Cover Story

CAR T cells may transform blood cancer treatment, but concerns remain about safety, availability

Cancer care has rapidly moved away from a one-size-fits-all approach.

Chemotherapy, surgery and radiation remain the backbones of therapy, but advances in immunotherapy have improved outcomes for patients who once had few options.

Chimeric antigen receptor (CAR) T-cell therapy — which involves removing and genetically engineering a patient’s T cells, then infusing them back into the person’s body — is among the most exciting areas of innovation.

Researchers have investigated the transfer of genetically modified cells since the 1980s, and the treatment originally was envisioned as a treatment for solid tumors. However, several more recent studies have demonstrated the approach’s efficacy in leukemia, multiple myeloma and various B-cell malignancies.

“The idea of engineering T cells to do a good job fighting cancer is nothing new,” Stephan A. Grupp, MD, PhD, director of the cancer immunotherapy program and director of translational research for the Center for Childhood Cancer at Children’s Hospital of Philadelphia, as well as professor of pediatrics at University of Pennsylvania Perelman School of Medicine, told HemOnc Today. “It was initially thought that engineered T cells were safe to use but did not do very much. That changed about 6 years ago, when three adult patients with chronic lymphocytic leukemia achieved very significant treatment outcomes.”

CAR T-cell therapies are unlikely to be readily available in community practices, according to Stephan A. Grupp, MD, PhD.
CAR T-cell therapies are unlikely to be readily available in community practices, according to Stephan A. Grupp, MD, PhD. “The toxicity involved with these therapies is significant and, generally, a place that handles toxicity well has a busy inpatient unit, experience in transplantation and an excellent ICU.”

Photo by The Children’s Hospital of Philadelphia.

Since then, there has been a convergence of very significant results, including the 90% efficacy rate Grupp and colleagues observed in children and adults with acute lymphoblastic leukemia, published in The New England Journal of Medicine.

Despite promising efficacy data, safety remains a considerable concern for CAR T-cell therapy. A clinical trial financed by Juno Therapeutics was temporarily halted in June after three patients with leukemia died unexpectedly of apparent treatment-related swelling in the brain.

Others have questioned the feasibility of the approach — specifically, whether it will ever be available outside of academic facilities and specialty centers.

“The number of patients in the world who have received highly active cell therapy is definitely less than 1,000 — probably less than 500,” Grupp said. “We are very excited about the success so far, but based on the number of patients treated, there is no question that there is still a lot to learn about how best to safely take care of cell therapy patients.”

HemOnc Today spoke with clinicians and researchers about the enormous potential CAR T cells may have for patients with few other options, the risk for cytokine release syndrome and other potentially serious adverse events, and the challenges that must be overcome prior to more widespread T-cell product development and FDA approval.

Therapeutic potential

Immunologists and oncologists have long worked to harness the body’s natural immune system to fight cancer. T-cell therapy has been viewed as a potential gold standard in this field.

“In patients with cancer, circulating T cells generally overlook cancer cells,” Edward A. Copelan, MD, FACP, chair of the department of hematologic oncology and blood disorders at Levine Cancer Institute at Carolinas HealthCare System, as well as a HemOnc Today Editorial Board member, told HemOnc Today. “These same T cells can be collected from blood by leukapheresis, stimulated in culture and modified using a viral vector so they express an artificial receptor specifically recognizing an antigen expressed on cancer cells.”

The receptor is linked to domains that signal the CAR T cells to proliferate and kill cancer cells, as well as recruit and stimulate other T cells.

Early solid tumor targets for CAR T-cell therapy included melanoma, gynecologic cancers and neurological malignancies. However, the most success reported thus far has occurred in hematologic malignancies.

“Researchers from the University of Pennsylvania first demonstrated the immense promise of CAR T cells expressing a receptor for CD19, an antigen expressed in B-cell hematologic malignancies and normal B cells,” Copelan said.

David L. Porter, MD, director of bone and marrow transplantation at Hospital of the University of Pennsylvania and Jodi Fisher Horowitz professor of leukemia care excellence at Perelman School of Medicine, and colleagues published a paper in 2011 in The New England Journal of Medicine that reported long-term remissions of two patients with advanced CLL who underwent CAR T-cell therapy.

Porter and colleagues subsequently reported that the approach was highly effective in patients with relapsed or refractory ALL, conferring complete remissions in 27 of 30 adults and children. This included 15 patients who previously underwent hematopoietic stem cell transplantation.

