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Abstract CT001: Major tumor regressions in H3K27M-mutated diffuse midline glioma (DMG) following sequential intravenous (IV) and intracerebroventricular (ICV) delivery of GD2-CAR T cells

Publication ,  Journal Article
Majzner, RG; Mahdi, J; Ramakrishna, S; Patel, S; Chinnasamy, H; Yeom, K; Schultz, L; Barsan, V; Richards, R; Campen, C; Reschke, A; Baggott, C ...
Published in: Cancer Research
June 15, 2022

Background: H3K27M-mutated DMGs are universally lethal central nervous system tumors that express high levels of the disialoganglioside GD2. IV administered GD2-CAR T cells (GD2-CART) regress DMG in preclinical models, and locoregionally delivered CARs demonstrate enhanced activity in xenograft models of brain tumors.Methods: NCT04196413 is a 3+3 Phase I dose escalation trial testing GD2-CART in patients with H3K27M DMG, with dose-limiting toxicities (DLT) considered independently for DIPG and spinal DMG (sDMG). Arm A tested escalating doses of IV GD2-CART (DL1: 1e6 GD2-CART/kg; DL2=3e6 GD2-CART/kg) following lymphodepletion (LD). After the DLT period, patients with clinical and/or radiographic benefit were eligible for subsequent ICV GD2-CART (10-30e6 GD2-CART) administered via Ommaya catheter without LD every 4-8 weeks for a maximum of 12 doses. We previously reported early results from 4 patients treated on DL1, which demonstrated clinical activity and manageable toxicity. Here we provide updated results for DL1 and DL2.Results: Thirteen subjects were enrolled and 11 treated [n=4 DL1 (3 DIPG/1 sDMG); n=9 DL2 (7 DIPG/2 sDMG)]. Two subjects were removed prior to treatment due to rapid progression. No DLTs were observed on DL1. Three subjects experienced DLT on DL2 (2 DIPG/1 sDMG) due to grade 4 cytokine release syndrome (CRS), successfully managed with tocilizumab, anakinra, and corticosteroids. CRS occurred earlier on DL2 vs. DL1 (Day 3 vs 7). On both dose levels, all subjects exhibited transient symptoms related to on-tumor inflammation, termed Tumor Inflammation-Associated Neurotoxicity (TIAN), which was successfully managed with anakinra and, in some cases, CSF drainage and dexamethasone. No DLT due to TIAN has occurred.Ten patients have had adequate follow-up to assess benefit. Nine experienced radiographic and/or clinical benefit after IV infusion, and they received subsequent ICV GD2-CART infusions (median= 4 ICV infusions/pt, range 1-6). ICV infusions were not associated with high-grade CRS, although some subjects developed transient fever, headache, meningismus, nausea, and/or vomiting, and several subjects developed TIAN. Four patients continue to receive ICV infusions on study and have experienced continued clinical and radiographic benefit at 11+, 9.5+, 8+ and 7+ months following enrollment. A 31-year-old with sDMG has experienced a near-complete (>95%) reduction in tumor volume and a 17-year-old with DIPG experienced a near-complete (>98%) reduction in volume of a pontine tumor.Conclusions: IV treatment of DIPG and sDMG with GD2-CART is safe at a dose of 1e6/kg, but associated with unacceptable rates of high-grade CRS at 3e6/kg. ICV GD2-CART without LD, administered following a previous course of IV GD2-CART with LD, has been well tolerated and has mediated impressive sustained clinical benefit in some patients with DIPG/sDMG. Given these findings, we are launching a new arm to assess safety and activity and to define the recommended phase 2 dose for ICV delivery of GD2-CART without LD. Patients are eligible for up to 12 ICV infusions of GD2-CART administered every 4-6 weeks. Clinical benefit will be formally assessed using patient-reported outcomes. GD2-CART has the potential to transform therapy for patients with H3K27M+ DIPG/sDMG.Citation Format: Robbie G. Majzner, Jasia Mahdi, Sneha Ramakrishna, Shabnum Patel, Harshini Chinnasamy, Kristen Yeom, Liora Schultz, Valentin Barsan, Rebecca Richards, Cynthia Campen, Agnes Reschke, Angus Martin Shaw Toland, Christina Baggott, Sharon Mavroukakis, Emily Egeler, Jennifer Moon, Ashley Jacobs, Karen Yamabe-Kwong, Lindsey Rasmussen, Esther Nie, Sean Green, Michael Kunicki, Michelle Fujimoto, Zach Ehlinger, Warren Reynolds, Snehit Prabhu, Katherine E. Warren, Tim Cornell, Sonia Partap, Paul Fisher, Gerald Grant, Hannes Vogel, Bita Sahaf, Kara Davis, Steven Feldman, Michelle Monje, Crystal L. Mackall. Major tumor regressions in H3K27M-mutated diffuse midline glioma (DMG) following sequential intravenous (IV) and intracerebroventricular (ICV) delivery of GD2-CAR T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT001.

