Extended Survival of Glioblastoma Patients After Chemoprotective HSC Gene Therapy

Gene therapy using P140K-modified hematopoietic progenitor cells is chemoprotective, enabling glioblastoma patients to withstand myelotoxic doses of chemotherapy. Arming Blood Stem Cells to Fight Cancer The toxic effects of chemotherapy (chemotoxicity) on blood and bone marrow cells of cancer patients can be a significant barrier to treating tumors. Delivery of a gene that can protect bone marrow stem and progenitor cells from chemotoxicity could overcome this barrier. In a new study by Adair et al., patients with chemotherapy-resistant brain tumors with very poor chances of survival were given a transplant with their own bone marrow hematopoietic stem cells after the cells had been modified with a gene that protects these cells from chemotherapy. After the bone marrow transplant, patients were then given dose-intensified chemotherapy. Adair et al. report that the patients were able to tolerate these chemotherapy doses better after transplant of the gene-modified bone marrow stem cells than did patients in previous studies who had received the same type of chemotherapy but without the gene-modified bone marrow stem cell transplant. The authors found that chemotherapy increased the number of gene-modified blood and bone marrow cells in these patients. These patients survived longer than predicted without any negative side effects from the transplanted cells or the treatment given. This strategy could be used for treating other types of cancer, or diseases treated with the same type of chemotherapy, to increase the efficacy of the drug regimen. This strategy could also be further developed as a clinical application in other diseases where defective bone marrow stem cells can be corrected by gene therapy but need to be increased to higher levels to produce a therapeutic benefit. Chemotherapy with alkylating agents for treating malignant disease results in myelosuppression that can significantly limit dose escalation and potential clinical efficacy. Gene therapy using mutant methylguanine methyltransferase (P140K) gene–modified hematopoietic stem and progenitor cells may circumvent this problem by abrogating the toxic effects of chemotherapy on hematopoietic cells. However, this approach has not been evaluated clinically. Here, we show efficient polyclonal engraftment of autologous P140K-modified hematopoietic stem and progenitor cells in three patients with glioblastoma. Increases in P140K-modified cells after transplant indicate selection of gene-modified hematopoietic repopulating cells. Longitudinal retroviral integration site (RIS) analysis identified more than 12,000 unique RISs in the three glioblastoma patients, with multiple clones present in the peripheral blood of each patient throughout multiple chemotherapy cycles. To assess safety, we monitored RIS distribution over the course of chemotherapy treatments. Two patients exhibited emergence of prominent clones harboring RISs associated with the intronic coding region of PRDM16 (PR domain–containing 16) or the 3′ untranslated region of HMGA2 (high-mobility group A2) genes with no adverse clinical outcomes. All three patients surpassed the median survival for glioblastoma patients with poor prognosis, with one patient alive and progression-free more than 2 years after diagnosis. Thus, transplanted P140K-expressing hematopoietic stem and progenitor cells are chemoprotective, potentially maximizing the drug dose that can be administered.