“Many studies have emerged since then,” James N. Kochenderfer, MD, investigator in the experimental translation and immunotherapy branch at NCI’s Center for Cancer Research, told HemOnc Today. “It is quite possible that anti–CD19 CAR T cells will become a standard therapy for some B-cell malignancies in the near future.”

The volume of CAR T-cell–related studies published in peer-reviewed journals and presented at major medical conferences has exploded.

Kochenderfer and colleagues published study results in Journal of Clinical Oncology that demonstrated the efficacy of CAR T-cell therapy in diffuse large B-cell lymphoma and other lymphoma subtypes.

At last year’s ASH Annual Meeting and Exposition, Kochenderfer reported for the first time on the clinical activity of CAR T cells in multiple myeloma. In a 2016 paper in Blood, his research group was the first to show the therapy — designed to target B-cell maturation antigen — induced remissions among patients with multiple myeloma.

“Lymphoma is more common than leukemia, so development of new therapies against lymphoma is very important,” Kochenderfer said. “Multiple companies are now conducting multicenter clinical trials of anti-CD19 CAR T cells for a variety of B-cell lymphomas, CLL and ALL. CAR T-cell therapies for multiple myeloma are at an early stage of development, but they offer a promising treatment modality for the disease.”

The excitement surrounding CAR T-cell therapy primarily is driven by the patient population it serves, Henry C. Fung, MD, FRCPE, vice chair of hematology at Fox Chase Cancer Center and director of the Fox Chase–Temple University Hospital Bone Marrow Transplant Program, told HemOnc Today.

Henry C. Fung, MD, FRCPE
Henry C. Fung

“Many of the patients treated on these clinical trials are among the sickest patients, with very few remaining treatment options,” Fung said. “These are patients who failed every treatment, who were going to die in a few weeks or months. Some patients went from being at the end of the road to having a complete remission, which is remarkable.”

These early, positive results have triggered tremendous excitement throughout the hematologic oncology community.

Still, questions remain about whether use of this therapy ever will be widespread.

“Every study is a variation on a theme, but most research on cancers that express a CD19 target — ALL, CLL, non-Hodgkin lymphoma — has converged on an approach to making engineered T cells that work in the space of these malignancies,” Grupp said. “The next challenge in the field is twofold: Can we get one of these therapies FDA approved — I think we can — and can we make this method work in anything other than a B-cell malignancy? I think the jury is completely out on that.”

Toxicity concerns

FDA approval of CAR T-cell therapy for specific indications seems almost a foregone conclusion, Fung said.

“It is going to come soon,” Fung said. “Patients are having unbelievable responses. FDA has given the designation of ‘breakthrough’ to various other drugs, but many of them are not really breakthroughs. CAR T-cell therapy is a genuine breakthrough treatment.”

Still, rates of toxicity are a major concern, even among proponents.

“The toxicities associated with these therapies can be significant,” Grupp said. “Because many of these patients have a lot of disease, that in itself increases the risk for significant toxicity.”

Cytokine release syndrome — which occurs when cytokine levels are elevated due to T-cell activity and proliferation — has emerged as a top concern. Some patients experience mild flulike symptoms, whereas other cases can become life-threatening.

“CAR T cells cause a variety of toxicities that are caused by cytokines, and perhaps by other substances released by the T cells,” Kochenderfer said. “Reactions include fever, tachycardia, low blood pressure and neurological toxicities, including confusion, tremors and seizures.”

In September, Kite Pharma announced positive results from the phase 1/phase 2 ZUMA-1 trial — designed to assess the use of CAR T cells in 62 patients with DLBCL, transformed follicular lymphoma or primary mediastinal B-cell lymphoma — based on a 76% overall response rate and 47% complete remission rate.

However, data also showed that 18% of patients experienced grade 3 or worse cytokine release syndrome and 34% experienced neurological toxicity.

“Neurological toxicity ranges from confusion to obfuscation, delirium, aphasia, seizures and visual hallucinations,” Copelan said. “Severe cytokine release syndrome can be life-threatening, but can usually be effectively resolved through therapy. Neurologic toxicity is more concerning.”

Most cases of toxicity resolved with treatment in the ZUMA-1 trial; however, two patients died of treatment-related toxicity in the setting of cytokine release syndrome — including one death due to hemophagocytic lymphohistiocytosis and one case of cardiac arrest.

