Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy
- 3 years ago
N Engl J Med. 2016 Dec 29; 375(26): 2561–2569.
doi: 10.1056/NEJMoa1610497
A 50-year-old man presented with glioblastoma in the right temporal lobe, with an unmethylated O6-methylguanine–DNA methyltransferase (MGMT) promoter, a nonmutated IDH1 R132H, and an IL13Ra2 H score of 100 (with no staining in 30% of cells, weak-intensity staining in 30%, moderate-intensity staining in 20%, and high-intensity staining in 10%) (Fig. S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). The H score, a method of quantitating immunohistochemical results, is based on the following formula: (3 × the percentage of strongly staining cells)+(2×the percentage of moderately staining cells) + (1 × the percentage of weakly staining cells), resulting in a range of 0 to 300.
The patient received standard-of-care therapy consisting of tumor resection, radiation therapy, and temozolomide.14 Six months after the diagnosis, magnetic resonance imaging (MRI) and positron-emission tomography–computed tomography (PET-CT) of the brain showed evidence of disease recurrence (Fig. S2A in the Supplementary Appendix). The patient was then enrolled in this clinical study of IL13Ra2-targeted CAR T cells (Fig. S2A in the Supplementary Appendix).
While the IL13BB?–CAR T cells were being manufactured, the patient participated in an investigational clinical trial (ClinicalTrials.gov number, NCT01975701) at a different institution (Fig. S2A in the Supplementary Appendix). However, the disease progressed rapidly during treatment, with the development of multifocal leptomeningeal glioblastoma involving both cerebral hemispheres (Figs. S3 and S4 in the Supplementary Appendix).
The patient then began to receive treatment in our clinical study and underwent resection of three of five progressing intracranial tumors (Figs. S4 and S5 in the Supplementary Appendix), including the largest tumor in the right temporal–occipital region (tumor 1) and two tumors in the right frontal lobe (tumors 2 and 3). Two smaller tumors in the left temporal lobe (tumors 4 and 5) were not surgically removed.
IL13BB?–CAR T cells were administered according to dose schedule 1 (an initial infusion of 2×106 CAR+ T cells followed by five infusions of 10×106 CAR+ T cells) (Table S1 in the Supplementary Appendix), and the patient received weekly intracavitary infusions of IL13BB?–CAR T cells into the resected cavity of tumor 1 through a catheter device. Treatment was paused for assessment of safety and disease after the third and sixth infusions (Fig. 1, and Fig. S2A in the Supplementary Appendix).
Although the local treated site (tumor 1) remained stable during this treatment phase, with no evidence of disease progression, two new lesions (tumors 6 and 7) appeared near the previously resected frontal-lobe tumors (tumors 2 and 3), and the nonresected tumors (tumors 4 and 5) continued to progress. Therefore, on the basis of the rationale that delivery of cells into the cerebrospinal
doi: 10.1056/NEJMoa1610497
A 50-year-old man presented with glioblastoma in the right temporal lobe, with an unmethylated O6-methylguanine–DNA methyltransferase (MGMT) promoter, a nonmutated IDH1 R132H, and an IL13Ra2 H score of 100 (with no staining in 30% of cells, weak-intensity staining in 30%, moderate-intensity staining in 20%, and high-intensity staining in 10%) (Fig. S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). The H score, a method of quantitating immunohistochemical results, is based on the following formula: (3 × the percentage of strongly staining cells)+(2×the percentage of moderately staining cells) + (1 × the percentage of weakly staining cells), resulting in a range of 0 to 300.
The patient received standard-of-care therapy consisting of tumor resection, radiation therapy, and temozolomide.14 Six months after the diagnosis, magnetic resonance imaging (MRI) and positron-emission tomography–computed tomography (PET-CT) of the brain showed evidence of disease recurrence (Fig. S2A in the Supplementary Appendix). The patient was then enrolled in this clinical study of IL13Ra2-targeted CAR T cells (Fig. S2A in the Supplementary Appendix).
While the IL13BB?–CAR T cells were being manufactured, the patient participated in an investigational clinical trial (ClinicalTrials.gov number, NCT01975701) at a different institution (Fig. S2A in the Supplementary Appendix). However, the disease progressed rapidly during treatment, with the development of multifocal leptomeningeal glioblastoma involving both cerebral hemispheres (Figs. S3 and S4 in the Supplementary Appendix).
The patient then began to receive treatment in our clinical study and underwent resection of three of five progressing intracranial tumors (Figs. S4 and S5 in the Supplementary Appendix), including the largest tumor in the right temporal–occipital region (tumor 1) and two tumors in the right frontal lobe (tumors 2 and 3). Two smaller tumors in the left temporal lobe (tumors 4 and 5) were not surgically removed.
IL13BB?–CAR T cells were administered according to dose schedule 1 (an initial infusion of 2×106 CAR+ T cells followed by five infusions of 10×106 CAR+ T cells) (Table S1 in the Supplementary Appendix), and the patient received weekly intracavitary infusions of IL13BB?–CAR T cells into the resected cavity of tumor 1 through a catheter device. Treatment was paused for assessment of safety and disease after the third and sixth infusions (Fig. 1, and Fig. S2A in the Supplementary Appendix).
Although the local treated site (tumor 1) remained stable during this treatment phase, with no evidence of disease progression, two new lesions (tumors 6 and 7) appeared near the previously resected frontal-lobe tumors (tumors 2 and 3), and the nonresected tumors (tumors 4 and 5) continued to progress. Therefore, on the basis of the rationale that delivery of cells into the cerebrospinal