Abstract 1309: HSV1 oncolytic therapy for breast cancer meningeal metastases
Authors: Kuruppu Darshini , Bhere Deepak , Shah Khalid , Brownell Anna-Liisa , Mahmood Umar , Tanabe Kenneth K. 
Published: July 2021

Abstract
Background: Meningeal metastasis is a fatal complication of breast cancer which results when cancer cells seed in the subarachnoid space. Subsequent tumor growth in the leptomeninges presents severe neurological complications of the cranial nerves, cerebrum and spinal cord limiting life expectancy to less than 4 months. Currently there is no cure. Aggressive multimodal therapies such as radiation, systemic and intra-cerebrospinal fluid (CSF) chemotherapy are ineffective. Chemotherapy is cleared rapidly from the CSF while doses deemed therapeutic are highly toxic. Oncolytic Herpes Simplex Virus type 1 (OHSV1) was selected as a potential therapeutic in this regard. Destruction of cancer cells by lytic virus replication is under clinical investigation where multiple virus replication cycles amplify the injected dose. We present OHSV1 therapeutics in a murine model of meningeal metastases where disease progression resembles that in the clinic.
Methods: Meningeal metastases were induced in nude Balb/c mice by stereotaxic injection of MDA-MB-231 breast cancer cells into the right lateral ventricle of the brain. OHSV1 (1x10^8 pfu) was injected into the lateral ventricle on either day 9, 12 or 16 to target the early, intermediate and late disease phases of tumor growth in the model. Virus replication kinetics, tumor response, neurological and physical changes, and survival were studied for each treatment group. Virus replication was imaged with 18F-FHBG-PET and Fluc bioluminescence while tumor response to oncolytic HSV1 was imaged with Gd-MRI and Rluc-bioluminescence. The brains were studied ex vivo to confirm in vivo scans, virus with LacZ and antibody to viral TK, and titer with plaque assay.
Results: A remarkable reduction metastatic growth to OHSV1 was evident in the early and intermediate groups where tumor growth was inhibited in some mice while existing tumors regressed in others. Tumor load in the base of the brain and spinal cord seen in control mice was markedly reduced in the two groups highlighted by minimal contrast uptake on Gd-MRI. As such the onset of neurological symptoms (bradykinesia, ataxia and paralysis) was delayed accompanied by weight gain. Inhibition of tumor growth in the late treatment group was relatively modest. Virus replication was evident as waves over the course of treatment in the three groups where the peaks represented virions released at the completion of a replication cycle. In vitro analyses correlated with in vivo observations. Early and intermediate OHSV1 therapy extended survival 12 and 7 days beyond the control group (day 21), while late OHSV1 therapy extended survival beyond 4 days.
Conclusion: OHSV1 is therapeutic against life threatening disease progression when administered at early and intermediate stage disease with potential to target late stage disease. This treatment holds promise for breast cancer meningeal metastases that can be translated to the clinic.
Citation Format: Darshini Kuruppu, Deepak Bhere, Khalid Shah, Anna-Liisa Brownell, Umar Mahmood, Kenneth K. Tanabe. HSV1 oncolytic therapy for breast cancer meningeal metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1309.