The goals of Dr. Carol Kruse’s laboratory are directed toward an understanding of the immunology of the brain and immunoresistance mechanisms used by tumor cells that will allow development of alternative therapies for treating patients with primary malignant brain tumors. They use glioma cell culture as a model system, in addition to syngeneic mouse and rat or human xenograft brain tumor models.
Current basic research projects involve:
- The development of algorithms that allow selection of allodonors to obtain robust alloreactive cytotoxic T lymphocytes (CTL) following one-way mixed lymphocyte reactions (MLR) based upon molecular HLA mismatch of responder:stimulator pairs
- Enhancing generation of immunotherapeutic CTL using dendritic cells (DC) for one-way lymphocyte DC reactions, where the DC have been differentially activated using pathogen associated signaling molecules (CLR or PRR agonists) contained with nanoparticles such that they better kill tumor and cancer stem cells, and
- Use of allogeneic glioma cell lines as sources of tumor associated antigens, which can be the target of tumor cell or dendritic cell vaccines.
Kruse’s translational research studies are focused on innovative cellular and gene therapy approaches. Her lab is engineering alloreactive CTL as retroviral vector producing cells. Alloreactive CTL that possess the capability of trafficking through tissues as part of their immune surveillance function will be used to deliver replication competent retroviruses within the brain to reach the infiltrating tumor cells. The retroviral vectors will code for suicide genes such that when prodrug is administered, the transduced tumor cells will die. Kruse’s lab is exploring this multi-modal therapy not only for primary malignant brain tumors, but for tumors metastatic to brain.
Kruse’s clinical research involves conduct of a Phase I dose escalation cellular therapy trial. The trial involves intratumoral adoptive transfer of alloreactive CTL that are directed against patient HLA antigens present on brain tumor cells but not normal neuroglia. Patients undergo resection for recurrent glioma and then receive multiple infusions of alloreactive CTL through a reservoir/catheter system that is implanted at the time of surgical debulking. Correlative laboratory experiments and immune responses are monitored in parallel.
Selected Cancer-Related Publications:
Hickey MJ, Malone CC, Erickson KL, Jadus MR, Prins RM, Liau LM, Kruse CA. Cellular and vaccine therapeutic approaches for gliomas. J Transl Med. 2010 Oct 14;8:100.
Tritz R, Hickey MJ, Lin AH, Hadwiger P, Sah DW, Neuwelt EA, Mueller BM, Kruse CA. FAPP2 gene downregulation increases tumor cell sensitivity to Fas-induced apoptosis. Biochem Biophys Res Commun. 2009 May 29;383(2):167-71. Epub 2009 Mar 31.
Gomez GG, Hickey MJ, Tritz R, Kruse CA. Immunoresistant human glioma cell clones selected with alloreactive cytotoxic T lymphocytes: downregulation of multiple proapoptotic factors. Gene Ther Mol Biol. 2008 Jun;12(1):101-110.
Tritz R, Mueller BM, Hickey MJ, Lin AH, Gomez GG, Hadwiger P, Sah DW, Muldoon L, Neuwelt EA, Kruse CA. siRNA Down-regulation of the PATZ1 Gene in Human Glioma Cells Increases Their Sensitivity to Apoptotic Stimuli. Cancer Ther. 2008;6(B):865-876.
Zhang JG, Eguchi J, Kruse CA, Gomez GG, Fakhrai H, Schroter S, Ma W, Hoa N, Minev B, Delgado C, Wepsic HT, Okada H, Jadus MR. Antigenic profiling of glioma cells to generate allogeneic vaccines or dendritic cell-based therapeutics. Clin Cancer Res. 2007 Jan 15;13(2 Pt 1):566-75.