualify for the treatment.

Kaufman reiterated that NK cells have been used as a successful immunotherapy to treat AML for almost 2 decades and that NK cells do not have to be matched to a specific patient.

“We can make these in the lab,” he said, adding that “they can be a standardized, off-the-shelf product.”

Murphy, however, warned that there are trade-off issues to consider when comparing allogenic and autologous cell therapies.

“First, if you are doing it autologously, which will always be the best because there won’t be rejection by the patient, it is problematic because by the time patients receive these therapies, they are usually older and more immunosuppressed, and their immune activity will be much more limited. If you do them at the source, like an off-the-shelf allogeneic type, that gives you a lot more flexibility on time and cost, but you will need to immune suppress the patient to allow those cells to graft and that represents a problem.”

Then there is an issue of sustainable responses, Murphy added. CAR T-cell therapy has been a game changer because it allows for the continuous triggering of a receptor and a response that keeps the T cell alive to attack tumors.

PAGE BREAK

“The biggest challenge to off-the-shelf cell therapy will always be sustainability because no matter how they are engineered, cells from another source will elicit an immune response,” Murphy said.

“The immune system seems to be exquisitely sensitive to cells from another individual, and that represents a real hurdle. The balance between off-the-shelf and autologous is that for off the shelf, it needs to produce its anti-tumor effects over a short period of time, whereas autologous T-cell therapies like CAR T have been successful because they are allowed to remain for a longer period of time and the tumor does not have a chance to escape.”

William J. Murphy, PhD
William J. Murphy

Less Toxic CARs

A new anti-cancer agent must balance its ability to fight the disease with its potential toxic side effects. It is in this area that NK cells may have a potential advantage over current CAR T-cell therapies. It may be that switching out T cells for NK cells and engineering them with modified CARs could produce less of the neurotoxicity and cytokine release syndrome that has been observed with CAR T-cell therapy.

“While there are some key advantages for T-cell immunotherapy, CAR-directed NK cells offer an alternative treatment modality that could overcome some of the challenges associated with T-cell CARs, most prominent among them is the manifestation of life-threatening toxicities which have led to the termination of clinical trials and drug development programs,” Murphy and colleagues wrote in a 2017 review in Immunotherapy.

“The fact that, unlike T cells, NK cells are generally perceived to be short-lived effector cells, which do not undergo clonal expansion, may allow CAR-directed NK cells to be utilized with less fear for the development of autoimmunity or adverse toxicities associated with rampant T-cell expansion that can occur in patients receiving CAR-T,” they added.

Murphy told Cell Therapy Next that not enough is known about the biology of NK or NKT cells, but the research continues. He said that what makes NK cells attractive as an anti-cancer therapy is, they can limit the activity of T cells and associated toxicities, which lends itself to combining CARs with NK cells and the potential for less toxic cell-based therapies.

“One of the problems with T cells is that they release so many cytokines when they are stimulated,” Miller said. “This is based on preclinical data, but the speculation is that there will be a better safety profile for allogeneic NK cell therapy then we are currently seeing with CAR T.”

PAGE BREAK

Alternate or Replacement Therapy?

Not all vehicles run on gasoline. Some use diesel, others use electricity, and some are still tinkering with hydrogen-based fuels. Just as the automobile has undergone continuous development, perhaps research on the usefulness of NK cells is not about replacing CAR-T, but rather widening the fleet of available vehicles to treat cancer. Perhaps given NK cells’ ability to avoid the immune response that causes the toxic side effects of CAR T-cell therapy, research may lead us to one day strap CARs on NK cells and drive killer CARs into solid tumors.

Kaufman does not see NK cells as a complete replacement for CAR T-cell therapy. Instead, he predicted that different cell-based products will have different roles in treating various forms of cancer.

FT500 is just one product that Fate Therapeutics is working on in the area of NK cells. While FT500 is an unmodified cell therapy, another investigational therapy, called FT516, is a genetically modified product designed to express CD16 in a stabilized fashion. A third product under development, FT596, is an NK cell therapy with an anti-CD19 CAR combined with a CD16 molecule and an IL-15 fusion protein to provide further anti-tumor activity and persistence.

“It’s likely that different products will be used to target certain tumors with different receptors,” Kaufman said.

Patel said it is hard to predict whether NK cells will be an alternative or a replacement for CAR T-cell therapy until some NK cell therapies are approved and comparison studies are conducted.

“My sense is there will be situations where a CAR T approach is more effective, or other situations where an NK approach or CAR NK approach is more efficacious,” he said.

“We will have to see where the data lead us, and determine which modality is best for treating a particular type of cancer, and which one has the best risk–benefit ratio for treating the disease. Cell therapies have major toxicities, both medical and financial, so anything that reduces both is attractive.”

Murphy pointed to the financial issues that surround autologous CAR T-cell therapy and says whatever direction the field takes, the issue of cost must be addressed.

“We need to either figure out ways to have a universal donor to avoid rejection, or the field will have to develop a way to do more cost-effective autologous CARs in humans. The cost issues not only revolve around manufacturing, but the large amount of toxicities that result in the need for acute post-treatment care,” Murphy noted.

PAGE BREAK

“In the end, we need a product that is both durable and sustainable in the body, with an acceptable amount of toxicity.”

Kaufman took pause and reflected on the reality of the situation — cell therapy is not a new frontier, but rather a maturing field. “People tend to think that cell therapy is a new thing, but we have been doing bone marrow transplants as a form of cell therapy for over 40 to 50 years,” he said with a laugh.

The only difference is that CAR T cells have popularized the field of cell therapy, and captivated a public looking for lab coat-wearing heroes who can cure cancer. CAR T-cell therapy was not the invention of cell therapy, but it has ushered in an era where it may have more widespread application.

“We are still in the first stages of these new targeted cell therapies. However, the way we are doing it now, I can almost guarantee we won’t be doing it the same way 10 or 20 years from now,” Kaufman said.

“CAR T cells were a great first step in the right direction, but people are coming up with different versions — whether they be NK cells or other modified cell therapies — so there will be many more strategies to choose from going forward.” – by Drew Amorosi

Disclosures: Miller reports a consulting role and research funding from Fate Therapeutics and GT Biopharma. Kaufman reports consulting/advisory roles, research funding and income, stock options and royalties from Fate Therapeutics. Murphy and Patel report no relevant financial disclosures.

Click here to read Cell Therapy Next’s interview with Yu-Wayne “Wayne” Chu, VP of clinical development for Fate Therapeutics.

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