Surgical Innovation & Research
Research in the Ilitch Department of Surgery
Research is strongly supported and encouraged. In addition to the large amount of research conducted by individual surgeons, the Department supports institutional research through several academic labs and commercial/industrial collaborations.
The Smart Sensors and Integrated Microsystems (SSIM) Lab at Wayne State University College of Engineering worked collaboratively with our surgeons for several years on such projects as handheld detectors for various cancers, transplant rejection, and MRSA, before being transferred in its entirety to the Ilitch Department of Surgery in the WSU School of Medicine.
Breast Cancer Research Lab — Dr. David H. Gorski
Ovarian & Pancreatic Cancer Research Lab — Dr. Ramesh Babu Batchu
Novel CAR T Cell/NK Cell Based Therapies for Pancreatic and Ovarian Cancers
Pancreatic and ovarian cancers are relatively resistant to chemotherapy and typically diagnosed at an advanced stage, thereby precluding surgical resection and underscoring the need for novel therapies. One promising approach is the utilization of chimeric antigen receptor (CAR) T cell-based technology, which has ushered in a new era in cancer immunotherapy especially in hematological malignancies. CARs are genetically engineered simulated receptors expressed on T cells containing an extracellular single chain fragment variable (scFv) antibody fragment linked to intracellular T cell activation domain.
Often known as a “living drug,” CAR T cells directly recognize tumor-specific antigen via scFv and kill tumor cells. Since this process circumvents the need for dendritic cell mediation in mounting immune responses, which often suffers from tumor-induced inhibition, it has revolutionized cancer immunotherapy. In other words, the extraordinary success of this therapy has been attributed to its ability to bypass tumor-imposed immune-inhibitory mechanisms.
We have previously demonstrated in vitro killing of BxPC-3 pancreatic cancer cell-line and SKOV-3 ovarian cancer cell-line using autologous CAR T cells targeting tumor-specific antigen, mesothelin, generated via lentiviral transduction using conventional DNA. However, it has several important limitations as follows:
- Autologous T cell preparation is patient-specific, time consuming and labor intensive.
- Lentiviral vectors preferentially integrate into transcriptionally active chromosomal sites thus increasing the chances of insertional mutagenesis.
- Use of conventional DNA vector electroporation to avoid lentiviral vectors expresses unwanted antibiotic resistance genes and further triggers inflammatory responses due to the presence of bacterial unmethylated CpG.
- CAR T cell activity in pancreatic and ovarian cancers in clinical settings, in vivo, is inhibited by immunosuppressive tumor milieu.
We developed two CAR related projects to address the above limitations. They are described below.
Project 1: “Off-the-shelf” Cellular Immuno-Therapy for Pancreatic and Ovarian Cancers
We have developed CAR therapy using bone marrow-derived primary natural killer (NK) cells as an alternative to autologous T cells which can be maintained as a continuously expandable off-the-shelf allogeneic therapy. We used sleeping beauty (SB) transposons, mobile genetic elements that are an alternative system for lentiviral transduction. SB transposons contain mesothelin scFv flanked by inverted terminal repeats enabling chromosomal integration. SB transposon chromosomal integration is without any preference for active transcriptional units, thus decreasing the risks of insertional mutagenesis. We further introduced novel minicircle (MC) plasmid technology in place of conventional DNA plasmids. MCs are devoid of redundant bacterial elements such as antibiotic resistant genes and unmethylated CpG. Being much smaller in size they are more efficient in entering cells.
Thus, using modified natural killer cell-line (NK-92) to electroporate SB/MC mesothelin-CAR plasmid vector, we developed an allogeneic off-the-shelf therapy overcoming the limitations associated with lentiviral transduction. We demonstrated efficient killing of both pancreatic and ovarian cancer cells in vitro with an enhanced mesothelin-CAR engraftment. This has the potential to the improve the clinical safety profile of CAR T cell therapy by eliminating both viral and bacterial concerns while simultaneously increasing engraftment and cancer cell cytotoxicity.
Project 2: Blocking Inhibitory Cytokines in the Tumor Microenvironment of Pancreatic and Ovarian Cancers Potentiates Mesothelin-Chimeric Antigen Receptor NK-92MI Activity
We have previously demonstrated that mesothelin-CAR T cells kill both pancreatic and ovarian cancer cells in vitro. However, the efficacy of CAR T cell therapy for pancreatic and ovarian solid tumor treatment in vivo has not yet been successful. Solid tumors create an immune suppressive milieu in their tumor microenvironment (TME) consisting of inhibitory cytokines such as IL-10 and TGF-β secreted by regulator T cells (Tregs). IL-2 is known to protect the functional ability of T cells to overcome the negative effects of the TME. The NK-92MI cell line, which is derived from natural killer (NK) cells but genetically modified to secrete IL-2, can be utilized as part of a CAR NK cell treatment strategy to localizing IL-2 intratumorally.
The pivotal challenge for the CAR T cell therapy against solid tumors such as pancreatic and ovarian cancers is the immunosuppressive TME that interferes with T cell activity. We posit that the blocking of IL-10 and TGF-β while producing immune-protective cytokines such as IL-2, may result in more effective CAR T and CAR NK cell therapy.
