Cartwheels for CAR T-Cell Therapy?
Chimeric antigen receptor (CAR) T-cell therapy is a revolutionary treatment to targeted immunotherapy to treat cancer, and the details can seem like the stuff of science fiction: A patient’s T cells are harvested, re-engineered to become targeted “cancer killers,” and infused back into the patient’s assets to proliferate and eradicate cancer cells. In some cases, these T cells have even been shown to minimize the risk of relapse. 1,Two
“This is the one implement I have where I know that, even if a patient has ninety percent bone marrow blasts and has not responded to any kind of chemotherapy, I still have an eighty to ninety percent chance of putting the cancer into remission,” Stephan A. Grupp, MD, PhD, director of the Cancer Immunotherapy Frontier Program and director of Translational Research for the Center for Childhood Cancer Research at Children’s Hospital of Philadelphia (CHOP), told ASH Clinical News. “There is nothing like that out there.”
The excitement about bringing CAR T-cell therapy into the real world, tho’, is hampered by unanswered questions about side effects, indications, treatment delivery, relapse, and manufacturing.
Several CAR T-cell therapies are expected to begin the process of securing U.S. Food and Drug Administration (FDA) approval this year. ASH Clinical News spoke with Dr. Grupp and others to better understand the excitement, and limitation, of using these novel therapies.
The immune system plays a pivotal role in preventing tumor initiation and progression. However, T cells have a limited repertoire against any specific tumor, and cancer cells often evade immune detection and elimination. Immunotherapy “outsmarts” tumor cells by optimizing the immune response to the malignancy; CAR-modified T cells are just one type of immunotherapy treatment under investigation.
“CAR T cells are an amazing lump of biologic innovation based on the concept of harnessing T cells’ amazing killing power and broadening their capability to recognize their target,” explained Stephanie L. Goff, MD, a surgeon at the National Cancer Institute (NCI) who works with Senior Investigator Steven A. Rosenberg, MD, PhD, head of the NCI’s Tumor Immunology Section.
CAR T-cell therapy relies on re-engineering autologous T cells to express a receptor that permits the T cells to recognize tumor cells. A CAR is a recombinant receptor composed of an extracellular antigen-binding domain and an intracellular T-cell signaling domain. When voiced in T cells, CARs redirect the T cells to target the cancer cells that express the targeted antigen in a human leukocyte antigen (HLA)-independent manner. These cells then expand and become very focused hunters and killers of specific cells, unlike the indiscriminate destruction wrought by classic chemotherapeutics.
“By combining the killing power with the recognition of an antibody, we can engineer T cells to target cells with any antigen on their surface,” Dr. Goff said.
For hematologic malignancies, that means CAR T cells can lightly attack markers like CD19 and CD22, which are very voiced in B-cell malignancies.
A number of different CARs have been attempted, using different receptor designs and viral vectors. The early CARs consisted of only the T-cell receptor elaborate (TCR), while newer CARs incorporate costimulatory domains, such as CD28 or CD137, that improve cell survival and proliferation. Trio
Many of the CARs in development – especially those that are furthest along clinically – are directed at CD19, a cell-surface protein voiced on B cells and B-cell precursors. CD19 is voiced on the surface of most B-cell malignancies, which include some leukemias and myelomas, and most non-Hodgkin lymphomas (NHLs).
Three pharmaceutical companies have second-generation CAR T-cell products in advanced development (TABLE); each of which has teamed with an academic center: Kite Pharma with the NCI; Novartis with the University of Pennsylvania (UPenn); and Juno Therapeutics with Memorial Sloan Kettering Cancer Center, Fred Hutchinson Cancer Research Center, and Seattle Children’s Hospital.
“Four or five years ago, people would have looked at the idea of immunotherapy as accomplish science fiction. They might say, ‘It’s too hard, complicated, boutique, [and] academic,’” Dr. Grupp said. Now, however, with two products expected to file FDA applications in the very first half of this year, he sees CAR T-cell therapies headed to the mainstream. “One could be an accident, but with two, we might be heading toward a trend.”
CD19-directed, CAR-modified T cells have shown promise in relapsed or chemotherapy-refractory B-cell acute lymphoblastic leukemia (ALL) and, to a lesser extent, benefit in relapsed/refractory chronic lymphocytic leukemia (CLL) and B-cell NHLs, including diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma. Four,Five (Editor’s note: At the two thousand sixteen ASH Annual Meeting, Sattva S. Neelapu, MD, introduced results from the phase II ZUMA-1 trial of anti-CD19 CAR T cells in patients with relapsed refractory DBLCL as a late-breaking abstract).
Ongoing investigations are attempting to expand these indications, including to ALL in children and adults. Treatment with CD19-targeted CAR T-cell therapies has produced remission rates as high as ninety four percent in children and youthful adults with relapsed and refractory ALL. Six “This probe also confirmed the high accomplish remission rate, including a disease-free survival rate of approximately fifty five percent at one year,” Dr. Grupp noted, adding that, “beyond one year, we have not observed much disease recurrence.”
