Intrathecal bivalent CAR T cells targeting EGFR and IL13Rα2 in recurrent glioblastoma: phase 1 trial interim results
Recurrent glioblastoma (rGBM) remains a major unmet medical need, with a median overall survival of less than 1 year. Here we report the first six patients with rGBM treated in a phase 1 trial of intrathecally delivered bivalent chimeric antigen receptor (CAR) T cells targeting epidermal growth fact...
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| Published in | Nature medicine Vol. 30; no. 5; pp. 1320 - 1329 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
New York
Nature Publishing Group US
01.05.2024
Nature Publishing Group |
| Subjects | |
| Online Access | Get full text |
| ISSN | 1078-8956 1546-170X 1546-170X |
| DOI | 10.1038/s41591-024-02893-z |
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| Abstract | Recurrent glioblastoma (rGBM) remains a major unmet medical need, with a median overall survival of less than 1 year. Here we report the first six patients with rGBM treated in a phase 1 trial of intrathecally delivered bivalent chimeric antigen receptor (CAR) T cells targeting epidermal growth factor receptor (EGFR) and interleukin-13 receptor alpha 2 (IL13Rα2). The study’s primary endpoints were safety and determination of the maximum tolerated dose. Secondary endpoints reported in this interim analysis include the frequency of manufacturing failures and objective radiographic response (ORR) according to modified Response Assessment in Neuro-Oncology criteria. All six patients had progressive, multifocal disease at the time of treatment. In both dose level 1 (1 ×10
7
cells;
n
= 3) and dose level 2 (2.5 × 10
7
cells;
n
= 3), administration of CART-EGFR-IL13Rα2 cells was associated with early-onset neurotoxicity, most consistent with immune effector cell-associated neurotoxicity syndrome (ICANS), and managed with high-dose dexamethasone and anakinra (anti-IL1R). One patient in dose level 2 experienced a dose-limiting toxicity (grade 3 anorexia, generalized muscle weakness and fatigue). Reductions in enhancement and tumor size at early magnetic resonance imaging timepoints were observed in all six patients; however, none met criteria for ORR. In exploratory endpoint analyses, substantial CAR T cell abundance and cytokine release in the cerebrospinal fluid were detected in all six patients. Taken together, these first-in-human data demonstrate the preliminary safety and bioactivity of CART-EGFR-IL13Rα2 cells in rGBM. An encouraging early efficacy signal was also detected and requires confirmation with additional patients and longer follow-up time. ClinicalTrials.gov identifier:
NCT05168423
.
In an interim analysis of an ongoing phase 1 trial of CAR T cells targeting EGFR and IL13Ra2 in patients with multifocal, recurrent glioblastoma, intrathecal delivery is feasible and well tolerated, with some reductions seen in tumor size. |
|---|---|
| AbstractList | Recurrent glioblastoma (rGBM) remains a major unmet medical need, with a median overall survival of less than 1 year. Here we report the first six patients with rGBM treated in a phase 1 trial of intrathecally delivered bivalent chimeric antigen receptor (CAR) T cells targeting epidermal growth factor receptor (EGFR) and interleukin-13 receptor alpha 2 (IL13Rα2). The study’s primary endpoints were safety and determination of the maximum tolerated dose. Secondary endpoints reported in this interim analysis include the frequency of manufacturing failures and objective radiographic response (ORR) according to modified Response Assessment in Neuro-Oncology criteria. All six patients had progressive, multifocal disease at the time of treatment. In both dose level 1 (1 ×107 cells; n = 3) and dose level 2 (2.5 × 107 cells; n = 3), administration of CART-EGFR-IL13Rα2 cells was associated with early-onset neurotoxicity, most consistent with immune effector cell-associated neurotoxicity syndrome (ICANS), and managed with high-dose dexamethasone and anakinra (anti-IL1R). One patient in dose level 2 experienced a dose-limiting toxicity (grade 3 anorexia, generalized muscle weakness and fatigue). Reductions in enhancement and tumor size at early magnetic resonance imaging timepoints were observed in all six patients; however, none met criteria for ORR. In exploratory endpoint analyses, substantial CAR T cell abundance and cytokine release in the cerebrospinal fluid were detected in all six patients. Taken together, these first-in-human data demonstrate the preliminary safety and bioactivity of CART-EGFR-IL13Rα2 cells in rGBM. An encouraging early efficacy signal was also detected and requires confirmation with additional patients and longer follow-up time. ClinicalTrials.gov identifier: NCT05168423.In an interim analysis of an ongoing phase 1 trial of CAR T cells targeting EGFR and IL13Ra2 in patients with multifocal, recurrent glioblastoma, intrathecal delivery is