“It is important to remember that many of these toxicities rapidly and completely resolve,” Kochenderfer said. “Medications such as corticosteroids and the interleukin-6 receptor blocker tocilizumab [Actemra, Genentech] can be used to effectively treat these toxicities.”

The most significant toxicity report to date occurred during a phase 2 trial conducted by Juno Therapeutics, in which three adults with ALL died due to cerebral edema. These deaths prompted the FDA to suspend the trial for about a week.

“Culpability was attributed to the inclusion of fludarabine as a preconditioning agent in the trial,” Copelan said. “From now on, only cyclophosphamide will be used for preconditioning in the trial. It seems unlikely, however, that these deaths resulted solely from fludarabine toxicity. Many question whether CAR T cells played a significant role in the deaths.”

The rates of toxicity in the Juno study are alarming, but they are not necessarily surprising, Fung said.

“The deaths highlight the important points surrounding patient selection,” Fung said. “The Juno study’s patient population has high-risk disease, and we have to compare the therapy that was being offered with existing treatment options, which are essentially none. That must be taken into account. The risk may be significant, but it is also similar to that from a stem cell transplant.”

The unpredictable toxicities also are like those observed with other breakthrough therapies, Kochenderfer said.

“Dealing with the toxicities associated with these therapies is an area of intense investigation,” he said. “Clinical management of toxicities is evolving and improving. Management of toxicity has already improved; it is likely to improve in the future.”

Such improvement in toxicity management is essential for the therapy to be more widely used.

“The acuity and severity of cytokine release syndrome and the deaths due to cerebral edema have created reasonable trepidation about the widespread application of CAR T-cell therapy,” Copelan said. “It is clear that centers administering the therapy must be vigilant in monitoring patients and experienced in managing severe cytokine release syndrome and neurological toxicities.”

‘Destination therapy’

Like many innovative therapies, CAR T-cell engineering has been developed and evaluated primarily at academic and specialty medical centers.

Despite the great interest in its potential widespread adoption, use of the therapy may not be feasible outside of select institutions.

CAR T cells may not be widely used because “there is an inherent selection bias” when selecting patients suitable for this treatment, John P. Leonard, MD, Richard T. Silver distinguished professor of hematology and medical oncology and associate dean for clinical research at Weill Cornell Medicine, as well as attending physician at NewYork-Presbyterian Hospital, told HemOnc Today.

“There are patients who are not candidates for this type of treatment because of their age and comorbidity burden, or because they have rapidly aggressive/growing disease,” Leonard said. “Because there is an inherent delay of a few weeks required to get a patient enrolled and get them CAR T cells, some ‘unfavorable prognosis’ patients with aggressive lymphoma are left out of trials because they cannot wait that long for therapy.”

Copelan agreed there are patients who will not be considered good candidates for the therapy.

“Those who likely will not be considered primarily include patients with extensive disease in whom preconditioning cannot effectively reduce the disease burden, and those with comorbid conditions who could not tolerate the toxicities,” he said.

Clinicians likely will be selective when choosing patients to receive this therapy, Kochenderfer said.

“I would not accept a patient with any history of myocardial infarction or any reduction in cardiac left-ventricular function,” he said. “I exclude patients with poor performance status and any abnormalities of major organ function.”

The process by which CAR T cells are extracted and engineered is complicated and time consuming, and the risks for adverse events present additional challenges, Grupp said.

“We are definitely not at the point of rolling this out to community hospitals,” he said. “The toxicity involved with these therapies is significant and, generally, a place that handles toxicity well has a busy inpatient unit, experience in transplantation and an excellent ICU. For the fraction of patients with very high, completely uncontrolled disease at the time of T-cell treatment, that fraction will get sick. They need a large hospital for their care management.”

CAR T-cell therapy likely will be viewed as a specialty treatment for some time, Copelan said.

“There is no doubt that the efforts required for CAR T-cell therapy will require more than the average hospital may be able to provide,” Copelan said. “The collection of cells by apheresis and the ability to immediately handle life-threatening complications are absolute requirements.”

Cost is another issue.

“It appears that total treatment costs will be in excess of what we see with stem cell transplantation,” Copelan said.

CAR T-cell therapy’s availability likely will be similar to bone marrow or stem cell transplantation.

“Bone marrow and stem cell transplant are standards of care for many diseases, but they are still not widely available at many hospitals,” Fung said. “They have been in use for decades, but you still usually need to go to a major city like New York, Philadelphia or Chicago, or to a major treatment center ... to receive these treatments. This is because these therapies require highly trained treatment teams and very specific facilities. I think we will see the same thing with CAR T cells, and it will become a destination therapy.”