He explained that, while some research groups are investigating CAR T cells as a bridge to hematopoietic cell transplantation (HCT), at CHOP, researchers are attempting to avoid transplants. “Skipping bone marrow transplant and substituting it with immunotherapy is an attractive, titillating idea.”
In CLL and NHL, response rates are approximately forty to fifty percent, with similar durability. In the most latest trial at NCI, Dr. Goff administered CAR T cells to nineteen patients with DLBCL who were refractory to standard therapies or had undergone autologous HCT. Nine of those patients achieved finish remission, and all nine remain in remission past one year of follow-up. Four “This is a population of patients who was looking for salvage therapy, and nine of them don’t have active lymphoma anymore,” Dr. Goff said.
A Complicated and Individualized Process
CAR T-cell therapy is a multistep process that can take anywhere from a few days to several weeks. After leukapheresis is ended, the T cells are activated and expanded ex vivo, then genetically modified for stable CAR expression, typically with the use of retroviral or lentiviral transduction. These reprogrammed cells are expanded to obtain a therapeutic dose of CAR T cells to be infused into the patient.
Before that happens, the patient undergoes chemotherapy to deplete his or her own remaining T cells. “The chemotherapy creates an environment within the figure that is ‘hungry’ for T cells,” Dr. Goff explained. “The immune system is then generating the right kind of cytokines to help the CAR T cells proliferate and expand.”
Figuring out the right combination (i.e., which chemotherapy to use and what dose and what amount of re-engineered T cells to reintroduce), tho’, is difficult, she said. For most candidate CARs, this has been a long process of trial and error, sometimes with fatal results.
In the summer of 2016, the FDA placed the phase II ROCKET trial of JCAR015 in adults with ALL on hold after two patients died of cerebral edema. The drug’s manufacturer (Juno Therapeutics, Inc.) reported that the deaths were related to the addition of fludarabine to the pre-conditioning regimen, and the trial was permitted to proceed after cyclophosphamide was used as a substitution. However, in November, Juno Therapeutics placed the trial on voluntary hold following two extra patient deaths from cerebral edema. These deaths, Juno Therapeutics reported, appeared to be correlated with the rapid proliferation of CAR T cells injected back into the figure, and it is working with the FDA to determine next steps.
Dr. Goff added that the DLBCL trial also required a modification due to issues with the chemotherapy preconditioning regimen. In a previous trial of the same agent and the same patient group, there was some concern that the high response rate observed might have been a result of the chemotherapy regimen used, as opposed to the CAR T-cell therapy. Seven They re-did the trial with low-dose chemotherapy, and these findings were similar and “maybe even a little better,” she said.
Determining the correct amount of T cells infused also requires precision. In one patient in the NCI trial, the investigators opted to infuse three times the normal amount of cells to see if more is better. “It may have been coincidence, but one patient experienced some of the most severe neurotoxicity we have seen, so we instantaneously backed away from that higher dose of cells,” said Dr. Goff.
The practices with the ROCKET trial illustrate why some researchers are reserving judgment about the game-changing potential of CAR T-cell therapies: The potential benefits of CAR T cells come with real risks.
“To securely manage the toxicities of the investigational therapies, it is best for patients to be treated in a large medical center with a transplant program and with a good intensive care unit (ICU),” said Dr. Grupp. “The toxicities are manageable – even in the sickest patients – but it is challenging to take a patient whose bone marrow has been substituted by, literally, pounds of leukemia through cytokine release syndrome (CRS).”
CAR T-cell therapy holds the distinction of being one of the very first cancer therapeutics wherein the best sign that it is working is how terribly ill the patient gets, Dr. Grupp noted. And, the greater the tumor cargo, the more the engineered T cells will work to eradicate it. The development of CRS – an inflammatory response that directly correlates with in vivo CAR T-cell expansion and proliferation – is the “flipside” of engineered T cells working effectively. CRS often presents very first as a fever, followed by myalgia, nausea, extreme weariness, encephalopathy, and transient hypotension. In some patients, it progresses to life-threatening vasodilatory shock. In most cases, it is self-limiting, but in others it requires anti-cytokine-directed therapy.
Researchers at UPenn have developed predictive models of CRS to learn if it is possible to intervene early enough to reduce morbidity and mortality. Eight They also have published data indicating that, while there seems to be a correlation inbetween the development of CRS and response to the CAR T-cell therapy, there does not show up to be a strong association inbetween the degree of CRS and outcome. 8
The very first child with ALL that Dr. Grupp treated at CHOP was a youthfull damsel named Emily Whitehead. 9,Ten “Most of her bone marrow was substituted by leukemia,” Dr. Grupp recounted. Emily’s case became public shortly after she recovered and her treatment was deemed a success. She remains in remission almost five years later.
“Emily got terribly, critically ill with CRS, but we found that one of the inflammatory proteins that was markedly elevated in her blood was interleukin-6 (IL-6), which we weren’t expecting,” he explained. “We subsequently found that other patients with CRS also have sky-high levels of IL-6.”
