Off the Shelf T Cell Immunotherapies Targeting Endogenous Retroviruses in Diffuse Intrinsic Pontine Glioma
Mentor: Dr. Conrad Russell Cruz
Diffuse intrinsic pontine glioma (DIPG) is a rapid and almost universally fatal brain cancer in very young children that has seen no improvement in outcomes in several decades. Clearly, developing novel therapies for this poor prognosis disease is much needed. Recently, T cell immunotherapies have shown great promise in multiple resistant cancers - using the patient’s own T cells to specifically and aggressively target and kill cancer cells. They have had tremendous success against virus associated malignancies (for example, EBV-positive lymphoma), because of an easily identified, tumor-specific, and highly immunogenic target. Translating this approach against DIPG is potentially feasible because T cells have been documented to penetrate the blood brain barrier. However, effective T cell therapy for this tumor will require identification of antigens as “potent” as viral antigens were in the hematologic malignancy setting. In addition, T cell therapy for this rapidly fatal tumor requires that these T cells are readily available for treating patients.
Potential targets in DIPG include endogenous retroviruses (ERV) - remnants of ancient retroviruses that integrated into the germline during our evolution. Their transcripts are normally silent in healthy cells; however, in various malignancies, these elements are transcribed. Mack et al (Cell 2019) recently showed that H3K27 acetylation leads to ERV expression in H3K27 DIPG
We posit that targeting endogenous retroviruses (ERVs) using a bank of pre-manufactured, healthy donor T cells will specifically recognize and kill DIPG tumor cells matched in at least one HLA and can therefore be used as an off-the-shelf immunotherapy for this disease. We propose to develop an ex vivo expansion protocol to generate ERV-specific T cells from healthy donors of different HLA types and target various DIPG cell lines.
