Right Column

RS1-00203-1: Genetic Enhancement of the Immune Response to Melanoma via hESC-derived T cells

Recommendation: Recommended if funds available
Scientific Score: 79

First Year Funds Requested: $321,250.00
Total Funds Requested: $642,501.00

Public Abstract (provided by applicant)

The overall goal of the proposed studies is to utilize human gene therapy approach using human embryonic stem cells to direct our body’s defenses to specifically attack melanoma tumor cells. Current technologies try to accomplish this by genetically manipulating certain circulating T lymphocytes, such that they will target tumor cells. T lymphocytes are the major cell type of our body’s immune system. However it is likely that this type of approach will not result in the presence of stable, lifelong genetically modified T cells. In contrast, a potentially more long-lasting approach would be to genetically modify human embryonic stem cells with the same therapeutic gene. Stem cells have the ability to form any type of blood cell, including T cells. Importantly, stem cells can persist for the life of the individual, and thus have the potential to produce genetically modified T cells for many years. In addition, these new tumor specific cells should expand in the body in response to the presence of the tumor, thus a large supply of tumor-fighting cells should be available as long as needed. This project proposes to develop novel means to introduce the anti-cancer gene into human embryonic stem cells. These stem cells will then be differentiated to generate tumor specific T cells utilizing animal model systems. We will then use several laboratory and mouse models to determine if the T cells derived from these genetically modified stem cells have anti-tumor activity. If successful, we will have provided proof-of principle that long-lived stem cells have the potential be utilized as a means of producing anti-cancer T cells. In the long run, these results could provide important information for design of future clinical trials designed to produce life-long improved anti-cancer immune responses.

Statement of Benefit to California (provided by applicant)

We propose to use human embryonic stem cells to develop a novel, yet potentially very effective method to treat invasive melanoma. Melanoma is a serious type of skin cancer which, if not removed early, spreads internally and is usually fatal. Overall melanoma is the 6th most common cancer in males and 7th in females and the incidence of this form of cancer is currently increasing at an epidemic rate. Although melanomas may occur in areas of skin that are not normally exposed to sunlight, sun exposure is believed to be a factor in about 70% of new cases. California’s mild winters and high number of sunny days provide opportunities for a number of occupational and recreational outdoor activities, and people in California are exposed to more than average levels of solar radiation. Consequently, there is a higher risk of developing this disease. As a matter of fact, California is one of the five US states with the highest predicted incidence of new cases of melanoma. According to the California Cancer Registry, each year 4,700 new cases of invasive melanoma and over 800 deaths related to this disease are reported in California, with the incidence rate increasing by 15% over the last decade. While the white population is at the greatest risk of developing this disease, it was recently reported that the rates of invasive melanoma have risen substantially in Hispanic people living in California as well. If our proposal is successful, our work could pave the way to the development of a new and effective form of melanoma therapy, one which would clearly benefit all the people of California affected by this disease.

Review

SYNOPSIS OF PROPOSAL: This is a well focused and developed proposal from a junior investigator to look at immune cells generated from hESCs, and how they interact with tumors in animals.

INNOVATION AND SIGNIFICANCE: This is a highly innovative proposal by a relatively junior, albeit established, young investigator who has assembled an experienced group of collaborators to help with this project. It represents a new approach to deriving tumor specific immune cells that is well worth pursuing and therefore the results of this research should be highly significant.

STRENGTHS OF THE PROPOSAL: This is a well developed proposal in which the investigator exhibits experience with a methodology and cognizance of the various challenges, both technical and biological. The rich research environment with senior collaborators having extensive expertise who are dedicated to the success of this project is a strength, and in fact the proposal is highly collaborative, both intra- and inter-institutionally.

The significant preliminary data establishing the potential feasibility of purposed approaches is considered a strength.

The proposal seeks to use hESCs to develop a new, effective treatment for an important and difficult cancer and this proposal is considered highly responsive to the CIRM SEED Grant RFA.

WEAKNESSES OF THE PROPOSAL: The ability to carry out the latter objective of this proposal is dependent on positive results obtained in the early objective. There is no provision in the research plan for “titration” of the transferred cells. The in vivo assay of the anti-tumor activity actually may underestimate the effectiveness of the therapeutic approach being evaluated.

There is a notable lack of detail on the imaging aspects of the proposal and possible difficulties and alternative plans were not adequately described.

The proposal could benefit from a modification of the in vivo tumor-regression model.

Although the work proposed includes radiotracers, “Radioisotopes” are not checked, “Yes,” in the “Biosafety” section.

DISCUSSION: This is a highly innovative proposal, highly responsive to the RFA, from a junior investigator. The work is highly significant as well, however the technical issues concerning the xenograft model tempered enthusiasm of the reviewers. In the tumorigenicity model, pre-formed tumors are targeted that in general are not well treated by therapeutics. There is no test of cell dosage which might give clues as to the inefficiencies of targeting. Titration is likely to be essential for success.

There was discussion over whether this work could be done with cells other than hESCs, but this PI has a track record in hES work and the therapeutic potential of the work was thought to be well-supported in the application.

The following Working Group members had a conflict of interest with this application and were therefore recused from participating in review of, discussion of, and voting on the application:

• Lansing, Sherry