Once Emily was treated with tocilizumab (an antibody against the IL-6 receptor used primarily to treat rheumatoid arthritis), her symptoms rapidly reversed.
“It was exceptionally fortuitous for her, and for the entire field, that tocilizumab was utterly transformative for treating severe CRS,” said Dr. Grupp. “Without the capability to block IL-6, I don’t think we could securely give these cells to patients.”
The drug is now part of the standard toxicity management protocol, and it works with all three available CAR T-cell therapies. Dr. Grupp stressed, however, that the side effects of CAR T cells shouldn’t be minimized; they require sophisticated ICU-level care and an experienced team to manage them, which may limit the number of centers able to administer the treatment.
While cytokine blockade with tocilizumab is effective in reversing CRS, it does not prevent expansion of CAR T cells or reduce their anti-leukemic efficacy.
Dr. Goff has found neurotoxicity to be a thicker issue than CRS, maybe, she speculated, because, “in leukemia, the cell being targeted is loosely circulating in the blood and marrow, which may make CRS more evident. In lymphoma, the targets are solid masses, rather than cells floating around in the blood.”
In the latest trial of CAR T-cell therapy conducted at NCI, only three patients (of Nineteen) required any sort of vasoactive medication to counteract CRS, while about half experienced grade three or four neurotoxicity.Four “We’ve seen a range of neurotoxicity, varying from mild confusion and word-finding issues to frank encephalopathy, hallucinations, seizures, and extreme agitation,” she said.
Some patients will practice both CRS and neurotoxicity – together or in sequential order – but, despite these side effects, most patients recover after careful monitoring and supportive care, Dr. Goff said. “Two patients required intubation because they were incapable to maintain their mental status enough to protect their airways,” she noted, “but even without extra treatment to stop the T cells with steroids, these patients recovered.”
Despite the promise seen in B-cell cancers, CAR T-cell therapy is only in its infancy. There are still many unanswered questions and ways in which the therapies might be improved or their use extended to other cancers.
“We don’t even know yet if the response rates we have seen will be replicated once the therapy starts being used more widely,” said Dr. Goff.
Assuming these therapies receive regulatory approval, myriad issues surround the implementation of such a groundbreaking therapy. Who will produce the therapy? Where will the cell processing be done? How does one mass produce a time-, labor-, and technology-intensive personalized therapy? How can efficacy and safety be ensured via the process? What will it cost?
Clinically, Dr. Goff does not see CAR T-cell therapy as being more complicated than hematopoietic cell transplantation, and, in some ways, it may be less complicated. Both are very individualized and require sophisticated chemotherapy regimens, and they need to be performed at centers used to dealing with life-threatening side effects.
“I don’t know if CAR T-cell therapy will ever become a firstline option because there are many patients who go into remission with standard chemotherapy,” Dr. Goff said, “but I think, in a world where transplant is a feasible option, CAR T-cell therapy is no more difficult.”
CAR T cells might not yet be poised to overtake chemotherapy as the standard of care, but they are looking promising as treatment for certain patients with no other feasible options.
“The success seen in lymphoma and leukemia is not necessarily going to translate to more common cancers, even tho’ we are still actively investigating its use in those settings,” Dr. Goff said. “The durability of the responses we’ve seen thus far is very good, so we now have something that is very effective for a population of patients in search of salvage therapy.” —By Debra L. Beck
Cartwheels for CAR T-Cell Therapy? ASH Clinical News
Cartwheels for CAR T-Cell Therapy?
Chimeric antigen receptor (CAR) T-cell therapy is a revolutionary treatment to targeted immunotherapy to treat cancer, and the details can seem like the stuff of science fiction: A patient’s T cells are harvested, re-engineered to become targeted “cancer killers,” and infused back into the patient’s assets to proliferate and eradicate cancer cells. In some cases, these T cells have even been shown to minimize the risk of relapse. 1,Two
“This is the one instrument I have where I know that, even if a patient has ninety percent bone marrow blasts and has not responded to any kind of chemotherapy, I still have an eighty to ninety percent chance of putting the cancer into remission,” Stephan A. Grupp, MD, PhD, director of the Cancer Immunotherapy Frontier Program and director of Translational Research for the Center for Childhood Cancer Research at Children’s Hospital of Philadelphia (CHOP), told ASH Clinical News. “There is nothing like that out there.”
The excitement about bringing CAR T-cell therapy into the real world, however, is hampered by unanswered questions about side effects, indications, treatment delivery, relapse, and manufacturing.
Several CAR T-cell therapies are expected to begin the process of securing U.S. Food and Drug Administration (FDA) approval this year. ASH Clinical News spoke with Dr. Grupp and others to better understand the excitement, and limitation, of using these novel therapies.
The immune system plays a pivotal role in preventing tumor initiation and progression. However, T cells have a limited repertoire against any specific tumor, and cancer cells often evade immune detection and elimination. Immunotherapy “outsmarts” tumor cells by optimizing the immune response to the malignancy; CAR-modified T cells are just one type of immunotherapy treatment under investigation.