Leonard agreed.

“This will be even more of a challenge than stem cell transplantation has been,” Leonard said. “It will take more time for the technology to be fine-tuned for optimal efficacy, feasibility and toxicity.”

Despite the limitations of CAR T cells, the therapy eventually will become more widely used, Grupp said.

“Novartis recently completed enrollment on a registration trial in pediatric ALL that was open in 25 centers across the world,” Grupp said. “To me, it stands to reason that CAR T-cell therapy will be available at many of the centers around the world where patients with cancer regularly receive inpatient therapy.”

Research and development

CAR T-cell therapy is viewed by many in the hematologic oncology community as a major step forward for a variety of diseases. As such, pharmaceutical companies have been clamoring to develop their own version of the therapy in preparation for FDA approval.

“CAR T cells have captured the interest of several biopharmaceutical companies,” Copelan said. “Novartis, Juno Therapeutics and Kite Pharma, among others, have multiple CD19–targeted CAR T-cell therapies in trials, and they anticipate expansion to additional diseases. Kite recently opened a 43,000-square foot facility with the capacity to produce CAR T cells for as many as 5,000 patients annually.”

Despite these advances, the decision by Novartis to close its dedicated CAR T-cell department has caused concerns among some in the research community.

The company disbanded its 400-person cell and gene unit in August; 120 staff members were laid off, and the others were reassigned to different departments.

“Novartis has championed CAR T cells,” Copelan said. “Despite assurances by Novartis of its continued commitment to CAR T-cell therapy, many see this as a pragmatic decision by a knowledgeable company, concerned with the prospect of high cost, limited application and the complexity of large-scale manufacturing of individualized cellular products.”

Although Novartis disbanded its cell unit, clinicians should not assume the company is no longer committed to CAR T-cell therapy, Grupp said.

“They have folded their unit into the overall oncology unit, but they are still going to be manufacturing products for cell therapy patients all over the world,” Grupp said. “From an outsider’s perspective, I don’t see this as a retreat. I see it as a reorganization.”

The continued advances of CAR T-cell therapy will be cause for conversation among doctors and patients, Leonard said.

“Patients and physicians considering these therapies need to carefully review the pros and cons and pay attention to the emerging data,” Leonard said. “I believe that we will start to see robust patient information and follow-up, with precise characterization of the patient populations best served by this approach.”

Despite the concerns that still must be addressed, Fung said he has little doubt that CAR T-cell therapy will be practice changing.

“These are the kind of developments I have been waiting for my entire career,” he said. “I don’t think it’s unfair to call it revolutionary.” – by Cameron Kelsall

Click here to read the POINTCOUNTER, “Will CAR T cells always be reserved for late lines of therapy?”

References:

Ali SA, et al. Blood. 2016;doi:10.1182/blood-2016-04-711903.

Grupp SA, et al. N Engl J Med. 2013;doi:10.1056/NEJMoa1215134.

Kochenderfer JN, et al. Blood. 2010;doi:10.1182/blood-2010-01-265041.

Kochenderfer JN, et al. J Clin Oncol. 2015;doi:10.1200/JCO.2014.56.2025.

Maude SL, et al. N Engl J Med. 2014;doi:10.1056/NEJMoa1407222.

Neelapu SS, et al. Abstract 7559. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.

Porter DL, et al. N Engl J Med. 2011;doi:10.1056/NEJMoa1103849.

Turtle CJ, et al. Sci Transl Med. 2016;doi:10.1126/scitranslmed.aaf8621.

For more information:

Edward A. Copelan, MD, FACP, can be reached at edward.copelan@carolinashealthcare.org.

Henry C. Fung, MD, FRCPE, can be reached at henry.fung@tuhs.temple.edu.

Stephan A. Grupp, MD, PhD, can be reached at grupp@email.chop.edu.

James N. Kochenderfer, MD, can be reached at kochendj@mail.nih.gov.

John P. Leonard, MD, can be reached at jpleonar@med.cornell.edu.

Disclosure: Grupp reports institutional research funding from and a consultant role with Novartis. Kochenderfer reports research funding from Bluebird Bio and Kite Pharma. Leonard reports financial relationships with Juno Therapeutics and Kite Pharma. Copelan and Fung report no relevant financial disclosures.

