Commentary

Guest commentary: Early trials support use of CAR T-cell therapy in glioblastoma

Marcela V. Maus

In this guest commentary, Marcela V. Maus, MD, PhD, assistant professor of medicine at Harvard Medical School and director of cellular immunotherapy at Massachusetts General Hospital Cancer Center, discusses early research regarding the use of chimeric antigen receptor (CAR) T-cell therapy for the treatment of glioblastoma following the approval of tisagenlecleucel -T suspension ( Kymriah , Novartis), the first CAR T - cell therapy approved in the United States.

The data for glioblastoma are much younger than the data that went into the registration trials for acute lymphoblastic leukemia and the approval of tisagenlecleucel-T suspension, which is composed of genetically modified T cells that target CD19. Three trials in glioblastoma are underway — all phase 1, early investigational research.

At City of Hope, Christine Brown, PhD, and colleagues are targeting IL13R2 by administering the therapy within the tumor and into the ventricles. What’s pretty remarkable about that trial is that they had a patient who experienced complete regression of multiple lesions after several infusions of the CAR T cells; they published that data last year. An open trial at Baylor is using CAR T cells to target HER-2. Duke also has a fairly new trial open. We recently published a paper on our CAR T-cell trial in glioblastoma that we had open at Penn while I was there, but that trial is closed to enrollment and is not ongoing.

We haven’t seen the same toxicity profile of CD19 CAR T-cell therapy in the glioblastoma trials. We haven’t seen patients with systemic cytokine release syndrome, fevers or low blood pressure; or the neurologic toxicity that has been observed with CD19 CAR T-cell therapy. Patients with glioblastoma have a more significant baseline neurologic issue due to the nature of the tumor type, the need for resection for the disease and, in some cases, radiation treatment. As a result, some of these patients may be prone to seizures or other neurologic events, but we haven’t seen anything manifest in a similar enough way where one could say, ‘Oh, yes, we saw that with CD19 CAR T-cell therapy, too.’

The major issue with CAR T-cell therapy for glioblastoma is that most patients do not experience dramatic responses. Unlike in blood cancers — where we are seeing incredible response rates, as well as some toxicity based on immune activation — with glioblastoma, we commonly see very rare responses. We need to turn up the potency on the CAR T cells to get more patients to respond. The agent is reaching the tumor, but it is not having a massive antitumor effect, which means toxicity is less likely. I think when we increase the potency, we also may start to see potential toxicities emerge.

We have several unanswered questions. One is whether we are targeting the right antigens; three are in trials. We are also asking whether we are giving the CAR T-cell therapy at the right dose and on the right schedule. We used data from blood cancer trials to inform the dose, schedule and route of administration for CAR T cells in glioblastoma, but that may not be the best model. Our group administered one dose; most of the other investigators gave one or maybe two doses, and researchers at City of Hope are giving multiple doses. We administered our therapy intravenously; others are delivering it intravenously — into the tumor, or into the cerebrospinal fluid or both. There is still a lot that needs to be tested regarding the target, the dose and schedule, and the frequency of administration. There also is the potential for combination therapies that could improve the potency of the CAR T cells.

CAR T-cell therapy has the potential to be effective in glioblastoma. The tumor burdens are not as high as with other cancers, even blood cancers, and we have a reasonable idea on the appropriate targets. This is important knowledge to have for exploring CAR T cells in solid tumors. There also is a lot of enthusiasm from patients, patient advocates, physicians and scientists. It’s still too early to discuss where in the treatment paradigm this therapy will fall and how much it will cost, but the use of CAR T-cell therapy in glioblastoma is an area that is ripe for further investigation.

References:

ClinicalTrials.gov. EGFRvIII CAR T cells for newly-diagnosed GBM (ExCeL). Available at: https://clinicaltrials.gov/ct2/show/NCT02664363. Accessed Sept. 20, 2017.

ClinicialTrials.gov. Genetically modified T-cells in treating patients with recurrent or refractory malignant glioma. Available at: https://clinicaltrials.gov/ct2/show/NCT02208362?term=car+t+cell%2C+brain+tumor&rank=5. Accessed Sept. 20, 2017.

ClinicialTrials.gov. T cells expressing HER2-specific chimeric antigen receptors (CAR) for patients with glioblastoma (iCAR). Available at: https://clinicaltrials.gov/ct2/show/NCT02442297. Accessed Sept. 20, 2017.

For more information:

Marcela V. Maus, MD, PhD , can be reached at Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114.

Disclosure: Maus reports consultant or advisory roles with Kite, Juno, Novartis and Uber. She also served as an inventor on a patent with Novartis.