“CAR T cells are an amazing lump of biologic innovation based on the concept of harnessing T cells’ amazing killing power and broadening their capability to recognize their target,” explained Stephanie L. Goff, MD, a surgeon at the National Cancer Institute (NCI) who works with Senior Investigator Steven A. Rosenberg, MD, PhD, head of the NCI’s Tumor Immunology Section.
CAR T-cell therapy relies on re-engineering autologous T cells to express a receptor that permits the T cells to recognize tumor cells. A CAR is a recombinant receptor composed of an extracellular antigen-binding domain and an intracellular T-cell signaling domain. When voiced in T cells, CARs redirect the T cells to target the cancer cells that express the targeted antigen in a human leukocyte antigen (HLA)-independent manner. These cells then expand and become very focused hunters and killers of specific cells, unlike the indiscriminate destruction wrought by classic chemotherapeutics.
“By combining the killing power with the recognition of an antibody, we can engineer T cells to target cells with any antigen on their surface,” Dr. Goff said.
For hematologic malignancies, that means CAR T cells can lightly attack markers like CD19 and CD22, which are very voiced in B-cell malignancies.
A number of different CARs have been attempted, using different receptor designs and viral vectors. The early CARs consisted of only the T-cell receptor complicated (TCR), while newer CARs incorporate costimulatory domains, such as CD28 or CD137, that improve cell survival and proliferation. Trio
Many of the CARs in development – especially those that are furthest along clinically – are directed at CD19, a cell-surface protein voiced on B cells and B-cell precursors. CD19 is voiced on the surface of most B-cell malignancies, which include some leukemias and myelomas, and most non-Hodgkin lymphomas (NHLs).
Three pharmaceutical companies have second-generation CAR T-cell products in advanced development (TABLE); each of which has teamed with an academic center: Kite Pharma with the NCI; Novartis with the University of Pennsylvania (UPenn); and Juno Therapeutics with Memorial Sloan Kettering Cancer Center, Fred Hutchinson Cancer Research Center, and Seattle Children’s Hospital.
“Four or five years ago, people would have looked at the idea of immunotherapy as accomplish science fiction. They might say, ‘It’s too hard, complicated, boutique, [and] academic,’” Dr. Grupp said. Now, however, with two products expected to file FDA applications in the very first half of this year, he sees CAR T-cell therapies headed to the mainstream. “One could be an accident, but with two, we might be heading toward a trend.”
CD19-directed, CAR-modified T cells have shown promise in relapsed or chemotherapy-refractory B-cell acute lymphoblastic leukemia (ALL) and, to a lesser extent, benefit in relapsed/refractory chronic lymphocytic leukemia (CLL) and B-cell NHLs, including diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma. Four,Five (Editor’s note: At the two thousand sixteen ASH Annual Meeting, Sattva S. Neelapu, MD, introduced results from the phase II ZUMA-1 trial of anti-CD19 CAR T cells in patients with relapsed refractory DBLCL as a late-breaking abstract).
Ongoing investigations are attempting to expand these indications, including to ALL in children and adults. Treatment with CD19-targeted CAR T-cell therapies has produced remission rates as high as ninety four percent in children and youthfull adults with relapsed and refractory ALL. Six “This investigate also confirmed the high finish remission rate, including a disease-free survival rate of approximately fifty five percent at one year,” Dr. Grupp noted, adding that, “beyond one year, we have not observed much disease recurrence.”
He explained that, while some research groups are investigating CAR T cells as a bridge to hematopoietic cell transplantation (HCT), at CHOP, researchers are attempting to avoid transplants. “Skipping bone marrow transplant and substituting it with immunotherapy is an attractive, titillating idea.”
In CLL and NHL, response rates are approximately forty to fifty percent, with similar durability. In the most latest trial at NCI, Dr. Goff administered CAR T cells to nineteen patients with DLBCL who were refractory to standard therapies or had undergone autologous HCT. Nine of those patients achieved accomplish remission, and all nine remain in remission past one year of follow-up. Four “This is a population of patients who was looking for salvage therapy, and nine of them don’t have active lymphoma anymore,” Dr. Goff said.
A Complicated and Individualized Process
CAR T-cell therapy is a multistep process that can take anywhere from a few days to several weeks. After leukapheresis is ended, the T cells are activated and expanded ex vivo, then genetically modified for stable CAR expression, typically with the use of retroviral or lentiviral transduction. These reprogrammed cells are expanded to obtain a therapeutic dose of CAR T cells to be infused into the patient.
Before that happens, the patient undergoes chemotherapy to deplete his or her own remaining T cells. “The chemotherapy creates an environment within the assets that is ‘hungry’ for T cells,” Dr. Goff explained. “The immune system is then generating the right kind of cytokines to help the CAR T cells proliferate and expand.”
Figuring out the right combination (i.e., which chemotherapy to use and what dose and what amount of re-engineered T cells to reintroduce), tho’, is difficult, she said. For most candidate CARs, this has been a long process of trial and error, sometimes with fatal results.