Cancer care has rapidly moved away from a one-size-fits-all approach.

Chemotherapy, surgery and radiation remain the backbones of therapy, but advances in immunotherapy have improved outcomes for patients who once had few options.

Chimeric antigen receptor (CAR) T-cell therapy — which involves removing and genetically engineering a patient’s T cells, then infusing them back into the person’s body — is among the most exciting areas of innovation.

Researchers have investigated the transfer of genetically modified cells since the 1980s, and the treatment originally was envisioned as a treatment for solid tumors. However, several more recent studies have demonstrated the approach’s efficacy in leukemia, multiple myeloma and various B-cell malignancies.

“The idea of engineering T cells to do a good job fighting cancer is nothing new,” Stephan A. Grupp, MD, PhD, director of the cancer immunotherapy program and director of translational research for the Center for Childhood Cancer at Children’s Hospital of Philadelphia, as well as professor of pediatrics at University of Pennsylvania Perelman School of Medicine, told HemOnc Today. “It was initially thought that engineered T cells were safe to use but did not do very much. That changed about 6 years ago, when three adult patients with chronic lymphocytic leukemia achieved very significant treatment outcomes.”

CAR T-cell therapies are unlikely to be readily available in community practices, according to Stephan A. Grupp, MD, PhD.
CAR T-cell therapies are unlikely to be readily available in community practices, according to Stephan A. Grupp, MD, PhD. “The toxicity involved with these therapies is significant and, generally, a place that handles toxicity well has a busy inpatient unit, experience in transplantation and an excellent ICU.”

Photo by The Children’s Hospital of Philadelphia.

Since then, there has been a convergence of very significant results, including the 90% efficacy rate Grupp and colleagues observed in children and adults with acute lymphoblastic leukemia, published in The New England Journal of Medicine.

Despite promising efficacy data, safety remains a considerable concern for CAR T-cell therapy. A clinical trial financed by Juno Therapeutics was temporarily halted in June after three patients with leukemia died unexpectedly of apparent treatment-related swelling in the brain.

Others have questioned the feasibility of the approach — specifically, whether it will ever be available outside of academic facilities and specialty centers.

“The number of patients in the world who have received highly active cell therapy is definitely less than 1,000 — probably less than 500,” Grupp said. “We are very excited about the success so far, but based on the number of patients treated, there is no question that there is still a lot to learn about how best to safely take care of cell therapy patients.”

HemOnc Today spoke with clinicians and researchers about the enormous potential CAR T cells may have for patients with few other options, the risk for cytokine release syndrome and other potentially serious adverse events, and the challenges that must be overcome prior to more widespread T-cell product development and FDA approval.

Therapeutic potential

Immunologists and oncologists have long worked to harness the body’s natural immune system to fight cancer. T-cell therapy has been viewed as a potential gold standard in this field.

“In patients with cancer, circulating T cells generally overlook cancer cells,” Edward A. Copelan, MD, FACP, chair of the department of hematologic oncology and blood disorders at Levine Cancer Institute at Carolinas HealthCare System, as well as a HemOnc Today Editorial Board member, told HemOnc Today. “These same T cells can be collected from blood by leukapheresis, stimulated in culture and modified using a viral vector so they express an artificial receptor specifically recognizing an antigen expressed on cancer cells.”

The receptor is linked to domains that signal the CAR T cells to proliferate and kill cancer cells, as well as recruit and stimulate other T cells.

PAGE BREAK

Early solid tumor targets for CAR T-cell therapy included melanoma, gynecologic cancers and neurological malignancies. However, the most success reported thus far has occurred in hematologic malignancies.

“Researchers from the University of Pennsylvania first demonstrated the immense promise of CAR T cells expressing a receptor for CD19, an antigen expressed in B-cell hematologic malignancies and normal B cells,” Copelan said.

David L. Porter, MD, director of bone and marrow transplantation at Hospital of the University of Pennsylvania and Jodi Fisher Horowitz professor of leukemia care excellence at Perelman School of Medicine, and colleagues published a paper in 2011 in The New England Journal of Medicine that reported long-term remissions of two patients with advanced CLL who underwent CAR T-cell therapy.

Porter and colleagues subsequently reported that the approach was highly effective in patients with relapsed or refractory ALL, conferring complete remissions in 27 of 30 adults and children. This included 15 patients who previously underwent hematopoietic stem cell transplantation.