Marcela V. Maus

In this guest commentary, Marcela V. Maus, MD, PhD, assistant professor of medicine at Harvard Medical School and director of cellular immunotherapy at Massachusetts General Hospital Cancer Center, discusses early research regarding the use of chimeric antigen receptor (CAR) T-cell therapy for the treatment of glioblastoma following the approval of tisagenlecleucel -T suspension ( Kymriah , Novartis), the first CAR T - cell therapy approved in the United States.

The data for glioblastoma are much younger than the data that went into the registration trials for acute lymphoblastic leukemia and the approval of tisagenlecleucel-T suspension, which is composed of genetically modified T cells that target CD19. Three trials in glioblastoma are underway — all phase 1, early investigational research.

At City of Hope, Christine Brown, PhD, and colleagues are targeting IL13R2 by administering the therapy within the tumor and into the ventricles. What’s pretty remarkable about that trial is that they had a patient who experienced complete regression of multiple lesions after several infusions of the CAR T cells; they published that data last year. An open trial at Baylor is using CAR T cells to target HER-2. Duke also has a fairly new trial open. We recently published a paper on our CAR T-cell trial in glioblastoma that we had open at Penn while I was there, but that trial is closed to enrollment and is not ongoing.

We haven’t seen the same toxicity profile of CD19 CAR T-cell therapy in the glioblastoma trials. We haven’t seen patients with systemic cytokine release syndrome, fevers or low blood pressure; or the neurologic toxicity that has been observed with CD19 CAR T-cell therapy. Patients with glioblastoma have a more significant baseline neurologic issue due to the nature of the tumor type, the need for resection for the disease and, in some cases, radiation treatment. As a result, some of these patients may be prone to seizures or other neurologic events, but we haven’t seen anything manifest in a similar enough way where one could say, ‘Oh, yes, we saw that with CD19 CAR T-cell therapy, too.’

The major issue with CAR T-cell therapy for glioblastoma is that most patients do not experience dramatic responses. Unlike in blood cancers — where we are seeing incredible response rates, as well as some toxicity based on immune activation — with glioblastoma, we commonly see very rare responses. We need to turn up the potency on the CAR T cells to get more patients to respond. The agent is reaching the tumor, but it is not having a massive antitumor effect, which means toxicity is less likely. I think when we increase the potency, we also may start to see potential toxicities emerge.

PAGE BREAK

We have several unanswered questions. One is whether we are targeting the right antigens; three are in trials. We are also asking whether we are giving the CAR T-cell therapy at the right dose and on the right schedule. We used data from blood cancer trials to inform the dose, schedule and route of administration for CAR T cells in glioblastoma, but that may not be the best model. Our group administered one dose; most of the other investigators gave one or maybe two doses, and researchers at City of Hope are giving multiple doses. We administered our therapy intravenously; others are delivering it intravenously — into the tumor, or into the cerebrospinal fluid or both. There is still a lot that needs to be tested regarding the target, the dose and schedule, and the frequency of administration. There also is the potential for combination therapies that could improve the potency of the CAR T cells.

CAR T-cell therapy has the potential to be effective in glioblastoma. The tumor burdens are not as high as with other cancers, even blood cancers, and we have a reasonable idea on the appropriate targets. This is important knowledge to have for exploring CAR T cells in solid tumors. There also is a lot of enthusiasm from patients, patient advocates, physicians and scientists. It’s still too early to discuss where in the treatment paradigm this therapy will fall and how much it will cost, but the use of CAR T-cell therapy in glioblastoma is an area that is ripe for further investigation.

References:

ClinicalTrials.gov. EGFRvIII CAR T cells for newly-diagnosed GBM (ExCeL). Available at: https://clinicaltrials.gov/ct2/show/NCT02664363. Accessed Sept. 20, 2017.

ClinicialTrials.gov. Genetically modified T-cells in treating patients with recurrent or refractory malignant glioma. Available at: https://clinicaltrials.gov/ct2/show/NCT02208362?term=car+t+cell%2C+brain+tumor&rank=5. Accessed Sept. 20, 2017.

ClinicialTrials.gov. T cells expressing HER2-specific chimeric antigen receptors (CAR) for patients with glioblastoma (iCAR). Available at: https://clinicaltrials.gov/ct2/show/NCT02442297. Accessed Sept. 20, 2017.

For more information:

Marcela V. Maus, MD, PhD , can be reached at Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114.

Disclosure: Maus reports consultant or advisory roles with Kite, Juno, Novartis and Uber. She also served as an inventor on a patent with Novartis.