In the summer of 2016, the FDA placed the phase II ROCKET trial of JCAR015 in adults with ALL on hold after two patients died of cerebral edema. The drug’s manufacturer (Juno Therapeutics, Inc.) reported that the deaths were related to the addition of fludarabine to the pre-conditioning regimen, and the trial was permitted to proceed after cyclophosphamide was used as a substitution. However, in November, Juno Therapeutics placed the trial on voluntary hold following two extra patient deaths from cerebral edema. These deaths, Juno Therapeutics reported, appeared to be correlated with the rapid proliferation of CAR T cells injected back into the bod, and it is working with the FDA to determine next steps.
Dr. Goff added that the DLBCL trial also required a modification due to issues with the chemotherapy preconditioning regimen. In a previous trial of the same agent and the same patient group, there was some concern that the high response rate observed might have been a result of the chemotherapy regimen used, as opposed to the CAR T-cell therapy. Seven They re-did the trial with low-dose chemotherapy, and these findings were similar and “maybe even a little better,” she said.
Determining the correct amount of T cells infused also requires precision. In one patient in the NCI trial, the investigators opted to infuse three times the normal amount of cells to see if more is better. “It may have been coincidence, but one patient experienced some of the most severe neurotoxicity we have seen, so we instantly backed away from that higher dose of cells,” said Dr. Goff.
The practices with the ROCKET trial illustrate why some researchers are reserving judgment about the game-changing potential of CAR T-cell therapies: The potential benefits of CAR T cells come with real risks.
“To securely manage the toxicities of the investigational therapies, it is best for patients to be treated in a large medical center with a transplant program and with a good intensive care unit (ICU),” said Dr. Grupp. “The toxicities are manageable – even in the sickest patients – but it is challenging to take a patient whose bone marrow has been substituted by, literally, pounds of leukemia through cytokine release syndrome (CRS).”
CAR T-cell therapy holds the distinction of being one of the very first cancer therapeutics wherein the best sign that it is working is how terribly ill the patient gets, Dr. Grupp noted. And, the greater the tumor cargo, the more the engineered T cells will work to eradicate it. The development of CRS – an inflammatory response that directly correlates with in vivo CAR T-cell expansion and proliferation – is the “flipside” of engineered T cells working effectively. CRS often presents very first as a fever, followed by myalgia, nausea, extreme tiredness, encephalopathy, and transient hypotension. In some patients, it progresses to life-threatening vasodilatory shock. In most cases, it is self-limiting, but in others it requires anti-cytokine-directed therapy.
Researchers at UPenn have developed predictive models of CRS to learn if it is possible to intervene early enough to reduce morbidity and mortality. Eight They also have published data indicating that, while there seems to be a correlation inbetween the development of CRS and response to the CAR T-cell therapy, there does not show up to be a strong association inbetween the degree of CRS and outcome. 8
The very first child with ALL that Dr. Grupp treated at CHOP was a youthfull female named Emily Whitehead. 9,Ten “Most of her bone marrow was substituted by leukemia,” Dr. Grupp recounted. Emily’s case became public shortly after she recovered and her treatment was deemed a success. She remains in remission almost five years later.
“Emily got terribly, critically ill with CRS, but we found that one of the inflammatory proteins that was markedly elevated in her blood was interleukin-6 (IL-6), which we weren’t expecting,” he explained. “We subsequently found that other patients with CRS also have sky-high levels of IL-6.”
Once Emily was treated with tocilizumab (an antibody against the IL-6 receptor used primarily to treat rheumatoid arthritis), her symptoms rapidly reversed.
“It was exceptionally fortuitous for her, and for the entire field, that tocilizumab was utterly transformative for treating severe CRS,” said Dr. Grupp. “Without the capability to block IL-6, I don’t think we could securely give these cells to patients.”
The drug is now part of the standard toxicity management protocol, and it works with all three available CAR T-cell therapies. Dr. Grupp stressed, however, that the side effects of CAR T cells shouldn’t be minimized; they require sophisticated ICU-level care and an experienced team to manage them, which may limit the number of centers able to administer the treatment.
While cytokine blockade with tocilizumab is effective in reversing CRS, it does not prevent expansion of CAR T cells or reduce their anti-leukemic efficacy.
Dr. Goff has found neurotoxicity to be a fatter issue than CRS, maybe, she speculated, because, “in leukemia, the cell being targeted is loosely circulating in the blood and marrow, which may make CRS more evident. In lymphoma, the targets are solid masses, rather than cells floating around in the blood.”
In the latest trial of CAR T-cell therapy conducted at NCI, only three patients (of Nineteen) required any sort of vasoactive medication to counteract CRS, while about half experienced grade three or four neurotoxicity.Four “We’ve seen a range of neurotoxicity, varying from mild confusion and word-finding issues to frank encephalopathy, hallucinations, seizures, and extreme agitation,” she said.
Some patients will practice both CRS and neurotoxicity – together or in sequential order – but, despite these side effects, most patients recover after careful monitoring and supportive care, Dr. Goff said. “Two patients required intubation because they were incapable to maintain their mental status enough to protect their airways,” she noted, “but even without extra treatment to stop the T cells with steroids, these patients recovered.”