“Many studies have emerged since then,” James N. Kochenderfer, MD, investigator in the experimental translation and immunotherapy branch at NCI’s Center for Cancer Research, told HemOnc Today. “It is quite possible that anti–CD19 CAR T cells will become a standard therapy for some B-cell malignancies in the near future.”

The volume of CAR T-cell–related studies published in peer-reviewed journals and presented at major medical conferences has exploded.

Kochenderfer and colleagues published study results in Journal of Clinical Oncology that demonstrated the efficacy of CAR T-cell therapy in diffuse large B-cell lymphoma and other lymphoma subtypes.

At last year’s ASH Annual Meeting and Exposition, Kochenderfer reported for the first time on the clinical activity of CAR T cells in multiple myeloma. In a 2016 paper in Blood, his research group was the first to show the therapy — designed to target B-cell maturation antigen — induced remissions among patients with multiple myeloma.

“Lymphoma is more common than leukemia, so development of new therapies against lymphoma is very important,” Kochenderfer said. “Multiple companies are now conducting multicenter clinical trials of anti-CD19 CAR T cells for a variety of B-cell lymphomas, CLL and ALL. CAR T-cell therapies for multiple myeloma are at an early stage of development, but they offer a promising treatment modality for the disease.”

The excitement surrounding CAR T-cell therapy primarily is driven by the patient population it serves, Henry C. Fung, MD, FRCPE, vice chair of hematology at Fox Chase Cancer Center and director of the Fox Chase–Temple University Hospital Bone Marrow Transplant Program, told HemOnc Today.

Henry C. Fung, MD, FRCPE
Henry C. Fung

“Many of the patients treated on these clinical trials are among the sickest patients, with very few remaining treatment options,” Fung said. “These are patients who failed every treatment, who were going to die in a few weeks or months. Some patients went from being at the end of the road to having a complete remission, which is remarkable.”

These early, positive results have triggered tremendous excitement throughout the hematologic oncology community.

Still, questions remain about whether use of this therapy ever will be widespread.

“Every study is a variation on a theme, but most research on cancers that express a CD19 target — ALL, CLL, non-Hodgkin lymphoma — has converged on an approach to making engineered T cells that work in the space of these malignancies,” Grupp said. “The next challenge in the field is twofold: Can we get one of these therapies FDA approved — I think we can — and can we make this method work in anything other than a B-cell malignancy? I think the jury is completely out on that.”

Toxicity concerns

FDA approval of CAR T-cell therapy for specific indications seems almost a foregone conclusion, Fung said.

PAGE BREAK

“It is going to come soon,” Fung said. “Patients are having unbelievable responses. FDA has given the designation of ‘breakthrough’ to various other drugs, but many of them are not really breakthroughs. CAR T-cell therapy is a genuine breakthrough treatment.”

Still, rates of toxicity are a major concern, even among proponents.

“The toxicities associated with these therapies can be significant,” Grupp said. “Because many of these patients have a lot of disease, that in itself increases the risk for significant toxicity.”

Cytokine release syndrome — which occurs when cytokine levels are elevated due to T-cell activity and proliferation — has emerged as a top concern. Some patients experience mild flulike symptoms, whereas other cases can become life-threatening.

“CAR T cells cause a variety of toxicities that are caused by cytokines, and perhaps by other substances released by the T cells,” Kochenderfer said. “Reactions include fever, tachycardia, low blood pressure and neurological toxicities, including confusion, tremors and seizures.”

In September, Kite Pharma announced positive results from the phase 1/phase 2 ZUMA-1 trial — designed to assess the use of CAR T cells in 62 patients with DLBCL, transformed follicular lymphoma or primary mediastinal B-cell lymphoma — based on a 76% overall response rate and 47% complete remission rate.

However, data also showed that 18% of patients experienced grade 3 or worse cytokine release syndrome and 34% experienced neurological toxicity.

“Neurological toxicity ranges from confusion to obfuscation, delirium, aphasia, seizures and visual hallucinations,” Copelan said. “Severe cytokine release syndrome can be life-threatening, but can usually be effectively resolved through therapy. Neurologic toxicity is more concerning.”

Most cases of toxicity resolved with treatment in the ZUMA-1 trial; however, two patients died of treatment-related toxicity in the setting of cytokine release syndrome — including one death due to hemophagocytic lymphohistiocytosis and one case of cardiac arrest.

