Σάββατο, 31 Δεκεμβρίου 2016

CAR-T CELLS FOR TREATMENT OF GLIOBLASTOMA

Chimeric antigen receptor (CAR)–modified T-cell therapies have already achieved great success in hematologic malignancies, with clinical trial data showing high complete response rates in leukemia and lymphoma. So far, however, there has been little success with this approach in solid tumors.
Now a case report indicates dramatic remission in a patient with recurrent and rapidly progressing glioblastoma.
The case is described in a brief report published December 29 in the New England Journal of Medicine. Treatment with CAR T-cell therapy led to a transient, complete response in a patient with recurrent multifocal glioblastoma, with dramatic improvements in quality of life, including the discontinuation of use of systemic glucocorticoids and a return to normal life activities. The remission was sustained for 7.5 months, although the patient subsequently developed new tumors.
"This study provides proof-of-principle data that...establish that CAR T cells can mediate profound antitumor activity against a difficult-to-treat solid tumor," the authors conclude.
In a statement, senior coauthor Behnam Badie, MD, chief of neurosurgery at City of Hope, Duarte, California, noted that this type of treatment has tremendous potential and is a "game changer" in how brain tumors may be treated in the future.
"I believe these recent results show we have a potential breakthrough treatment that may have a remarkable impact on patients with malignant brain tumors," Dr Badie said.
Different Target, Local Administration
The CAR T cells that have been used in hematologic malignancies have in the main been focussed on targeting CD19, which is expressed on B cells.
In the latest report, the researchers at the City of Hope developed another type of CAR T cells that target the high-affinity IL-13 receptor IL13Rα2, which is overexpressed in a majority of glioblastomas.
They administered the therapy locally in the brain by directly injecting it into the tumor site and/or through infusion in the ventricular system. (By contrast, for hematologic malignancies, the CAR T cells are administered by intravenous infusion.)
This method of administration was associated with a much lower incidence of adverse events, which have been life-threatening in some of the patients with hematologic malignancies.
In the glioblastoma patient treated with CAR T cells administrated intraventricullarly, the team reports that there was a significant increase in a number of inflammatory cytokines in the cerebrospinal fluid. This increase appeared to correspond with the incidence of grade 1 and 2 symptoms, such as fever, fatigue, and myalgia. The cytokine levels returned to near baseline levels between weekly treatment cycles.
They also note that these immunologic changes were restricted to the cerebrospinal fluid; no notable increases in levels of cytokines and no CAR+ T cells were detectable in the peripheral blood.
"The absence of systemic toxic effects is particularly noteworthy given the severe cytokine release syndrome and neurotoxicity that are often associated with antitumor responses against high disease burden in patients receiving CD19-targeted CAR T-cell therapy," the authors comment.
Details of the Case Report
The patient described in the case report was a 50-year old man who presented with glioblastoma in the right temporal lobe. The patient received standard-of-care therapy that included tumor resection, radiation therapy, and temozolomide (Temodar, Merck & Co).
Six months after his diagnosis, there was evidence of disease recurrence, and he was enrolled into the phase 1 study of IL13Rα2-targeted CAR T cells.
While the experimental therapy was being manufactured, the patient participated in another clinical trial at a different institution. His disease continued to rapidly progress, and he subsequently developed multifocal leptomeningeal glioblastoma involving both cerebral hemispheres.
The patient underwent surgery. Three of the five intracranial tumors that were progressing were resected. These included the largest tumor, which was in the right temporal-occipital region, and two tumors in the right frontal lobe. Two smaller tumors in the left temporal lobe were not removed.
The patient then received CAR T cell therapy at an initial intraventricular infusion of 2 x 106 CAR+ T cells followed by five infusions of 10 x 106 CAR+ T cells, along with weekly intracavitary infusions into the cavity of the resected largest tumor via a catheter device. The patient was assessed after the third and sixth infusions.
During treatment, the patient developed two new lesions, which emerged near the previously resected frontal-lobe tumors. In addition, the two nonresected tumors continued to progress, and new metastatic lesions developed in the patient's spine, causing numbness in his legs.
The researchers felt that delivering treatment into the cerebrospinal fluid would improve their access to sites with multifocal disease, and a second catheter device was placed in the right lateral ventricle. This decision enabled the patient to receive 10 additional intraventricular treatment cycles at 1- to 3-week intervals.
Dramatic Responses
Multiple infusions of CAR T cells were administered over 220 days through two intracranial delivery routes. These infusions were delivered directly into the resected tumor cavity and were delivered into the ventricular system.
The researchers report that after the first three intraventricular infusions (on day 133), they "observed a dramatic reduction in the size of all intracranial and spinal tumors, and after the fifth intraventricular infusion (on day 190), all tumors had decreased by 77% to 100%."
The patient received five additional intraventricular infusions (cycles 12 through 16). During this consolidation phase, all lesions continued to resolve. They were not measurable by MRI and remained undetectable with positron-emission tomography scanning.
What was most remarkable, note the authors, is that after the intraventicular delivery of CAR T cells, all metastatic tumors in the spine resolved. Dexamethasone was also gradually eliminated during intraventricular treatment (day 108 through day 284), and the patient returned to his normal daily life, including returning to work.
The dramatic clinical response was sustained for 7.5 months following the initiation of CAR T-cell therapy, and none of the initial tumors (tumors 1 through 7 and spinal tumors) recurred.
Unfortunately, the patient experienced a recurrence after cycle 16 (228 days after the first CAR T-cell treatment), but at four new locations that were "distinct and nonadjacent to tumors 1 through 7 and the spinal tumors," the researchers emphasize.

They are currently investigating the reasons for the recurrence. Preliminary results suggest decreased expression of IL13Rα2.

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