Despite the promise seen in B-cell cancers, CAR T-cell therapy is only in its infancy. There are still many unanswered questions and ways in which the therapies might be improved or their use extended to other cancers.
“We don’t even know yet if the response rates we have seen will be replicated once the therapy starts being used more widely,” said Dr. Goff.
Assuming these therapies receive regulatory approval, myriad issues surround the implementation of such a groundbreaking therapy. Who will produce the therapy? Where will the cell processing be done? How does one mass produce a time-, labor-, and technology-intensive personalized therapy? How can efficacy and safety be ensured across the process? What will it cost?
Clinically, Dr. Goff does not see CAR T-cell therapy as being more complicated than hematopoietic cell transplantation, and, in some ways, it may be less complicated. Both are very individualized and require elaborate chemotherapy regimens, and they need to be performed at centers used to dealing with life-threatening side effects.
“I don’t know if CAR T-cell therapy will ever become a firstline option because there are many patients who go into remission with standard chemotherapy,” Dr. Goff said, “but I think, in a world where transplant is a feasible option, CAR T-cell therapy is no more difficult.”
CAR T cells might not yet be poised to overtake chemotherapy as the standard of care, but they are looking promising as treatment for certain patients with no other feasible options.
“The success seen in lymphoma and leukemia is not necessarily going to translate to more common cancers, even however we are still actively investigating its use in those settings,” Dr. Goff said. “The durability of the responses we’ve seen thus far is very good, so we now have something that is very effective for a population of patients in search of salvage therapy.” —By Debra L. Beck
Cartwheels for CAR T-Cell Therapy? ASH Clinical News
Cartwheels for CAR T-Cell Therapy?
Chimeric antigen receptor (CAR) T-cell therapy is a revolutionary treatment to targeted immunotherapy to treat cancer, and the details can seem like the stuff of science fiction: A patient’s T cells are harvested, re-engineered to become targeted “cancer killers,” and infused back into the patient’s bod to proliferate and eradicate cancer cells. In some cases, these T cells have even been shown to minimize the risk of relapse. 1,Two
“This is the one instrument I have where I know that, even if a patient has ninety percent bone marrow blasts and has not responded to any kind of chemotherapy, I still have an eighty to ninety percent chance of putting the cancer into remission,” Stephan A. Grupp, MD, PhD, director of the Cancer Immunotherapy Frontier Program and director of Translational Research for the Center for Childhood Cancer Research at Children’s Hospital of Philadelphia (CHOP), told ASH Clinical News. “There is nothing like that out there.”
The excitement about bringing CAR T-cell therapy into the real world, however, is hampered by unanswered questions about side effects, indications, treatment delivery, relapse, and manufacturing.
Several CAR T-cell therapies are expected to begin the process of securing U.S. Food and Drug Administration (FDA) approval this year. ASH Clinical News spoke with Dr. Grupp and others to better understand the excitement, and limitation, of using these novel therapies.
The immune system plays a pivotal role in preventing tumor initiation and progression. However, T cells have a limited repertoire against any specific tumor, and cancer cells often evade immune detection and elimination. Immunotherapy “outsmarts” tumor cells by optimizing the immune response to the malignancy; CAR-modified T cells are just one type of immunotherapy treatment under investigation.
“CAR T cells are an amazing chunk of biologic innovation based on the concept of harnessing T cells’ amazing killing power and broadening their capability to recognize their target,” explained Stephanie L. Goff, MD, a surgeon at the National Cancer Institute (NCI) who works with Senior Investigator Steven A. Rosenberg, MD, PhD, head of the NCI’s Tumor Immunology Section.
CAR T-cell therapy relies on re-engineering autologous T cells to express a receptor that permits the T cells to recognize tumor cells. A CAR is a recombinant receptor composed of an extracellular antigen-binding domain and an intracellular T-cell signaling domain. When voiced in T cells, CARs redirect the T cells to target the cancer cells that express the targeted antigen in a human leukocyte antigen (HLA)-independent manner. These cells then expand and become very focused hunters and killers of specific cells, unlike the indiscriminate destruction wrought by classic chemotherapeutics.
“By combining the killing power with the recognition of an antibody, we can engineer T cells to target cells with any antigen on their surface,” Dr. Goff said.
For hematologic malignancies, that means CAR T cells can lightly attack markers like CD19 and CD22, which are very voiced in B-cell malignancies.
A number of different CARs have been attempted, using different receptor designs and viral vectors. The early CARs consisted of only the T-cell receptor sophisticated (TCR), while newer CARs incorporate costimulatory domains, such as CD28 or CD137, that improve cell survival and proliferation. Three
Many of the CARs in development – especially those that are furthest along clinically – are directed at CD19, a cell-surface protein voiced on B cells and B-cell precursors. CD19 is voiced on the surface of most B-cell malignancies, which include some leukemias and myelomas, and most non-Hodgkin lymphomas (NHLs).
