Feature

Natural Killer Cell Therapy: A Look Inside a ‘Living Drug in a Bottle’

Yu-wayne "Wayne" Chu, MD
Yu-wayne "Wayne" Chu

The ability to harness the human immune system and use it to fight cancer remains a significant area of focused research and is likely to remain so until the next great advancement occurs. Meanwhile, companies like Fate Therapeutics are going all-in on their own versions of immune effector cell therapies to treat cancer.

Fate Therapeutics’ investigational therapies are based on the immune system’s natural killer (NK) cells and, more specifically, allogeneic induced pluripotent stem cell (iPSC)-derived therapies that do not require a treatment comprising patient-specific cells that take weeks to manufacture. The company is currently in different stages of development on several investigational therapies that use the iPSC platform.

Yu-Wayne “Wayne” Chu, MD, vice president of clinical development, spoke with Cell Therapy Next to discuss the advantages of NK cell-based cancer therapies compared with currently available chimeric antigen receptor T-cell therapy.

Question: What makes the use of NK cells unique compared with CAR T cells?

Answer: CAR T cells have been shown to be highly effective therapies in the treatment of certain hematologic malignancies, which clearly demonstrate the potential of adoptive immune cell therapy in the treatment of cancer. The clinical experience with CAR T cells has provided important insights about the biology of immune responses, as well as their risk–benefit profile, and highlight the features of NK cells that are distinct from, and even complementary to, T cell-based therapies.

First, although both NK cells and T-cells are highly effective in directed killing of targeted cells, including cancer cells, the mechanisms of target cancer cell recognition and immune function are fundamentally different. T cells rely on priming interactions between the T-cell receptor (TCR) and MHC-peptide complexes on target cells as a necessary first step in T-cell activation. As a result, T cells can only recognize a single antigen, and multiple studies have demonstrated that tumor cells avoid T-cell recognition through genetic alterations that significantly reduce antigen presentation.

In contrast, NK cells can recognize a multitude of transformed and infected cells without being dependent on the presentation of a single antigen. Importantly, this means that treatment with NK cells can bypass some of the resistance mechanisms to T-cell based therapy.

Moreover, as innate cells, NK cells can secrete proinflammatory chemokines and cytokines to recruit and activate the body’s adaptive immune system, consisting of T and B cells, creating a second wave of durable antitumor response.

Q: How does the potential toxicity associated with NK cells differ compared with CAR T cells?

A: Although clinical experience with CAR T cells has demonstrated that they are highly effective in eliciting durable antitumor responses, they are also associated with unique and potentially severe toxicities, namely cytokine release syndrome (CRS) and central nervous system toxicity. Notably, NK cells have not been associated with these same toxicities and are expected to have a better safety profile compared with CAR T while maintaining a high level of antitumor activity.

T cell-based therapies have a risk for graft-versus-host disease, which has been clearly shown to be a major barrier to successful clinical outcomes in patients. Because NK cells do not express T cell receptors, they present a significantly lower risk for graft-versus-host disease, which makes NK cells an attractive source for allogeneic immune cells.

Q: Do stem cell-derived NK cells have the potential to treat solid tumors?

A: One major potential advantage of iPSC-based therapies is their ability to be true off-the-shelf cellular therapies. Currently approved autologous CAR T-cell therapies, such as axicabtagene ciloleucel (Yescarta; Kite Pharma, Gilead) and tisagenlecleucel (Kymriah; Novartis), require a long and complex manufacturing process, which is a significant limitation especially for patients with aggressive tumors who cannot afford to wait for treatment. iPSC-derived therapies avoid this time delay, so a patient can receive treatment as soon as possible.

Further, iPSC-derived cells can be administered repeatedly, with opportunities to maximize clinical benefit based on optimization of dose and schedule. In contrast, autologous CAR T-cells can only be given once with no option for additional doses without an additional round of manufacturing.

