Mature T cells with specificity for NY-ESO-1 express a T-cell receptor (TCR). Our group has identified and cloned a novel TCR with specificity for NY-ESO-1. We introduce this molecule into stem cells, effectively reprogramming them to express the NY-ESO-1 TCR. When the reengineered stem cells are infused back into the patient, a portion of the cells expand for life-long self-renewal and the remaining cells develop into mature T cells that have NY-ESO-1 specificity. These T cells represent a distinct subset of immune cells that have the capacity to recognize NY-ESO-1–expressing tumor cells and initiate a series of processes to destroy the tumor cell. This is the basis of the immune-mediated tumor debulking.
The stem cells expressing the NY-ESO-1 TCR have the potential to provide a life-long source of T cells with specificity for NY-ESO-1–expressing tumor cells.
How would the stem cells do this? Would it be automatic? And if, for example, a patient developed another primary cancer expressing the same antigen, would the HSCs target that cancer?
The unique aspect of HSCs is their innate capacity for self-renewal and their ability to develop into mature immune cells. The infused HSCs persist and serve as a source of mature T cells. There is the potential for the stem-cell-derived mature T cells to recognize other NY-ESO-1–expressing tumor cells and eliminate them as well.
Would the HSC immunotherapy you are working on be offered as a frontline therapy or after remission to prevent relapse or as a salvage therapy?
We expect that the stem cell approach will initially be used as salvage therapy. In the future, we anticipate that it may also be used after remission to minimize the risk of relapse.
Much oncology research has focused on combining immunotherapy with other types of agents, like cytotoxics or targeted therapies; do you anticipate combining HSC immunotherapy with other types of therapy?
In this new study, re-engineered stem cell therapy is being utilized to augment the anti-tumor response elicited by the adoptive cell therapy with mature T cells. There are studies under way by our group and others to examine outcomes in treatments that combine immunotherapies.
Would this therapy be expected to be more effective against certain types of ovarian cancer? For example, would it matter whether the ovarian cancer was BRCA1 positive or negative?
We expect the treatment to be effective against any type of ovarian cancer that expresses the NY-ESO-1 antigen target. While it is a personalized-medicine approach, the treatment strategy we propose is not dependent on BRCA1 or other genetic markers.
Often, ovarian cancer is not detected until it is advanced. Would the stage of disease at the time of diagnosis be expected to effect outcomes with immunotherapy?
Development of immunotherapies and tumor vaccines is a rapidly growing field. The various types of immunotherapies are selected based on the stage of the disease, as this will improve the likelihood of an antitumor immune response.
Is there any possible advantage to giving immunotherapy like HSCs to prevent cancer in a woman with high-risk due to a genetic mutation or to prevent relapse in a woman who has an elevated CA-125 level after remission of ovarian cancer?
Using immunotherapy to prevent cancer in high-risk women is conceptually appealing, but this would be a difficult study to perform. However, for a patient who develops elevated CA125 after remission, immunotherapy is an attractive strategy.
Might the stem cell immunotherapy approach you are working on be effective against other types of cancer?
This approach is first being tested in patients with ovarian cancer, but the biological principle is similar for other types of cancers that express a tumor antigen that is targeted by the TCR. There are a number of such cancers, including melanoma, lung, breast, and colon.
What are the advantages of immunotherapy over traditional chemotherapy?
Traditional chemotherapies poison the tumor cells along with healthy normal cells. The severity of this collateral damage limits the efficacy and long-term use of many types of chemotherapy. One potential advantage of immunotherapies, such as vaccines and adoptive cell therapies, is the ability to minimize unwanted destruction of healthy tissue. Specificity of responses directed against tumor cells is a hallmark of immunotherapies. With the current HSC study, an additional beneficial feature is the potential for generating a life-long source of antitumor mature T cells.
For further information on Odunsi and RPCI’s Center for Immunotherapy:https://www.roswellpark.edu/kunle-odunsi