feasible and well tolerated, with some reductions seen in tumor size. Recurrent glioblastoma (rGBM) remains a major unmet medical need, with a median overall survival of less than 1 year. Here we report the first six patients with rGBM treated in a phase 1 trial of intrathecally delivered bivalent chimeric antigen receptor (CAR) T cells targeting epidermal growth factor receptor (EGFR) and interleukin-13 receptor alpha 2 (IL13Rα2). The study's primary endpoints were safety and determination of the maximum tolerated dose. Secondary endpoints reported in this interim analysis include the frequency of manufacturing failures and objective radiographic response (ORR) according to modified Response Assessment in Neuro-Oncology criteria. All six patients had progressive, multifocal disease at the time of treatment. In both dose level 1 (1 ×10 cells; n = 3) and dose level 2 (2.5 × 10 cells; n = 3), administration of CART-EGFR-IL13Rα2 cells was associated with early-onset neurotoxicity, most consistent with immune effector cell-associated neurotoxicity syndrome (ICANS), and managed with high-dose dexamethasone and anakinra (anti-IL1R). One patient in dose level 2 experienced a dose-limiting toxicity (grade 3 anorexia, generalized muscle weakness and fatigue). Reductions in enhancement and tumor size at early magnetic resonance imaging timepoints were observed in all six patients; however, none met criteria for ORR. In exploratory endpoint analyses, substantial CAR T cell abundance and cytokine release in the cerebrospinal fluid were detected in all six patients. Taken together, these first-in-human data demonstrate the preliminary safety and bioactivity of CART-EGFR-IL13Rα2 cells in rGBM. An encouraging early efficacy signal was also detected and requires confirmation with additional patients and longer follow-up time. ClinicalTrials.gov identifier: NCT05168423 . Recurrent glioblastoma (rGBM) remains a major unmet medical need, with a median overall survival of less than 1 year. Here we report the first six patients with rGBM treated in a phase 1 trial of intrathecally delivered bivalent chimeric antigen receptor (CAR) T cells targeting epidermal growth factor receptor (EGFR) and interleukin-13 receptor alpha 2 (IL13Rα2). The study’s primary endpoints were safety and determination of the maximum tolerated dose. Secondary endpoints reported in this interim analysis include the frequency of manufacturing failures and objective radiographic response (ORR) according to modified Response Assessment in Neuro-Oncology criteria. All six patients had progressive, multifocal disease at the time of treatment. In both dose level 1 (1 ×10 7 cells; n = 3) and dose level 2 (2.5 × 10 7 cells; n = 3), administration of CART-EGFR-IL13Rα2 cells was associated with early-onset neurotoxicity, most consistent with immune effector cell-associated neurotoxicity syndrome (ICANS), and managed with high-dose dexamethasone and anakinra (anti-IL1R). One patient in dose level 2 experienced a dose-limiting toxicity (grade 3 anorexia, generalized muscle weakness and fatigue). Reductions in enhancement and tumor size at early magnetic resonance imaging timepoints were observed in all six patients; however, none met criteria for ORR. In exploratory endpoint analyses, substantial CAR T cell abundance and cytokine release in the cerebrospinal fluid were detected in all six patients. Taken together, these first-in-human data demonstrate the preliminary safety and bioactivity of CART-EGFR-IL13Rα2 cells in rGBM. An encouraging early efficacy signal was also detected and requires confirmation with additional patients and longer follow-up time. ClinicalTrials.gov identifier: NCT05168423 . In an interim analysis of an ongoing phase 1 trial of CAR T cells targeting EGFR and IL13Ra2 in patients with multifocal, recurrent glioblastoma, intrathecal delivery is feasible and well tolerated, with some reductions seen in tumor size. Recurrent glioblastoma (rGBM) remains a major unmet medical need, with a median overall survival of less than 1 year. Here we report the first six patients with rGBM treated in a phase 1 trial of intrathecally delivered bivalent chimeric antigen receptor (CAR) T cells targeting epidermal growth factor receptor (EGFR) and interleukin-13 receptor alpha 2 (IL13Rα2). The study's primary endpoints were safety and determination of the maximum tolerated dose. Secondary endpoints reported in this interim analysis include the frequency of manufacturing failures and objective radiographic response (ORR) according to modified Response Assessment in Neuro-Oncology criteria. All six patients had progressive, multifocal disease at the time of treatment. In both dose level 1 (1 ×107 cells; n = 3) and dose level 2 (2.5 × 107 cells; n = 3), administration of CART-EGFR-IL13Rα2 cells was associated with early-onset neurotoxicity, most consistent with immune effector cell-associated neurotoxicity