As with T cell-based therapies, there exist numerous opportunities to optimize NK cell-based therapies against solid tumors through genetic engineering elements that enhance NK cell specificity, activity and persistence. Finally, NK cell-based therapies provide a complementary mechanism of tumor cell recognition and killing that can potentially be used in combination with other antitumor agents, including monoclonal antibodies and T cell-based therapies.

Q: How does the cell manufacturing process differ from CAR T-cell therapy?

A: Unlike conventional manufacturing processes where each sourced material results in a single dose, a single manufacturing campaign of FT500 results in the generation of hundreds of doses. Because each manufacturing campaign starts from a master cell bank that represents a renewable source of starting material, manufacturing campaigns can be initiated repeatedly to produce thousands of doses. This strategy creates unique, off-the-shelf availability and is highly cost effective because the cost of each manufacturing campaign is divided across hundreds of doses produced by that manufacturing run. This is dramatically different than current CAR T-cell therapies where the treatment is not immediately available, and the cost is completely carried by one dose.

Q: Have there been any side effects in the initial patients?

A: We have started enrolling patients on a phase 1 clinical trial of FT500, Fate’s first NK cell product derived from iPSC, in patients with relapsed or refractory cancers that have failed standard cancer treatments. Information on this trial is publicly available through www.clinicaltrials.gov (NCT03841110). Because of the extremely early stage of the trial, information regarding side effects from FT500 are currently not available.

Q : Is there a timeline for preliminary results?

A: There is currently no specific timeline for reporting preliminary results. Safety and antitumor activity observed with FT500 based on the ongoing phase 1 trial will be reported at an upcoming medical conference when data are available.

Q: Are stem cell-derived NK cells like those you are developing a replacement for CAR T cells, or an alternative to them? What are your expectations?

A: The current thinking is that stem cell-derived NK cells can be used either as an alternative to CAR T-cell therapies, or even in combination with CAR T-cell therapies, given their mechanisms of action and potential differences in their clinical activity profiles. It is too early to firmly state expectations around the positioning of these therapies, as they may differ based on specific cancers, patient populations and other factors.

Q: What are your thoughts about the advancement of the cell therapy industry over the last decade?

A: The concept of cell-based therapies for the treatment of cancer has been around for quite some time, dating back to the initial experiences of allogeneic bone marrow transplant for the treatment of leukemia in the 1950s. The advancement in cell-based therapies for cancer in the past decade is a culmination of knowledge and experience in immunology, cell biology, genetic engineering and cell manufacturing. The clinical experience with CAR T-cell therapies in hematologic malignancies has demonstrated the potential of cell-based therapies to transform the way cancer is treated. At the same time, experience with CAR T-cell therapy has highlighted the barriers for their broad use in patients with cancer, including toxicity, treatment failures, access, scalability and affordability. I fully expect that many of these barriers will be overcome with evolving knowledge in immunobiology, continued improvements in genetic engineering techniques and improved manufacturing processes.

Q: Where do you see the cell therapy field in 10 years?

A: In the coming years, the field is headed toward the creation of precise, fine-tuned immune cells, provided on demand and off-the-shelf, at a nearby specialty pharmacy. Think of it as a living drug in a bottle.

Q: Are you currently researching the use of modified NK cells for indications beyond cancers?

A: In addition to FT500, which is a nongenetically engineered iPSC-derived NK cell product that is currently in clinical trials, Fate is planning to test several products representing iterations of genetically modified iPSC-derived NK cells as early as this year. These products have been genetically engineered to enhance the activity, specificity and persistence of the NK cell product. These products will be tested in hematologic malignancies, such as lymphoma and multiple myeloma, as well as in multiple solid tumor indications. Additionally, NK cells can be used in other disease applications such as infectious disease and autoimmunity. – by Drew Amorosi

For more information:

Yu-Wayne “Wayne” Chu, MD, can be reached at Fate Therapeutics, 3535 General Atomics Ct., Suite 200, San Diego, CA 92121; email: yuwaye.chu@fatetherapeutics.com.

