Funding opportunities

Funding Type: 
Early Translational II
Grant Number: 
Principle Investigator: 
Funds requested: 
$3 370 607
Funding Recommendations: 
Grant approved: 
Public Abstract: 

Modified viruses can be used to infect tumor cells and alter the tumor cell to make anti-tumor proteins. Most researchers use virus that can infect and modify the tumor cell it enters, but can not make more of itself to infect additional cells surrounding the original infected cell. This type of virus is called replication-incompetent virus. Use of replication-incompetent virus is considered safe because no additional virus, which potentially could get out of control, is generated inside of the tumor. However such therapies have been shown to have only limited beneficial effects, presumably because too many tumor cells never get infected.

Newer approaches investigate the use of replication-competent viruses to achieve highly efficient gene transfer to tumors. A successfully transduced tumor cell itself becomes a virus-producing cell, sustaining further transduction events even after initial administration. We propose here to use a type of replication-competent virus that only infects dividing cells and therefore will infect the rapidly dividing cancer cells but not normal brain cells.

The use of replication-competent virus is potentially more risky but is well justified in clinical scenarios involving highly aggressive and rapidly progressing metastatic tumor growth in the brain. To administer therapeutic virus into the brain, the virus is injected right into the center of the tumor. Yet, human brain tumors are often found as diffusely spreading foci in the brain and may be difficult to eliminate by locally-administered replication-competent retrovirus (RCR) vectors alone.

In this study we propose to use a type of adult stem cell called a "mesenchymal stem cell" (MSC) as a delivery system for the RCR vectors. Mesenchymal stem cells (MSCs) have been shown to have natural tumor-homing abilities, and can migrate to tumor foci and penetrate through into the interior of tumor masses. We propose to engineer them into "aircraft carriers" that release tumor-selective viruses, which can then efficiently spread suicide genes from one cancer cell to another in multiple tumor foci in the brain.

Statement of Benefit to California: 

This research is based on a solid foundation that combines two innovative technologies for the treatment of primary brain tumors, particularly glioblastoma multiforme (GBM) the most malignant form of brain tumor, which afflicts men, women, and children in California and elsewhere. Each of these technologies has been approved separately by FDA for clinical testing in humans: human mesenchymal stem cells (MSCs), and replication-competent retrovirus (RCR) vectors.

MSCs have been reported to exhibit a natural ability to migrate to solid tumors and penetrate into the tissue mass. Once inside a tumor, RCR vectors can spread selectively in the cancer cells and their replication can keep up with their uncontrolled proliferation, and their ability to integrate themselves into the cancer cell genome allows them to permanently "seed" tumor cells with therapeutic genes.

Here we propose to utilize the natural tumor homing ability of MSCs to deliver RCR vectors into brain tumors. This "virus vs. cancer" strategy takes advantage of the amplification process inherent in the spread of virus from cell to cell, and by using MSCs to initiate the virus infection efficiently in brain tumors, represents an approach that will have the potential to effectively treat this poor prognosis disease.

If successful, clinical application of this strategy can be implemented by an "off-the-shelf" mesenchymal stem cell (MSC) primary cell lines that have been pre-characterized for their tumor homing ability and virus production capability, and can be offered to patients without requiring an invasive procedure to harvest their own stem cells. Furthermore, this represents a treatment that could potentially be administered through a needle, thus making it unnecessary for patients to undergo major neurosurgical procedures entailing craniotomy at an advanced medical center. Hence this research could lead to a novel treatment approach that would particularly address the needs of brain tumor patients in California who are underserved due to socioeconomic and geographic constraints, as well as the elderly who are poor-risk for surgical interventions.

Review Summary: 

This application for a Development Candidate Award focuses on a combination product that includes genetically modified cells to treat glioblastoma. The applicant proposes to use mesenchymal stem cells (MSCs) as stem cell-based carriers for tumor-homing delivery of replication competent retroviral vectors (RCRs) encoding a suicide gene payload. The FDA has recently approved a Phase I clinical trial of an RCR engineered to deliver a therapeutic payload administered by direct injection, but this approach is limited by the viral dosage that can be delivered and the slow spread of the virus through the brain. Published and preliminary data suggest that MSCs migrate to tumors and the applicant plans to take advantage of this property by engineering MSCs to function as RCR producing cells. Three Specific Aims are proposed: (1) to develop processes for the generation and validation of RCR producing MSCs; (2) to evaluate these cells for efficacy in vivo, in both xenogeneic and syngeneic models of glioblastoma; and (3) to conduct safety and biodistribution studies with RCR producing MSCs.

Reviewers agreed that this proposal addresses a tremendous unmet medical need and could have a significant impact if successful. Glioblastoma is a devastating malignancy for which there are no effective treatment options. This approach could also potentially be applied to other brain resident tumors. Reviewers generally found the scientific rationale for this proposal to be strong. They noted that MSCs migrating through the tumor mass would be a major improvement for the delivery of viral vectors, which diffuse slowly when injected directly. Reviewers raised some safety concerns about the potential for MSCs to become oncogenically transformed or feed tumor growth, but recognized that the suicide gene approach largely addresses these issues. They also noted that because RCRs replicate only in actively proliferating cells, they may not target dormant tumor cells, which could lead to recurrence at some point after therapy. Due to this possibility, reviewers suggested it might be of value to assess the durability of the proposed therapy beyond the 135-day time point.

The reviewers described the research plan as feasible and appreciated that the RCR vector has already been approved for clinical testing by the FDA. They did make a number of suggestions for improving the plan and increasing the likelihood of clinical translation. For example, reviewers had little enthusiasm for the subcutaneous and U-87 xenograft tumor models, commenting that the field has moved beyond these models. They recommended that the applicant instead focus on the primary orthotopic xenografts and syngeneic models. With regard to imaging studies, reviewers noted that while GFP transduced MSCs are acceptable for preclinical studies, the FDA prefers non-genetic imaging with clinical products, and they suggested that the applicant consider other imaging approaches, such as iron oxide or 19F perfluorocarbon labeling. To provide a non-invasive measure of suicide gene expression one reviewer suggested that the applicant consider the use of HSV-TK, which could function both as a reporter as well as a suicide gene. The activity could then be imaged by Positron emission tomography (PET) imaging using various uracil analogs. Reviewers stressed the importance of choosing MSC lines that are suitable for eventual clinical use (e.g. they meet donor eligibility criteria) and strongly recommended that the applicant use a clinically compatible source of MSCs from the beginning to ensure translatability. Reviewers were confused by the plan to generate “mock” Master and Working Cell Banks in Aim 1.

Reviewers found the Principal Investigator (PI) and assembled research team to be superbly qualified to perform the proposed studies. The PI is an expert in the field of gene therapy and the team has experience working with the FDA. The environment and resources available are excellent. Reviewers did note that there is a tremendous number of employees proposed, resulting in an excessive and loosely justified budget.

Overall, reviewers were impressed by this proposal to combine gene and cell therapy to treat glioblastoma. While they presented a number of suggestions for improving the research plan, they were ultimately confident in its feasibility. Reviewers praised the PI and research team and agreed that they have an excellent chance of advancing a candidate to IND-enabling studies within the three-year timeframe.