syndrome (ICANS), and managed with high-dose dexamethasone and anakinra (anti-IL1R). One patient in dose level 2 experienced a dose-limiting toxicity (grade 3 anorexia, generalized muscle weakness and fatigue). Reductions in enhancement and tumor size at early magnetic resonance imaging timepoints were observed in all six patients; however, none met criteria for ORR. In exploratory endpoint analyses, substantial CAR T cell abundance and cytokine release in the cerebrospinal fluid were detected in all six patients. Taken together, these first-in-human data demonstrate the preliminary safety and bioactivity of CART-EGFR-IL13Rα2 cells in rGBM. An encouraging early efficacy signal was also detected and requires confirmation with additional patients and longer follow-up time. ClinicalTrials.gov identifier: NCT05168423 .Recurrent glioblastoma (rGBM) remains a major unmet medical need, with a median overall survival of less than 1 year. Here we report the first six patients with rGBM treated in a phase 1 trial of intrathecally delivered bivalent chimeric antigen receptor (CAR) T cells targeting epidermal growth factor receptor (EGFR) and interleukin-13 receptor alpha 2 (IL13Rα2). The study's primary endpoints were safety and determination of the maximum tolerated dose. Secondary endpoints reported in this interim analysis include the frequency of manufacturing failures and objective radiographic response (ORR) according to modified Response Assessment in Neuro-Oncology criteria. All six patients had progressive, multifocal disease at the time of treatment. In both dose level 1 (1 ×107 cells; n = 3) and dose level 2 (2.5 × 107 cells; n = 3), administration of CART-EGFR-IL13Rα2 cells was associated with early-onset neurotoxicity, most consistent with immune effector cell-associated neurotoxicity syndrome (ICANS), and managed with high-dose dexamethasone and anakinra (anti-IL1R). One patient in dose level 2 experienced a dose-limiting toxicity (grade 3 anorexia, generalized muscle weakness and fatigue). Reductions in enhancement and tumor size at early magnetic resonance imaging timepoints were observed in all six patients; however, none met criteria for ORR. In exploratory endpoint analyses, substantial CAR T cell abundance and cytokine release in the cerebrospinal fluid were detected in all six patients. Taken together, these first-in-human data demonstrate the preliminary safety and bioactivity of CART-EGFR-IL13Rα2 cells in rGBM. An encouraging early efficacy signal was also detected and requires confirmation with additional patients and longer follow-up time. ClinicalTrials.gov identifier: NCT05168423 . |
| Author | Leskowitz, Rachel Bagley, Linda J. Maloney, Eileen Wang, Xin Bagley, Stephen J. June, Carl H. Stein, Carly Jarocha, Danuta Oner, Bike Su O’Rourke, Donald M. Desai, Arati S. Marshall, Amy Barrett, David Binder, Zev A. Martins, Rene Hexner, Elizabeth O. Ming, Guo-Li Jadlowsky, Julie K. Nasrallah, MacLean P. Siegel, Donald L. Nabavizadeh, Ali Brennan, Andrea Sun, Yusha Lledo, Lester Chen, Fang Gladney, Whitney Hwang, Wei-Ting Gonzalez, Vanessa Christensen, Shannon Fraietta, Joseph A. Plesa, Gabriela Song, Hongjun Logun, Meghan |
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School of Medicine – sequence: 4 givenname: Xin surname: Wang fullname: Wang, Xin organization: Department of Neuroscience, University of Pennsylvania Perelman School of Medicine – sequence: 5 givenname: Arati S. surname: Desai fullname: Desai, Arati S. organization: Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine – sequence: 6 givenname: Linda J. surname: Bagley fullname: Bagley, Linda J. organization: Department of Neurosurgery, University of Pennsylvania Perelman School of Medicine, Department of Radiology, University of Pennsylvania Perelman School of Medicine – sequence: 7 givenname: Ali surname: Nabavizadeh fullname: Nabavizadeh, Ali organization: Department of Radiology, University of Pennsylvania Perelman School of Medicine – sequence: 8 givenname: Danuta surname: Jarocha fullname: Jarocha, Danuta organization: Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine – sequence: 9 givenname: Rene surname: Martins fullname: Martins, Rene organization: Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine – sequence: 10 givenname: Eileen surname: Maloney fullname: Maloney, Eileen organization: Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Department of Neurosurgery, University of Pennsylvania Perelman School of Medicine – sequence: 11 givenname: Lester surname: Lledo fullname: Lledo, Lester organization: Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine – sequence: 12 givenname: Carly surname: Stein fullname: Stein, Carly organization: Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine – sequence: 13 givenname: Amy surname: Marshall fullname: Marshall, Amy organization: Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine – sequence: 