Using pancreatic (BKPC-3) and ovarian (SKOV-3) tumor-conditioned medium and patient-derived malignant ascites simulating the in vivo conditions, we can assess the effect of the TME and its reversal via depletion of IL10/TGF-β on mesothelin-CAR-NK cell cytotoxic activity. Our approach has led to the establishment of an ex vivo system for testing various vaccine candidates against pancreatic and ovarian cancers.
We have demonstrated a significant reversal of TME-mediated inhibition of mesothelin CAR-NK cell activity by antibody/siRNA mediated depleting IL10/TGF-β. This has been achieved with mesothelin-CAR T cells in autologous setting and more efficiently with an allogeneic off-the-shelf IL-2 secreting mesothelin-CAR-NK-92MI. This has potential for more effective clinical translation of mesothelin-engrafted CAR T cells or NK cells.
We are in the process of deciphering various signaling pathways; if successful, our results will facilitate the development of therapeutic modalities that are non-overlapping and potentially synergistic with conventional treatment.
Breast Cancer Research Lab — Dr. Cecelia Speyer
For the past five years, my collaborator and I have identified and established a role for the metabotropic glutamate receptor-1 (mGluR1) in breast cancer. Our specific focus includes i) determining the mechanism and novel pathways by which mGluR1 regulates the angiogenic process in endothelial cells ii) examining the molecular pathways by which mGluR1 mediates growth and metastatic properties of breast cancer cells iii) elucidating the mGluR1-dependent and independent role of the drug, Riluzole, in regulating breast tumor progression iv) examining the anti-inflammatory properties of mGluR1 and Riluzole within the tumor microenvironment.
My past research focus has been in the area of inflammation where I discovered the expression of novel chemokine receptors on neutrophils in sepsis. These findings have shed light on the concept of neutrophil subsets in various chronic inflammatory diseases such as sepsis, autoimmune diseases, and cancer. Currently, my laboratory’s focus is expanding into the area of tumor inflammation where we are examining the role and function of the various PMN subsets, their expression of various receptors (CC chemokine, mGluR1), and the role of the receptors themselves within the tumor microenvironment in the hopes of identifying targets for the therapeutic treatment of breast cancer.
To a very great extent, simulation is the future of surgery. Within a few years, no surgical procedure will be performed without first perfecting it on a full-sized, 3D, and possibly haptic simulation of the specific patient; and most surgical training and skills assessment will be conducted on simulators.
Recognizing that this is the future of surgery, the Department is actively involved in the research and development of simulation technologies both within the Department and in partnership with both global and local hardware engineering and software development corporations.
The surgery faculty, through SEMCE, teach both a basic and advanced US simulation course. To learn ultrasound skills medical students usually use real portable ultrasound machines on crude, short-lived, gel-and-noodles models of the abdomen. The machines are expensive, and the models are time consuming for the surgeon-teacher to build and therefore expensive also. Measuring/monitoring the students as they practice requires direct expert observation and manual recording of performance and is therefore expensive. Teaching by demonstration requires one-on-one learner to educator.
The Department has developed an ultrasound simulator with a dummy probe whose position is tracked with 6 degrees of freedom as it is manipulated in contact with a physical model of the abdomen. The coordinate data stream will be used to interrogate a virtual digitized model of the abdomen, resulting in an image that varies in real time with the probe position.
Fundamentals of Laparoscopic Surgery (FLS)
Official Testing Center The Department of Surgery at Wayne State University/Detroit Medical Center is an official testing center for surgeons and general surgery residents who are interested in becoming certified in the Fundamentals of Laparoscopic Surgery (FLS). More than 100 residents and surgeons have undergone FLS certification testing since 2007. Currently the Department of Surgery has 2 FLS certified test proctors.
Fundamentals of Endoscopic Surgery (FES)
Official Testing Center The Department of Surgery at Wayne State University/Detroit Medical Center is one of two sites in Michigan designated as an official testing center for surgeons and general surgery residents who are interested in becoming certified in the Fundamentals of Endoscopic Surgery (FES). Currently we are doing over 20 tests a year with two proctors.
David A. Edelman, M.D., Director, Clinical Professor of Surgery, Educational Planner
Simulation, Scoring, and Proficiency Monitoring System
The Department of Surgery has 4 FLS machines associated with a Simulation Support Platform that allows us to record and score all practice attempts of FLS. We have over 10,000 trials saved.
Surgical Skills and Simulation Center The Department of Surgery has a surgical skills and simulation training laboratory (established in 2007) to further enhance the teaching of open, laparoscopic, endoscopic and endovascular surgical skills of medical students, residents, fellows, allied health professionals, academic faculty and community physicians alike. The Department has designed their own curriculum that is used by both the MS4s (ACES) and the PGY-1 residents.
David A. Edelman, M.D., Director, Clinical Professor of Surgery, Educational Planner
Patient Specific Surgical Simulation
The Department is developing a patient-specific surgical simulator. The simulations, based on 64-slice CT images, will enable surgeons to plan and practice virtual procedures on models of their actual individual patients. The project has reached proof-of-concept stage..