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DIPG-15. 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
Monje, M; Majzner, R; Mahdi, J; Ramakrishna, S; Patel, S; Chinnasamy, H; Yeom, K; Schultz, L; Barsan, V; Richards, R; Campen, C; Reschke, A ...
Published in: Neuro-Oncology
June 3, 2022

BACKGROUND: H3K27M-mutated DMGs express high levels of the disialoganglioside GD2 and GD2-CAR T-cells (GD2-CART) regress DMG in preclinical models. METHODS: NCT04196413 is a 3 + 3 Phase I dose escalation trial testing GD2-CART in patients with biopsy-proved 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 infusions (10-30e6 GD2-CART) administered via Ommaya without LD. RESULTS: Twelve subjects were treated after standard radiotherapy, 7 of whom began treatment at the time of progression [n=4 DL1 (3 DIPG/1 sDMG); n=8 DL2 (6 DIPG/2 sDMG)]. No DLTs were observed on DL1. Three subjects experienced DLT on DL2 (2 DIPG/1 sDMG) due to grade-4 cytokine release syndrome (CRS). On both dose levels, all subjects exhibited transient symptoms related to on-tumor inflammation, termed Tumor Inflammation-Associated Neurotoxicity (TIAN); no DLT due to TIAN has occurred. Ten subjects experienced radiographic and/or clinical benefit after IV infusion and received subsequent ICV infusions (median=4 ICV infusions/pt, range=1-7). ICV infusions were not associated with high-grade CRS. Four patients continue to receive ICV infusions on study and have experienced continued clinical and radiographic benefit, currently 7-11 months following enrollment. Two patients (one sDMG, one DIPG) have experienced near-complete (>95%) tumor volume reduction. CONCLUSIONS: IV treatment of DIPG and sDMG with GD2-CART is safe at a dose of 1e6/kg, but associated with frequent high-grade CRS at 3e6/kg. ICV GD2-CART 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.

Duke Scholars

Published In

Neuro-Oncology

DOI

EISSN

1523-5866

ISSN

1522-8517

Publication Date

June 3, 2022

Volume

24

Issue

Supplement_1

Start / End Page

i20 / i21

Publisher

Oxford University Press (OUP)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 1112 Oncology and Carcinogenesis
  • 1109 Neurosciences
 

Citation

APA
Chicago
ICMJE
MLA
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Monje, M., Majzner, R., Mahdi, J., Ramakrishna, S., Patel, S., Chinnasamy, H., … Mackall, C. (2022). DIPG-15. Major tumor regressions in H3K27M-mutated diffuse midline glioma (DMG) following sequential intravenous (IV) and intracerebroventricular (ICV) delivery of GD2-CAR T-cells. Neuro-Oncology, 24(Supplement_1), i20–i21. https://doi.org/10.1093/neuonc/noac079.072
Monje, Michelle, Robbie Majzner, Jasia Mahdi, Sneha Ramakrishna, Shabnum Patel, Harshini Chinnasamy, Kristen Yeom, et al. “DIPG-15. Major tumor regressions in H3K27M-mutated diffuse midline glioma (DMG) following sequential intravenous (IV) and intracerebroventricular (ICV) delivery of GD2-CAR T-cells.” Neuro-Oncology 24, no. Supplement_1 (June 3, 2022): i20–21. https://doi.org/10.1093/neuonc/noac079.072.
Monje M, Majzner R, Mahdi J, Ramakrishna S, Patel S, Chinnasamy H, et al. DIPG-15. Major tumor regressions in H3K27M-mutated diffuse midline glioma (DMG) following sequential intravenous (IV) and intracerebroventricular (ICV) delivery of GD2-CAR T-cells. Neuro-Oncology. 2022 Jun 3;24(Supplement_1):i20–1.
Monje, Michelle, et al. “DIPG-15. Major tumor regressions in H3K27M-mutated diffuse midline glioma (DMG) following sequential intravenous (IV) and intracerebroventricular (ICV) delivery of GD2-CAR T-cells.” Neuro-Oncology, vol. 24, no. Supplement_1, Oxford University Press (OUP), June 2022, pp. i20–21. Crossref, doi:10.1093/neuonc/noac079.072.
Monje M, Majzner R, Mahdi J, Ramakrishna S, Patel S, Chinnasamy H, Yeom K, Schultz L, Barsan V, Richards R, Campen C, Reschke A, Toland AM, 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, Mackall C. DIPG-15. Major tumor regressions in H3K27M-mutated diffuse midline glioma (DMG) following sequential intravenous (IV) and intracerebroventricular (ICV) delivery of GD2-CAR T-cells. Neuro-Oncology. Oxford University Press (OUP); 2022 Jun 3;24(Supplement_1):i20–i21.
Journal cover image

Published In

Neuro-Oncology

DOI

EISSN

1523-5866

ISSN

1522-8517

Publication Date

June 3, 2022

Volume

24

Issue

Supplement_1

Start / End Page

i20 / i21

Publisher

Oxford University Press (OUP)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 1112 Oncology and Carcinogenesis
  • 1109 Neurosciences