“It is important to remember that many of these toxicities rapidly and completely resolve,” Kochenderfer said. “Medications such as corticosteroids and the interleukin-6 receptor blocker tocilizumab [Actemra, Genentech] can be used to effectively treat these toxicities.”

The most significant toxicity report to date occurred during a phase 2 trial conducted by Juno Therapeutics, in which three adults with ALL died due to cerebral edema. These deaths prompted the FDA to suspend the trial for about a week.

“Culpability was attributed to the inclusion of fludarabine as a preconditioning agent in the trial,” Copelan said. “From now on, only cyclophosphamide will be used for preconditioning in the trial. It seems unlikely, however, that these deaths resulted solely from fludarabine toxicity. Many question whether CAR T cells played a significant role in the deaths.”

The rates of toxicity in the Juno study are alarming, but they are not necessarily surprising, Fung said.

“The deaths highlight the important points surrounding patient selection,” Fung said. “The Juno study’s patient population has high-risk disease, and we have to compare the therapy that was being offered with existing treatment options, which are essentially none. That must be taken into account. The risk may be significant, but it is also similar to that from a stem cell transplant.”

The unpredictable toxicities also are like those observed with other breakthrough therapies, Kochenderfer said.

“Dealing with the toxicities associated with these therapies is an area of intense investigation,” he said. “Clinical management of toxicities is evolving and improving. Management of toxicity has already improved; it is likely to improve in the future.”

Such improvement in toxicity management is essential for the therapy to be more widely used.

“The acuity and severity of cytokine release syndrome and the deaths due to cerebral edema have created reasonable trepidation about the widespread application of CAR T-cell therapy,” Copelan said. “It is clear that centers administering the therapy must be vigilant in monitoring patients and experienced in managing severe cytokine release syndrome and neurological toxicities.”

PAGE BREAK

‘Destination therapy’

Like many innovative therapies, CAR T-cell engineering has been developed and evaluated primarily at academic and specialty medical centers.

Despite the great interest in its potential widespread adoption, use of the therapy may not be feasible outside of select institutions.

CAR T cells may not be widely used because “there is an inherent selection bias” when selecting patients suitable for this treatment, John P. Leonard, MD, Richard T. Silver distinguished professor of hematology and medical oncology and associate dean for clinical research at Weill Cornell Medicine, as well as attending physician at NewYork-Presbyterian Hospital, told HemOnc Today.

“There are patients who are not candidates for this type of treatment because of their age and comorbidity burden, or because they have rapidly aggressive/growing disease,” Leonard said. “Because there is an inherent delay of a few weeks required to get a patient enrolled and get them CAR T cells, some ‘unfavorable prognosis’ patients with aggressive lymphoma are left out of trials because they cannot wait that long for therapy.”

Copelan agreed there are patients who will not be considered good candidates for the therapy.

“Those who likely will not be considered primarily include patients with extensive disease in whom preconditioning cannot effectively reduce the disease burden, and those with comorbid conditions who could not tolerate the toxicities,” he said.

Clinicians likely will be selective when choosing patients to receive this therapy, Kochenderfer said.

“I would not accept a patient with any history of myocardial infarction or any reduction in cardiac left-ventricular function,” he said. “I exclude patients with poor performance status and any abnormalities of major organ function.”

The process by which CAR T cells are extracted and engineered is complicated and time consuming, and the risks for adverse events present additional challenges, Grupp said.

“We are definitely not at the point of rolling this out to community hospitals,” he said. “The toxicity involved with these therapies is significant and, generally, a place that handles toxicity well has a busy inpatient unit, experience in transplantation and an excellent ICU. For the fraction of patients with very high, completely uncontrolled disease at the time of T-cell treatment, that fraction will get sick. They need a large hospital for their care management.”

CAR T-cell therapy likely will be viewed as a specialty treatment for some time, Copelan said.

“There is no doubt that the efforts required for CAR T-cell therapy will require more than the average hospital may be able to provide,” Copelan said. “The collection of cells by apheresis and the ability to immediately handle life-threatening complications are absolute requirements.”

Cost is another issue.

“It appears that total treatment costs will be in excess of what we see with stem cell transplantation,” Copelan said.

CAR T-cell therapy’s availability likely will be similar to bone marrow or stem cell transplantation.

“Bone marrow and stem cell transplant are standards of care for many diseases, but they are still not widely available at many hospitals,” Fung said. “They have been in use for decades, but you still usually need to go to a major city like New York, Philadelphia or Chicago, or to a major treatment center ... to receive these treatments. This is because these therapies require highly trained treatment teams and very specific facilities. I think we will see the same thing with CAR T cells, and it will become a destination therapy.”

