Chimeric antigen receptor (CAR) T-cell therapy is an innovative cancer treatment that engineers a patient’s own T cells to target and destroy cancer cells. While the field has sparked significant excitement in both the medical and investment communities in recent years, its success has predominantly been confined to treating B-cell leukemias and lymphomas. To assess the current state of CAR T-cell therapy—including advancements in manufacturing processes and the potential for treating solid tumors—GEN spoke with four leading companies in the field.
Amit Kumar, PhD, chairman, president, and CEO of Anixa Biosciences, emphasizes that CAR T technology has proven highly effective for treating blood cancers and autoimmune disorders. “However, no approved CAR T therapies for solid tumors exist,” he notes.
In the case of blood cancers, one of the hallmarks of successful CAR T-cell therapies is that they exclusively target B cells. “They don’t target or attack any other cell in the body. That is one reason why this therapy has been so useful for these liquid cancers,” he notes.
In contrast, treating solid tumors with CAR T-therapy has proved more challenging. “With solid tumors, it has been very difficult to find a protein that exists on the tumor but not on any other healthy cells,” he says.
Nevertheless, Anixa hopes to develop the first approved CAR T-cell therapy for a solid tumor indication. The company has identified a protein called the follicle-stimulating hormone receptor (FSHR), which is expressed only in the ovaries (Figure 1).
Figure 1. While most successful CAR T programs target B-cell cancers (right), Anixa’s CAR T program for ovarian cancer targets the follicle-stimulating hormone receptor (FSHR) found on the surface of ovarian cells (left).
“The interesting thing about the FSHR is that it also exists in blood vessels of tumors,” he notes. “We don’t know why this is yet. When a woman develops a tumor in an organ other than the ovary, such as the lung, the blood vessels in that tumor also express FSHR.”
Kumar notes that Anixa’s therapy works like a combination drug as it targets both the tumor cells and the associated blood vessels that nourish the tumor. Another benefit of Anixa’s approach is that the CAR T cells can be delivered directly into the peritoneal sac, which contains the ovaries and nearby organs to which most ovarian cancer lesions tend to spread.
“In contrast, when CAR T cells are delivered through the vein, they go all through the body and cause all sorts of side effects,” says Kumar.
Anixa’s lead ovarian cancer asset has already demonstrated its ability to destroy ovarian cancer very effectively in mice. Thus far, the company has tested the treatment on nine patients, most of whom had a life expectancy of three to four months. Out of eight patients followed so far, some have lived 12 months, while another has survived for nearly two years.
Furthermore, Kumar stresses that dosages are still low, and adverse events have been minimal. “As we increase the dosages over time with successive patients, we expect that we will get better and better results,” he says.
As Rosanna Ricafort, MD, vice president and head of late development program leadership, hematology and cell therapy at Bristol Myers Squibb (BMS), explains, “There are so many cell therapy companies out there. But very few have what we have in terms of the breadth and depth of our portfolio and pipeline.”
Rosanna Ricafort, MD
VP, Bristol Myers Squibb
She highlights that the company has more than 20 years of experience and more than $17 billion in investments. “To date, more than 10,000 patients have been treated with a BMS cell therapy across clinical and commercial settings,” she notes.
Ricafort explains the company’s first-generation strategy for producing CAR T cells (Figure 2). “We collect each patient’s white blood cells, enrich them, activate them, transduce them with a lentiviral vector, expand them, and then infuse them back into the patient after lympho-depleting chemotherapy,” she says.
However, she also notes that the company’s engineering approaches are diverse and that it leverages multiple technologies as well as partnerships with different companies. “We believe that it takes more than just one approach for different cell therapy indications,” she stresses.
She highlights that BMS has two CAR T-cell assets with two distinct targets on the market for cancer. Breyanzi is a CAR T therapy for various forms of non-Hodgkin lymphoma. “Breyanzi has demonstrated efficacy and manageable safety in five cancer types, the most of any CD19-directed CAR T-cell therapy,” she adds. Meanwhile, Abecma is an FDA-approved B-cell maturation antigen (BCMA)-targeted therapy for relapsed or refractory multiple myeloma.
Figure 2. BMS’s first-generation strategy for producing CAR T-cell therapy. This involves leukapheresis to extract white blood cells from each patient, activation of the appropriate population of cells, genetic engineering with a lentiviral vector, T-cell expansion, and reinfusion into the patient.
Ricafort is particularly excited about the results from the Breyanzi TRANSFORM trial presented at ASCO 2024. This Phase III randomized controlled trial went head-to-head against the established standard of care for patients with relapsed or refractory large B-cell lymphoma. A three-year follow-up showed a median event-free survival of 29.5 months compared with 2.4 months with the standard of care. “This is pretty compelling data,” she notes.
