# Development of Immunostimulatory Virotherapy Without Neurotoxicity for the Treatment of Brain Malignancies

> **NIH NIH R43** · IMPLICYTE, INC. · 2021 · $399,335

## Abstract

PROJECT SUMMARY
Glioblastoma is one of the most lethal and recalcitrant of all malignant solid tumors. Treatment modalities have
not improved significantly in two decades. Glioblastoma is difficult to treat because of its inherent heterogeneity,
a low mutational load that reduces its intrinsic immunogenicity, and a highly immunosuppressive
microenvironment that prevents infiltration by critical immune cells. Although immunotherapy has transformed
modern cancer treatment, patients with glioblastoma have generally not demonstrated strong or durable
responses, leading to the classification of glioblastoma as an immunologically ‘cold’ tumor. Novel therapies
that can augment immunotherapy and enhance the anti-tumor immune response are urgently needed.
Oncolytic virotherapy is a novel platform for treating brain malignancies and potentiating tumors that respond
poorly to standard therapeutic approaches, including immunotherapy. Recombinantly-modified oncolytic
viruses permit a multifaceted and synergistic therapeutic drug design approach that directly destroys the tumor
through targeted lysis, while also expressing immunostimulatory transgenes in a complementary manner that
enhance immune-mediated tumor eradication. Implicyte, Inc. has developed two non-neurotoxic chimeric
vesicular stomatitis viruses (VSV) that selectively infect and destroy glioblastoma cells, but not normal
brain tissue. This virotherapy platform features several key innovations: it is non-neurotoxic and safe for use
in the brain; it can be further engineered to express multiple immunostimulatory transgenes; it has the ability to
destroy secondary tumors in the brain; it can evade neutralizing antibodies allowing for re-dosing; and it can
target multiple cancer types. Here we propose to further advance our novel non-neurotoxic chimeric
VSVs by engineering them to express immunostimulatory transgenes that will significantly enhance
the anti- tumor immune response. In Specific Aim 1, we will further improve Implicyte’s chimeric VSV viruses
by ‘arming’ them with two immunostimulatory transgenes. These novel viruses will be validated using in vitro
cell culture assays to ensure they replicate as well as the parental viruses, are non-toxic to primary human
neurons, and express the immunostimulatory transgenes at high levels. In Specific Aim 2, we will use in vivo
syngeneic mouse models to evaluate the efficacy and immunostimulatory enhancement of these viruses. In
these in vivo studies, we expect expression of the immunostimulatory transgenes to accelerate elimination of
the tumor, improve overall survival, and induce immunological memory in mice challenged with a second
tumor. Once this study is complete, we will have a lead clinical candidate that can be advanced to Phase
II-supported IND-enabling studies to secure approval for future clinical trials. Implicyte’s non-neurotoxic
oncolytic virotherapy, which combines direct tumor lysis with an anti-tumor immune response, has the potentia...

## Key facts

- **NIH application ID:** 10323138
- **Project number:** 1R43CA265525-01
- **Recipient organization:** IMPLICYTE, INC.
- **Principal Investigator:** Matthew Stremlau
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $399,335
- **Award type:** 1
- **Project period:** 2021-09-10 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10323138

## Citation

> US National Institutes of Health, RePORTER application 10323138, Development of Immunostimulatory Virotherapy Without Neurotoxicity for the Treatment of Brain Malignancies (1R43CA265525-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10323138. Licensed CC0.

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