Three pharmaceutical companies have second-generation CAR T-cell products in advanced development (TABLE); each of which has teamed with an academic center: Kite Pharma with the NCI; Novartis with the University of Pennsylvania (UPenn); and Juno Therapeutics with Memorial Sloan Kettering Cancer Center, Fred Hutchinson Cancer Research Center, and Seattle Children’s Hospital.
“Four or five years ago, people would have looked at the idea of immunotherapy as accomplish science fiction. They might say, ‘It’s too hard, complicated, boutique, [and] academic,’” Dr. Grupp said. Now, tho’, with two products expected to file FDA applications in the very first half of this year, he sees CAR T-cell therapies headed to the mainstream. “One could be an accident, but with two, we might be heading toward a trend.”
CD19-directed, CAR-modified T cells have shown promise in relapsed or chemotherapy-refractory B-cell acute lymphoblastic leukemia (ALL) and, to a lesser extent, benefit in relapsed/refractory chronic lymphocytic leukemia (CLL) and B-cell NHLs, including diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma. Four,Five (Editor’s note: At the two thousand sixteen ASH Annual Meeting, Sattva S. Neelapu, MD, introduced results from the phase II ZUMA-1 trial of anti-CD19 CAR T cells in patients with relapsed refractory DBLCL as a late-breaking abstract).
Ongoing investigations are attempting to expand these indications, including to ALL in children and adults. Treatment with CD19-targeted CAR T-cell therapies has produced remission rates as high as ninety four percent in children and youthful adults with relapsed and refractory ALL. Six “This investigate also confirmed the high finish remission rate, including a disease-free survival rate of approximately fifty five percent at one year,” Dr. Grupp noted, adding that, “beyond one year, we have not observed much disease recurrence.”
He explained that, while some research groups are investigating CAR T cells as a bridge to hematopoietic cell transplantation (HCT), at CHOP, researchers are attempting to avoid transplants. “Skipping bone marrow transplant and substituting it with immunotherapy is an attractive, titillating idea.”
In CLL and NHL, response rates are approximately forty to fifty percent, with similar durability. In the most latest trial at NCI, Dr. Goff administered CAR T cells to nineteen patients with DLBCL who were refractory to standard therapies or had undergone autologous HCT. Nine of those patients achieved finish remission, and all nine remain in remission past one year of follow-up. Four “This is a population of patients who was looking for salvage therapy, and nine of them don’t have active lymphoma anymore,” Dr. Goff said.
A Complicated and Individualized Process
CAR T-cell therapy is a multistep process that can take anywhere from a few days to several weeks. After leukapheresis is ended, the T cells are activated and expanded ex vivo, then genetically modified for stable CAR expression, typically with the use of retroviral or lentiviral transduction. These reprogrammed cells are expanded to obtain a therapeutic dose of CAR T cells to be infused into the patient.
Before that happens, the patient undergoes chemotherapy to deplete his or her own remaining T cells. “The chemotherapy creates an environment within the assets that is ‘hungry’ for T cells,” Dr. Goff explained. “The immune system is then generating the right kind of cytokines to help the CAR T cells proliferate and expand.”
Figuring out the right combination (i.e., which chemotherapy to use and what dose and what amount of re-engineered T cells to reintroduce), however, is difficult, she said. For most candidate CARs, this has been a long process of trial and error, sometimes with fatal results.
In the summer of 2016, the FDA placed the phase II ROCKET trial of JCAR015 in adults with ALL on hold after two patients died of cerebral edema. The drug’s manufacturer (Juno Therapeutics, Inc.) reported that the deaths were related to the addition of fludarabine to the pre-conditioning regimen, and the trial was permitted to proceed after cyclophosphamide was used as a substitution. However, in November, Juno Therapeutics placed the trial on voluntary hold following two extra patient deaths from cerebral edema. These deaths, Juno Therapeutics reported, appeared to be correlated with the rapid proliferation of CAR T cells injected back into the assets, and it is working with the FDA to determine next steps.
Dr. Goff added that the DLBCL trial also required a modification due to issues with the chemotherapy preconditioning regimen. In a previous trial of the same agent and the same patient group, there was some concern that the high response rate observed might have been a result of the chemotherapy regimen used, as opposed to the CAR T-cell therapy. Seven They re-did the trial with low-dose chemotherapy, and these findings were similar and “maybe even a little better,” she said.
Determining the correct amount of T cells infused also requires precision. In one patient in the NCI trial, the investigators opted to infuse three times the normal amount of cells to see if more is better. “It may have been coincidence, but one patient experienced some of the most severe neurotoxicity we have seen, so we instantly backed away from that higher dose of cells,” said Dr. Goff.
The practices with the ROCKET trial illustrate why some researchers are reserving judgment about the game-changing potential of CAR T-cell therapies: The potential benefits of CAR T cells come with real risks.
“To securely manage the toxicities of the investigational therapies, it is best for patients to be treated in a large medical center with a transplant program and with a good intensive care unit (ICU),” said Dr. Grupp. “The toxicities are manageable – even in the sickest patients – but it is challenging to take a patient whose bone marrow has been substituted by, literally, pounds of leukemia through cytokine release syndrome (CRS).”