Beyond currently approved assets, the company has a robust mid-stage portfolio of assets in active clinical trials, exploring new, promising targets and patient populations. For example, BMS is researching arlocabtagene autoleucel (arlo-cel), a GPRC5D-targeting CAR T-cell asset for the treatment of adult patients with relapsed or refractory multiple myeloma who have cycled through available therapies.
Ying Huang, PhD, chief executive officer of Legend Biotech, explains that, with over 5,600 patients treated worldwide, the company is laying the groundwork for the broader adoption of CAR T-cell therapies.
Ying Huang, PhD
CEO, Legend Biotech
The company’s CARVYKTI works by recognizing a protein called the B-cell maturation antigen (BCMA) that is highly expressed on myeloma cells. “While other BCMA-targeted immunotherapies bind to one place, CARVYKTI binds to BCMA in two places,” he explains. Ultimately, this binding leads to the destruction of cells that express BCMA, thereby eliminating myeloma cells.
Huang highlights that CARVYKTI is the first and only cell therapy to improve overall survival versus the current standard-of-care therapies for patients with relapsed or lenalidomide-refractory multiple myeloma.
Data from the Phase III CARTITUDE-4 study demonstrated how a single infusion of CARVYKTI significantly extended overall survival. Furthermore, CARVYKTI was also shown to reduce the risk of death by 45% compared with the current standard of care. The company has also initiated two trials to support the advancement of CARVYKTI into the front-line setting.
Outpatient administration is another key advantage of the treatment. Due to the delayed onset of cytokine release syndrome associated with CARVYKTI, healthcare providers can offer treatment in outpatient settings, allowing for a more comfortable patient experience.
Currently, Legend is doubling its manufacturing capacity to keep pace with patient demand. Huang stresses the role of automation. “As the demand for CAR T-cell therapy increases, manufacturers are exploring solutions to continue scaling production to meet patient needs,” he notes. “We are leveraging advanced technologies and partnerships to evaluate robotic automation to replace repetitive manual steps—such as pipetting—to help engineer the cells.”
Lastly, Legend is building a new, state-of-the-art R&D facility in Philadelphia, which happens to be the birthplace of CAR T-cell therapy. “Our hope is to enhance our position in the cell therapy field by focusing on emerging technology platforms that extend beyond traditional therapies,” he says. More specifically, the company is hoping to enable in vivo CAR T therapy, thereby eliminating the need for ex vivo manufacturing.
Chantale Bernatchez, PhD, director of cell therapy process development at CTMC, highlights how the organization helps other companies develop CAR T therapies in a quicker and more efficient manner.
“We apply our expertise in manufacturing sciences, technology, and regulatory affairs to support and advance their innovations,” she says. “This enables our partners to remain focused on their core strength—developing novel technologies.”
Bernatchez explains how CTMC has established robust CAR T platform processes and analytical assays designed for seamless adaptation (Figure 3). This streamlined process greatly expedites the timeline for Investigational New Drug (IND) filings.
Figure 3. CTMC’s CAR T platform for process development is designed with flexibility and adaptability in mind, allowing for different steps to cater to a wide range of products.
Bernatchez emphasizes that a primary challenge facing CAR T-cell therapies involves demonstrating consistent efficacy against solid tumors. “Unlike hematologic malignancies, solid tumors exhibit heterogeneous antigen expression, making them more difficult to eradicate with single antigen-targeting approaches,” she says.
To overcome these challenges, CTMC and its partners are exploring innovative strategies for solid tumors—including techniques such as logic-gating. She notes that logic-gating involves the application of Boolean logic principles—referred to as AND, OR, and NOT gates—to the design of CAR T cells. Ultimately, CAR T cells are programmed to be more selective against tumors while sparing normal tissues.
Chantale Bernatchez, PhD
Director, CTMC
CTMC also provides regulatory guidance to partners preparing for first-in-human studies. “Over the past three years, CTMC’s regulatory team has engaged extensively with the FDA on early-phase CAR T products. This extensive experience provides our partners with deep insights into FDA expectations, helping to streamline the regulatory pathway and accelerate clinical development,” she says.
Finally, Bernatchez stresses that access to patient samples is often extremely limited during the early manufacturing stages for CAR T therapy. As a result, processes are often developed using normal donor blood products, which do not accurately represent patient material.
To address this challenge, CTMC has established a patient material bank, enabling early-stage process development with clinically relevant samples. This resource also supports continuous process improvement following clinical introduction, ultimately enhancing the reliability and efficiency of CAR T manufacturing.