Yu-wayne "Wayne" Chu, MD
Yu-wayne "Wayne" Chu

The ability to harness the human immune system and use it to fight cancer remains a significant area of focused research and is likely to remain so until the next great advancement occurs. Meanwhile, companies like Fate Therapeutics are going all-in on their own versions of immune effector cell therapies to treat cancer.

Fate Therapeutics’ investigational therapies are based on the immune system’s natural killer (NK) cells and, more specifically, allogeneic induced pluripotent stem cell (iPSC)-derived therapies that do not require a treatment comprising patient-specific cells that take weeks to manufacture. The company is currently in different stages of development on several investigational therapies that use the iPSC platform.

Yu-Wayne “Wayne” Chu, MD, vice president of clinical development, spoke with Cell Therapy Next to discuss the advantages of NK cell-based cancer therapies compared with currently available chimeric antigen receptor T-cell therapy.

Question: What makes the use of NK cells unique compared with CAR T cells?

Answer: CAR T cells have been shown to be highly effective therapies in the treatment of certain hematologic malignancies, which clearly demonstrate the potential of adoptive immune cell therapy in the treatment of cancer. The clinical experience with CAR T cells has provided important insights about the biology of immune responses, as well as their risk–benefit profile, and highlight the features of NK cells that are distinct from, and even complementary to, T cell-based therapies.

First, although both NK cells and T-cells are highly effective in directed killing of targeted cells, including cancer cells, the mechanisms of target cancer cell recognition and immune function are fundamentally different. T cells rely on priming interactions between the T-cell receptor (TCR) and MHC-peptide complexes on target cells as a necessary first step in T-cell activation. As a result, T cells can only recognize a single antigen, and multiple studies have demonstrated that tumor cells avoid T-cell recognition through genetic alterations that significantly reduce antigen presentation.

In contrast, NK cells can recognize a multitude of transformed and infected cells without being dependent on the presentation of a single antigen. Importantly, this means that treatment with NK cells can bypass some of the resistance mechanisms to T-cell based therapy.

Moreover, as innate cells, NK cells can secrete proinflammatory chemokines and cytokines to recruit and activate the body’s adaptive immune system, consisting of T and B cells, creating a second wave of durable antitumor response.

PAGE BREAK

Q: How does the potential toxicity associated with NK cells differ compared with CAR T cells?

A: Although clinical experience with CAR T cells has demonstrated that they are highly effective in eliciting durable antitumor responses, they are also associated with unique and potentially severe toxicities, namely cytokine release syndrome (CRS) and central nervous system toxicity. Notably, NK cells have not been associated with these same toxicities and are expected to have a better safety profile compared with CAR T while maintaining a high level of antitumor activity.

T cell-based therapies have a risk for graft-versus-host disease, which has been clearly shown to be a major barrier to successful clinical outcomes in patients. Because NK cells do not express T cell receptors, they present a significantly lower risk for graft-versus-host disease, which makes NK cells an attractive source for allogeneic immune cells.

Q: Do stem cell-derived NK cells have the potential to treat solid tumors?

A: One major potential advantage of iPSC-based therapies is their ability to be true off-the-shelf cellular therapies. Currently approved autologous CAR T-cell therapies, such as axicabtagene ciloleucel (Yescarta; Kite Pharma, Gilead) and tisagenlecleucel (Kymriah; Novartis), require a long and complex manufacturing process, which is a significant limitation especially for patients with aggressive tumors who cannot afford to wait for treatment. iPSC-derived therapies avoid this time delay, so a patient can receive treatment as soon as possible.

Further, iPSC-derived cells can be administered repeatedly, with opportunities to maximize clinical benefit based on optimization of dose and schedule. In contrast, autologous CAR T-cells can only be given once with no option for additional doses without an additional round of manufacturing.