Leonard agreed.

“This will be even more of a challenge than stem cell transplantation has been,” Leonard said. “It will take more time for the technology to be fine-tuned for optimal efficacy, feasibility and toxicity.”

Despite the limitations of CAR T cells, the therapy eventually will become more widely used, Grupp said.

“Novartis recently completed enrollment on a registration trial in pediatric ALL that was open in 25 centers across the world,” Grupp said. “To me, it stands to reason that CAR T-cell therapy will be available at many of the centers around the world where patients with cancer regularly receive inpatient therapy.”

PAGE BREAK

Research and development

CAR T-cell therapy is viewed by many in the hematologic oncology community as a major step forward for a variety of diseases. As such, pharmaceutical companies have been clamoring to develop their own version of the therapy in preparation for FDA approval.

“CAR T cells have captured the interest of several biopharmaceutical companies,” Copelan said. “Novartis, Juno Therapeutics and Kite Pharma, among others, have multiple CD19–targeted CAR T-cell therapies in trials, and they anticipate expansion to additional diseases. Kite recently opened a 43,000-square foot facility with the capacity to produce CAR T cells for as many as 5,000 patients annually.”

Despite these advances, the decision by Novartis to close its dedicated CAR T-cell department has caused concerns among some in the research community.

The company disbanded its 400-person cell and gene unit in August; 120 staff members were laid off, and the others were reassigned to different departments.

“Novartis has championed CAR T cells,” Copelan said. “Despite assurances by Novartis of its continued commitment to CAR T-cell therapy, many see this as a pragmatic decision by a knowledgeable company, concerned with the prospect of high cost, limited application and the complexity of large-scale manufacturing of individualized cellular products.”

Although Novartis disbanded its cell unit, clinicians should not assume the company is no longer committed to CAR T-cell therapy, Grupp said.

“They have folded their unit into the overall oncology unit, but they are still going to be manufacturing products for cell therapy patients all over the world,” Grupp said. “From an outsider’s perspective, I don’t see this as a retreat. I see it as a reorganization.”

The continued advances of CAR T-cell therapy will be cause for conversation among doctors and patients, Leonard said.

“Patients and physicians considering these therapies need to carefully review the pros and cons and pay attention to the emerging data,” Leonard said. “I believe that we will start to see robust patient information and follow-up, with precise characterization of the patient populations best served by this approach.”

Despite the concerns that still must be addressed, Fung said he has little doubt that CAR T-cell therapy will be practice changing.

“These are the kind of developments I have been waiting for my entire career,” he said. “I don’t think it’s unfair to call it revolutionary.” – by Cameron Kelsall

Click here to read the POINTCOUNTER, “Will CAR T cells always be reserved for late lines of therapy?”

References:

Ali SA, et al. Blood. 2016;doi:10.1182/blood-2016-04-711903.

Grupp SA, et al. N Engl J Med. 2013;doi:10.1056/NEJMoa1215134.

Kochenderfer JN, et al. Blood. 2010;doi:10.1182/blood-2010-01-265041.

Kochenderfer JN, et al. J Clin Oncol. 2015;doi:10.1200/JCO.2014.56.2025.

Maude SL, et al. N Engl J Med. 2014;doi:10.1056/NEJMoa1407222.

Neelapu SS, et al. Abstract 7559. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.

Porter DL, et al. N Engl J Med. 2011;doi:10.1056/NEJMoa1103849.

Turtle CJ, et al. Sci Transl Med. 2016;doi:10.1126/scitranslmed.aaf8621.

For more information:

Edward A. Copelan, MD, FACP, can be reached at edward.copelan@carolinashealthcare.org.

Henry C. Fung, MD, FRCPE, can be reached at henry.fung@tuhs.temple.edu.

Stephan A. Grupp, MD, PhD, can be reached at grupp@email.chop.edu.

James N. Kochenderfer, MD, can be reached at kochendj@mail.nih.gov.

John P. Leonard, MD, can be reached at jpleonar@med.cornell.edu.

Disclosure: Grupp reports institutional research funding from and a consultant role with Novartis. Kochenderfer reports research funding from Bluebird Bio and Kite Pharma. Leonard reports financial relationships with Juno Therapeutics and Kite Pharma. Copelan and Fung report no relevant financial disclosures.