
==== Front
Neurooncol Adv
Neurooncol Adv
noa
Neuro-Oncology Advances
2632-2498
Oxford University Press US

10.1093/noajnl/vdae090.015
vdae090.015
Final Category: Basic Science Leptomeningeal Disease
AcademicSubjects/MED00300
AcademicSubjects/MED00310
BSLM-04 INTRATHECAL DELIVERY OF PEPTIDE-PULSED TYPE 1 CONVENTIONAL DENDRITIC CELL VACCINE IS HIGHLY EFFICACIOUS FOR THE TREATMENT OF BREAST CANCER-ASSOCIATED LEPTOMENINGEAL DISEASE IN PRECLINICAL MODELS
Law Vincent H. Lee Moffitt Cancer Center and Research Institute, Tampa/FL, USA

Snyder Colin H. Lee Moffitt Cancer Center and Research Institute, Tampa/FL, USA

Chen Zhihua H. Lee Moffitt Cancer Center and Research Institute, Tampa/FL, USA

Kalinski Pawel Roswell Park Comprehensive Cancer Center, Buffalo/NY, USA

Czerniecki Brian H. Lee Moffitt Cancer Center and Research Institute, Tampa/FL, USA

Forsyth Peter H. Lee Moffitt Cancer Center and Research Institute, Tampa/FL, USA

8 2024
02 8 2024
02 8 2024
6 Suppl 1 2024 SNO/ASCO CNS Metastases Conference i5i6
© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

Abstract

BACKGROUND

Approximately 5% of advanced stage breast cancer (BC) will develop leptomeningeal disease (LMD), a rare form of metastasis in the meninges. The prognosis for LMD is dismal and current treatments are ineffective. Here, we found intrathecal (IT) delivery of MHC class II peptide-pulsed conventional Type 1 dendritic cells (cDC1s) could cure mice harbouring either HER2+ or triple negative breast cancer (TBNC) LMD. The data from our preclinical studies led to a Phase 1 clinical trial of cDC1s in HER2+ and TNBC LMD (NCT05809752; in progress).

METHODS

We created a “murine Ommaya” that mimics the clinically used Ommaya reservoir and allows for repeated IT injections of novel drugs at 3 – 7ml volume directly into the cerebral spinal fluid (CSF). A pipeline was developed for screening immunogenic MHC class II peptides from tumor-associated oncodrivers and using these targets we generated tumor-targeting cDC1 vaccine. We tested the efficacy of this therapy in murine BC-LMD by administering through the murine Ommaya.

RESULTS

We found cDC1 vaccine was highly effective against HER2+ LMD and TNBC-LMD; LMD mice that received IT cDC1s had reduced tumour burden and prolonged survival. Complete responses to treatment ranged between 30 - 70% in HER2+ LMD and TNBC-LMD and were CD4+ T cell and B cell dependent. Notably, some cured mice were protected against LMD reinoculation. Subsequent single cell RNA-sequencing analyses of pre- and post-treatment CSF revealed an adaptive change in the immune cellular landscape. We noted an elevation of Th1 proinflammatory cytokines such as IFN-g in the CSF. This was recapitulated in the CSF samples of patients enrolled in an on-going phase 1 trial, where early data showed IT cDC1 vaccine triggered a dramatic increase in the concentration of several proinflammatory Th1 cytokines.

CONCLUSIONS

IT cDC1 vaccine is effective against BC-LMD and prevents LMD recurrence. A future approach includes testing IT cDC1 platform in LMD from other cancers (e.g. melanoma etc.).
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