As with T cell-based therapies, there exist numerous opportunities to optimize NK cell-based therapies against solid tumors through genetic engineering elements that enhance NK cell specificity, activity and persistence. Finally, NK cell-based therapies provide a complementary mechanism of tumor cell recognition and killing that can potentially be used in combination with other antitumor agents, including monoclonal antibodies and T cell-based therapies.

Q: How does the cell manufacturing process differ from CAR T-cell therapy?

A: Unlike conventional manufacturing processes where each sourced material results in a single dose, a single manufacturing campaign of FT500 results in the generation of hundreds of doses. Because each manufacturing campaign starts from a master cell bank that represents a renewable source of starting material, manufacturing campaigns can be initiated repeatedly to produce thousands of doses. This strategy creates unique, off-the-shelf availability and is highly cost effective because the cost of each manufacturing campaign is divided across hundreds of doses produced by that manufacturing run. This is dramatically different than current CAR T-cell therapies where the treatment is not immediately available, and the cost is completely carried by one dose.

PAGE BREAK

Q: Have there been any side effects in the initial patients?

A: We have started enrolling patients on a phase 1 clinical trial of FT500, Fate’s first NK cell product derived from iPSC, in patients with relapsed or refractory cancers that have failed standard cancer treatments. Information on this trial is publicly available through www.clinicaltrials.gov (NCT03841110). Because of the extremely early stage of the trial, information regarding side effects from FT500 are currently not available.

Q : Is there a timeline for preliminary results?

A: There is currently no specific timeline for reporting preliminary results. Safety and antitumor activity observed with FT500 based on the ongoing phase 1 trial will be reported at an upcoming medical conference when data are available.

Q: Are stem cell-derived NK cells like those you are developing a replacement for CAR T cells, or an alternative to them? What are your expectations?

A: The current thinking is that stem cell-derived NK cells can be used either as an alternative to CAR T-cell therapies, or even in combination with CAR T-cell therapies, given their mechanisms of action and potential differences in their clinical activity profiles. It is too early to firmly state expectations around the positioning of these therapies, as they may differ based on specific cancers, patient populations and other factors.

Q: What are your thoughts about the advancement of the cell therapy industry over the last decade?

A: The concept of cell-based therapies for the treatment of cancer has been around for quite some time, dating back to the initial experiences of allogeneic bone marrow transplant for the treatment of leukemia in the 1950s. The advancement in cell-based therapies for cancer in the past decade is a culmination of knowledge and experience in immunology, cell biology, genetic engineering and cell manufacturing. The clinical experience with CAR T-cell therapies in hematologic malignancies has demonstrated the potential of cell-based therapies to transform the way cancer is treated. At the same time, experience with CAR T-cell therapy has highlighted the barriers for their broad use in patients with cancer, including toxicity, treatment failures, access, scalability and affordability. I fully expect that many of these barriers will be overcome with evolving knowledge in immunobiology, continued improvements in genetic engineering techniques and improved manufacturing processes.

PAGE BREAK

Q: Where do you see the cell therapy field in 10 years?

A: In the coming years, the field is headed toward the creation of precise, fine-tuned immune cells, provided on demand and off-the-shelf, at a nearby specialty pharmacy. Think of it as a living drug in a bottle.

Q: Are you currently researching the use of modified NK cells for indications beyond cancers?

A: In addition to FT500, which is a nongenetically engineered iPSC-derived NK cell product that is currently in clinical trials, Fate is planning to test several products representing iterations of genetically modified iPSC-derived NK cells as early as this year. These products have been genetically engineered to enhance the activity, specificity and persistence of the NK cell product. These products will be tested in hematologic malignancies, such as lymphoma and multiple myeloma, as well as in multiple solid tumor indications. Additionally, NK cells can be used in other disease applications such as infectious disease and autoimmunity. – by Drew Amorosi

For more information:

Yu-Wayne “Wayne” Chu, MD, can be reached at Fate Therapeutics, 3535 General Atomics Ct., Suite 200, San Diego, CA 92121; email: yuwaye.chu@fatetherapeutics.com.

    See more from Immuno-Oncology Resource Center