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Published In

Cancer Research

DOI

EISSN

1538-7445

Publication Date

June 15, 2022

Volume

82

Issue

12_Supplement

Start / End Page

CT001 / CT001

Publisher

American Association for Cancer Research (AACR)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 1112 Oncology and Carcinogenesis
 

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Majzner, R. G., Mahdi, J., Ramakrishna, S., Patel, S., Chinnasamy, H., Yeom, K., … Mackall, C. L. (2022). Abstract CT001: Major tumor regressions in H3K27M-mutated diffuse midline glioma (DMG) following sequential intravenous (IV) and intracerebroventricular (ICV) delivery of GD2-CAR T cells. Cancer Research, 82(12_Supplement), CT001–CT001. https://doi.org/10.1158/1538-7445.am2022-ct001
Majzner, Robbie G., Jasia Mahdi, Sneha Ramakrishna, Shabnum Patel, Harshini Chinnasamy, Kristen Yeom, Liora Schultz, et al. “Abstract CT001: Major tumor regressions in H3K27M-mutated diffuse midline glioma (DMG) following sequential intravenous (IV) and intracerebroventricular (ICV) delivery of GD2-CAR T cells.” Cancer Research 82, no. 12_Supplement (June 15, 2022): CT001–CT001. https://doi.org/10.1158/1538-7445.am2022-ct001.
Majzner RG, Mahdi J, Ramakrishna S, Patel S, Chinnasamy H, Yeom K, et al. Abstract CT001: Major tumor regressions in H3K27M-mutated diffuse midline glioma (DMG) following sequential intravenous (IV) and intracerebroventricular (ICV) delivery of GD2-CAR T cells. Cancer Research. 2022 Jun 15;82(12_Supplement):CT001–CT001.
Majzner, Robbie G., et al. “Abstract CT001: Major tumor regressions in H3K27M-mutated diffuse midline glioma (DMG) following sequential intravenous (IV) and intracerebroventricular (ICV) delivery of GD2-CAR T cells.” Cancer Research, vol. 82, no. 12_Supplement, American Association for Cancer Research (AACR), June 2022, pp. CT001–CT001. Crossref, doi:10.1158/1538-7445.am2022-ct001.
Majzner RG, Mahdi J, Ramakrishna S, Patel S, Chinnasamy H, Yeom K, Schultz L, Barsan V, Richards R, Campen C, Reschke A, Toland AMS, Baggott C, Mavroukakis S, Egeler E, Moon J, Jacobs A, Yamabe-Kwong K, Rasmussen L, Nie E, Green S, Kunicki M, Fujimoto M, Ehlinger Z, Reynolds W, Prabhu S, Warren KE, Cornell T, Partap S, Fisher P, Grant G, Vogel H, Sahaf B, Davis K, Feldman S, Monje M, Mackall CL. Abstract CT001: Major tumor regressions in H3K27M-mutated diffuse midline glioma (DMG) following sequential intravenous (IV) and intracerebroventricular (ICV) delivery of GD2-CAR T cells. Cancer Research. American Association for Cancer Research (AACR); 2022 Jun 15;82(12_Supplement):CT001–CT001.

Published In

Cancer Research

DOI

EISSN

1538-7445

Publication Date

June 15, 2022

Volume

82

Issue

12_Supplement

Start / End Page

CT001 / CT001

Publisher

American Association for Cancer Research (AACR)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 1112 Oncology and Carcinogenesis