CAR T-cell therapy holds the distinction of being one of the very first cancer therapeutics wherein the best sign that it is working is how terribly ill the patient gets, Dr. Grupp noted. And, the greater the tumor cargo, the more the engineered T cells will work to eradicate it. The development of CRS – an inflammatory response that directly correlates with in vivo CAR T-cell expansion and proliferation – is the “flipside” of engineered T cells working effectively. CRS often presents very first as a fever, followed by myalgia, nausea, extreme tiredness, encephalopathy, and transient hypotension. In some patients, it progresses to life-threatening vasodilatory shock. In most cases, it is self-limiting, but in others it requires anti-cytokine-directed therapy.
Researchers at UPenn have developed predictive models of CRS to learn if it is possible to intervene early enough to reduce morbidity and mortality. Eight They also have published data indicating that, while there seems to be a correlation inbetween the development of CRS and response to the CAR T-cell therapy, there does not emerge to be a strong association inbetween the degree of CRS and outcome. 8
The very first child with ALL that Dr. Grupp treated at CHOP was a youthfull woman named Emily Whitehead. 9,Ten “Most of her bone marrow was substituted by leukemia,” Dr. Grupp recounted. Emily’s case became public shortly after she recovered and her treatment was deemed a success. She remains in remission almost five years later.
“Emily got terribly, critically ill with CRS, but we found that one of the inflammatory proteins that was markedly elevated in her blood was interleukin-6 (IL-6), which we weren’t expecting,” he explained. “We subsequently found that other patients with CRS also have sky-high levels of IL-6.”
Once Emily was treated with tocilizumab (an antibody against the IL-6 receptor used primarily to treat rheumatoid arthritis), her symptoms rapidly reversed.
“It was exceptionally fortuitous for her, and for the entire field, that tocilizumab was utterly transformative for treating severe CRS,” said Dr. Grupp. “Without the capability to block IL-6, I don’t think we could securely give these cells to patients.”
The drug is now part of the standard toxicity management protocol, and it works with all three available CAR T-cell therapies. Dr. Grupp stressed, however, that the side effects of CAR T cells shouldn’t be minimized; they require sophisticated ICU-level care and an experienced team to manage them, which may limit the number of centers able to administer the treatment.
While cytokine blockade with tocilizumab is effective in reversing CRS, it does not prevent expansion of CAR T cells or reduce their anti-leukemic efficacy.
Dr. Goff has found neurotoxicity to be a thicker issue than CRS, maybe, she speculated, because, “in leukemia, the cell being targeted is loosely circulating in the blood and marrow, which may make CRS more evident. In lymphoma, the targets are solid masses, rather than cells floating around in the blood.”
In the latest trial of CAR T-cell therapy conducted at NCI, only three patients (of Nineteen) required any sort of vasoactive medication to counteract CRS, while about half experienced grade three or four neurotoxicity.Four “We’ve seen a range of neurotoxicity, varying from mild confusion and word-finding issues to frank encephalopathy, hallucinations, seizures, and extreme agitation,” she said.
Some patients will practice both CRS and neurotoxicity – together or in sequential order – but, despite these side effects, most patients recover after careful monitoring and supportive care, Dr. Goff said. “Two patients required intubation because they were incapable to maintain their mental status enough to protect their airways,” she noted, “but even without extra treatment to stop the T cells with steroids, these patients recovered.”
Despite the promise seen in B-cell cancers, CAR T-cell therapy is only in its infancy. There are still many unanswered questions and ways in which the therapies might be improved or their use extended to other cancers.
“We don’t even know yet if the response rates we have seen will be replicated once the therapy starts being used more widely,” said Dr. Goff.
Assuming these therapies receive regulatory approval, myriad issues surround the implementation of such a groundbreaking therapy. Who will produce the therapy? Where will the cell processing be done? How does one mass produce a time-, labor-, and technology-intensive personalized therapy? How can efficacy and safety be ensured across the process? What will it cost?
Clinically, Dr. Goff does not see CAR T-cell therapy as being more complicated than hematopoietic cell transplantation, and, in some ways, it may be less complicated. Both are very individualized and require sophisticated chemotherapy regimens, and they need to be performed at centers used to dealing with life-threatening side effects.
“I don’t know if CAR T-cell therapy will ever become a firstline option because there are many patients who go into remission with standard chemotherapy,” Dr. Goff said, “but I think, in a world where transplant is a feasible option, CAR T-cell therapy is no more difficult.”
CAR T cells might not yet be poised to overtake chemotherapy as the standard of care, but they are looking promising as treatment for certain patients with no other feasible options.
“The success seen in lymphoma and leukemia is not necessarily going to translate to more common cancers, even tho’ we are still actively investigating its use in those settings,” Dr. Goff said. “The durability of the responses we’ve seen thus far is very good, so we now have something that is very effective for a population of patients in search of salvage therapy.” —By Debra L. Beck