The post CAR T-Cell Therapy: New Advances Move On Past Setbacks appeared first on GEN - Genetic Engineering and Biotechnology News.
Tackling ovarian cancer
Amit Kumar, PhD, chairman, president, and CEO of Anixa Biosciences, emphasizes that CAR T technology has proven highly effective for treating blood cancers and autoimmune disorders. “However, no approved CAR T therapies for solid tumors exist,” he notes.
In the case of blood cancers, one of the hallmarks of successful CAR T-cell therapies is that they exclusively target B cells. “They don’t target or attack any other cell in the body. That is one reason why this therapy has been so useful for these liquid cancers,” he notes.
In contrast, treating solid tumors with CAR T-therapy has proved more challenging. “With solid tumors, it has been very difficult to find a protein that exists on the tumor but not on any other healthy cells,” he says.
Nevertheless, Anixa hopes to develop the first approved CAR T-cell therapy for a solid tumor indication. The company has identified a protein called the follicle-stimulating hormone receptor (FSHR), which is expressed only in the ovaries (Figure 1).
Figure 1. While most successful CAR T programs target B-cell cancers (right), Anixa’s CAR T program for ovarian cancer targets the follicle-stimulating hormone receptor (FSHR) found on the surface of ovarian cells (left).
“The interesting thing about the FSHR is that it also exists in blood vessels of tumors,” he notes. “We don’t know why this is yet. When a woman develops a tumor in an organ other than the ovary, such as the lung, the blood vessels in that tumor also express FSHR.”
Kumar notes that Anixa’s therapy works like a combination drug as it targets both the tumor cells and the associated blood vessels that nourish the tumor. Another benefit of Anixa’s approach is that the CAR T cells can be delivered directly into the peritoneal sac, which contains the ovaries and nearby organs to which most ovarian cancer lesions tend to spread.
“In contrast, when CAR T cells are delivered through the vein, they go all through the body and cause all sorts of side effects,” says Kumar.
Anixa’s lead ovarian cancer asset has already demonstrated its ability to destroy ovarian cancer very effectively in mice. Thus far, the company has tested the treatment on nine patients, most of whom had a life expectancy of three to four months. Out of eight patients followed so far, some have lived 12 months, while another has survived for nearly two years.
Furthermore, Kumar stresses that dosages are still low, and adverse events have been minimal. “As we increase the dosages over time with successive patients, we expect that we will get better and better results,” he says.
Blood cancers and beyond
As Rosanna Ricafort, MD, vice president and head of late development program leadership, hematology and cell therapy at Bristol Myers Squibb (BMS), explains, “There are so many cell therapy companies out there. But very few have what we have in terms of the breadth and depth of our portfolio and pipeline.”
Rosanna Ricafort, MD
VP, Bristol Myers Squibb
She highlights that the company has more than 20 years of experience and more than $17 billion in investments. “To date, more than 10,000 patients have been treated with a BMS cell therapy across clinical and commercial settings,” she notes.
Ricafort explains the company’s first-generation strategy for producing CAR T cells (Figure 2). “We collect each patient’s white blood cells, enrich them, activate them, transduce them with a lentiviral vector, expand them, and then infuse them back into the patient after lympho-depleting chemotherapy,” she says.
However, she also notes that the company’s engineering approaches are diverse and that it leverages multiple technologies as well as partnerships with different companies. “We believe that it takes more than just one approach for different cell therapy indications,” she stresses.
She highlights that BMS has two CAR T-cell assets with two distinct targets on the market for cancer. Breyanzi is a CAR T therapy for various forms of non-Hodgkin lymphoma. “Breyanzi has demonstrated efficacy and manageable safety in five cancer types, the most of any CD19-directed CAR T-cell therapy,” she adds. Meanwhile, Abecma is an FDA-approved B-cell maturation antigen (BCMA)-targeted therapy for relapsed or refractory multiple myeloma.
Figure 2. BMS’s first-generation strategy for producing CAR T-cell therapy. This involves leukapheresis to extract white blood cells from each patient, activation of the appropriate population of cells, genetic engineering with a lentiviral vector, T-cell expansion, and reinfusion into the patient.
Ricafort is particularly excited about the results from the Breyanzi TRANSFORM trial presented at ASCO 2024. This Phase III randomized controlled trial went head-to-head against the established standard of care for patients with relapsed or refractory large B-cell lymphoma. A three-year follow-up showed a median event-free survival of 29.5 months compared with 2.4 months with the standard of care. “This is pretty compelling data,” she notes.