14 givenname: Rachel surname: Leskowitz fullname: Leskowitz, Rachel organization: Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine – sequence: 15 givenname: Julie K. orcidid: 0009-0005-5115-1321 surname: Jadlowsky fullname: Jadlowsky, Julie K. organization: Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine – sequence: 16 givenname: Shannon surname: Christensen fullname: Christensen, Shannon organization: Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine – sequence: 17 givenname: Bike Su surname: Oner fullname: Oner, Bike Su organization: Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine – sequence: 18 givenname: Gabriela surname: Plesa fullname: Plesa, Gabriela organization: Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine – sequence: 19 givenname: Andrea surname: Brennan fullname: Brennan, Andrea organization: Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine – sequence: 20 givenname: Vanessa surname: Gonzalez fullname: Gonzalez, Vanessa organization: Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine – sequence: 21 givenname: Fang orcidid: 0000-0002-1719-3887 surname: Chen fullname: Chen, Fang organization: Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine – sequence: 22 givenname: Yusha surname: Sun fullname: Sun, Yusha organization: Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Department of Neuroscience, University of Pennsylvania Perelman School of Medicine – sequence: 23 givenname: Whitney surname: Gladney fullname: Gladney, Whitney organization: Kite Pharma, a Gilead Company – sequence: 24 givenname: David surname: Barrett fullname: Barrett, David organization: Kite Pharma, a Gilead Company – sequence: 25 givenname: MacLean P. orcidid: 0000-0003-4861-0898 surname: Nasrallah fullname: Nasrallah, MacLean P. organization: Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine – sequence: 26 givenname: Wei-Ting orcidid: 0000-0003-2829-2167 surname: Hwang fullname: Hwang, Wei-Ting organization: Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine – sequence: 27 givenname: Guo-Li orcidid: 0000-0002-2517-6075 surname: Ming fullname: Ming, Guo-Li organization: Department of Neuroscience, University of Pennsylvania Perelman School of Medicine, Institute for Regenerative Medicine, University of Pennsylvania Perelman School of Medicine – sequence: 28 givenname: Hongjun orcidid: 0000-0002-8720-5310 surname: Song fullname: Song, Hongjun organization: Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Department of Neuroscience, University of Pennsylvania Perelman School of Medicine, Institute for Regenerative Medicine, University of Pennsylvania Perelman School of Medicine – sequence: 29 givenname: Donald L. orcidid: 0000-0003-2098-2251 surname: Siegel fullname: Siegel, Donald L. organization: Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine – sequence: 30 givenname: Carl H. orcidid: 0000-0003-0241-3557 surname: June fullname: June, Carl H. organization: Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine – sequence: 31 givenname: Elizabeth O. orcidid: 0000-0002-1125-4060 surname: Hexner fullname: Hexner, Elizabeth O. organization: Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine – sequence: 32 givenname: Zev A. surname: Binder fullname: Binder, Zev A. organization: Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Department of Neurosurgery, University of Pennsylvania Perelman School of Medicine, Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine – sequence: 33 givenname: Donald M. orcidid: 0000-0002-8479-7314 surname: O’Rourke fullname: O’Rourke, Donald M. email: donald.orourke@pennmedicine.upenn.edu organization: Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Department of Neurosurgery, University of Pennsylvania Perelman School of Medicine, Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/38480922$$D View this record in MEDLINE/PubMed |
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| ContentType | Journal Article |
| Copyright | The Author(s), under exclusive licence to Springer Nature America, Inc. 2024 corrected publication 2024 Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. 2024. The Author(s), under exclusive licence to Springer Nature America, Inc. Copyright Nature Publishing Group May 2024 |
| Copyright_xml | – notice: The Author(s), under exclusive licence to Springer Nature America, Inc. 2024 corrected publication 2024 Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. – notice: 2024. The Author(s), under exclusive licence to Springer Nature America, Inc. – notice: Copyright Nature Publishing Group May 2024 |
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| DOI | 10.1038/s41591-024-02893-z |
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| Title | Intrathecal bivalent CAR T cells targeting EGFR and IL13Rα2 in recurrent glioblastoma: phase 1 trial interim results |
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