Beyond currently approved assets, the company has a robust mid-stage portfolio of assets in active clinical trials, exploring new, promising targets and patient populations. For example, BMS is researching arlocabtagene autoleucel (arlo-cel), a GPRC5D-targeting CAR T-cell asset for the treatment of adult patients with relapsed or refractory multiple myeloma who have cycled through available therapies.
New options for relapsed myeloma
Ying Huang, PhD, chief executive officer of Legend Biotech, explains that, with over 5,600 patients treated worldwide, the company is laying the groundwork for the broader adoption of CAR T-cell therapies.
Ying Huang, PhD
CEO, Legend Biotech
The company’s CARVYKTI works by recognizing a protein called the B-cell maturation antigen (BCMA) that is highly expressed on myeloma cells. “While other BCMA-targeted immunotherapies bind to one place, CARVYKTI binds to BCMA in two places,” he explains. Ultimately, this binding leads to the destruction of cells that express BCMA, thereby eliminating myeloma cells.
Huang highlights that CARVYKTI is the first and only cell therapy to improve overall survival versus the current standard-of-care therapies for patients with relapsed or lenalidomide-refractory multiple myeloma.
Data from the Phase III CARTITUDE-4 study demonstrated how a single infusion of CARVYKTI significantly extended overall survival. Furthermore, CARVYKTI was also shown to reduce the risk of death by 45% compared with the current standard of care. The company has also initiated two trials to support the advancement of CARVYKTI into the front-line setting.
Outpatient administration is another key advantage of the treatment. Due to the delayed onset of cytokine release syndrome associated with CARVYKTI, healthcare providers can offer treatment in outpatient settings, allowing for a more comfortable patient experience.
Currently, Legend is doubling its manufacturing capacity to keep pace with patient demand. Huang stresses the role of automation. “As the demand for CAR T-cell therapy increases, manufacturers are exploring solutions to continue scaling production to meet patient needs,” he notes. “We are leveraging advanced technologies and partnerships to evaluate robotic automation to replace repetitive manual steps—such as pipetting—to help engineer the cells.”
Lastly, Legend is building a new, state-of-the-art R&D facility in Philadelphia, which happens to be the birthplace of CAR T-cell therapy. “Our hope is to enhance our position in the cell therapy field by focusing on emerging technology platforms that extend beyond traditional therapies,” he says. More specifically, the company is hoping to enable in vivo CAR T therapy, thereby eliminating the need for ex vivo manufacturing.
Enhancing CAR T manufacturing
Chantale Bernatchez, PhD, director of cell therapy process development at CTMC, highlights how the organization helps other companies develop CAR T therapies in a quicker and more efficient manner.
“We apply our expertise in manufacturing sciences, technology, and regulatory affairs to support and advance their innovations,” she says. “This enables our partners to remain focused on their core strength—developing novel technologies.”
Bernatchez explains how CTMC has established robust CAR T platform processes and analytical assays designed for seamless adaptation (Figure 3). This streamlined process greatly expedites the timeline for Investigational New Drug (IND) filings.
Figure 3. CTMC’s CAR T platform for process development is designed with flexibility and adaptability in mind, allowing for different steps to cater to a wide range of products.
Bernatchez emphasizes that a primary challenge facing CAR T-cell therapies involves demonstrating consistent efficacy against solid tumors. “Unlike hematologic malignancies, solid tumors exhibit heterogeneous antigen expression, making them more difficult to eradicate with single antigen-targeting approaches,” she says.
To overcome these challenges, CTMC and its partners are exploring innovative strategies for solid tumors—including techniques such as logic-gating. She notes that logic-gating involves the application of Boolean logic principles—referred to as AND, OR, and NOT gates—to the design of CAR T cells. Ultimately, CAR T cells are programmed to be more selective against tumors while sparing normal tissues.
Chantale Bernatchez, PhD
Director, CTMC
CTMC also provides regulatory guidance to partners preparing for first-in-human studies. “Over the past three years, CTMC’s regulatory team has engaged extensively with the FDA on early-phase CAR T products. This extensive experience provides our partners with deep insights into FDA expectations, helping to streamline the regulatory pathway and accelerate clinical development,” she says.
Finally, Bernatchez stresses that access to patient samples is often extremely limited during the early manufacturing stages for CAR T therapy. As a result, processes are often developed using normal donor blood products, which do not accurately represent patient material.
To address this challenge, CTMC has established a patient material bank, enabling early-stage process development with clinically relevant samples. This resource also supports continuous process improvement following clinical introduction, ultimately enhancing the reliability and efficiency of CAR T manufacturing.
The post CAR T-Cell Therapy: New Advances Move On Past Setbacks appeared first on GEN - Genetic Engineering and Biotechnology News.