Developing Better Immunotherapies for Cancer
From bench to bedside and beyondOur Lab comprises diverse projects centered on the premise that the immune system is capable of destroying tumor cells with the ultimate goal of benefiting all patients suffering from cancer.
T lymphocytes can be harnessed to elicit cancer cell destruction in a very specific and effective way. Our lab focuses on different ways to genetically engineer these T cells with T Cell Receptors (TCRs) or Chimeric Antigen Receptors (CARs) in combination with other transgenes or elements that can boost T cell function.
- We investigate how T cells behave in the Tumor Microenvironment (TME), how they interact and are influenced by other cells (myeloid-lineage cells, fibroblasts / extra-cellular matrix) and diverse factors (chemotactic proteins, cytokine milieu, epigenetic regulation).
- We develop new platforms based upon Oncolytic Virotherapy, which can significantly enhance anti-tumor immune responses.
- Our lab dedicates efforts in understanding how Hematopoietic Progenitor/Stem Cells (HSC) can be used towards an effective and long-living anti-tumor T cell responses.
- We are currently studying novel Nanoparticle platforms that facilitate T cell killing of tumor targets.
- Our lab also develop and generate Viral Vectors to be utilized in Clinical Trials (Phase I/II) through the UChicago cGMP Facility.
- Finally, based upon our translational research, we perform IND-enabling studies, and develop clinical protocols to initiate Clinical Trials based upon novel Immunotherapeutic approaches.
T Cell Receptor (TCR) engineering of lymphocytes to target solid tumors
T Cell Receptor engineered T cells
induce cancer cell destruction
The cells in GREEN are T lymphocytes expressing the T Cell Receptor (TCR) to recognize cancer antigen in a specific Major Histocompatibility Complex class I (MHC I) context. The RED cell is a cancer cell expressing the cancer antigen being targeted. Please click the > to run the video.
Addressing the immunosuppressive Tumor Microenvironment
The Tumor Microenvionment (TME) contains many factors and cellular components that suppress anti-cancer immune responses
We are developing new strategies to counter the various immunosuppressive factors present in the Tumor Microenvironment in order to allow T cells to work more efficiently against cancer cells.
Immunosuppressive factors that can be targeted to allow better anti-tumor T cell responses:
- Physical Barriers
Extracellular Matrix; Abnormal/ Irregular vasculature
- Metabolic Milieu
Glucose ↓; Lactic Acid ↑ ; pH ↓ ; Arginine ↓; NO↑; Hypoxia ↑; ROS ↑↑; IDO↑
- Cellular Components
CAFs, TAMs, MDSCs, TANs, Tregs
- Soluble Factors and Ligands
PD-L1↑;PD-L2↑;FasL↑;TGFbeta ↑; LIF↑ ; GAS6↑ ; HGF↑;CXCL1↑ ; CXCL2↑;CXCL9↑;IL-6↑;ARG1 (Arginase)↑;IL-23↑ ; IL17↑ ;IL-1b ↑;IL-8↑; IL-10↑; IL13↑;MMPs ↑;Cathepsins ↑;VEGF↑;IL-18↑; iNOS↑;COX2↑;CCL2↑ ; CCL5↑;CCL17↑; CXCL14↑; CD39/CD73(ATP ⇢ adenosine), etc.
Oncolytic Virotherapy to support anti-cancer T cell responses
ONCOLYTIC VIROTHERAPY
Oncolytic Virus (O.V.) selectively infects cancer cells but not normal cells.
Oncolytic Virus replicates in cancer cells, inducing cancer cell killing, spreading into more cancer cells, promoting inflammatory responses, and increases T cell infiltration into the tumor.
There is release of various cytokines and chemokines, antigens and payload transgenes (which we genetically engineer in our lab).
These processes result in enhanced T cell priming, activity and anti-cancer responses.
Clinical Trials based on T cell immunotherapies
Our team develops clinical trials for patients (Phase I / II trials). The treatment is based upon infusion of T cells capable of specifically finding and recognizing cancer cells and induce tumor destruction. The process starts with collection of blood, followed by an activation protocol of T cells and their transduction with engineered vectors. The T cells are then tested for identity, potency and sterility; and infused back into the patient.
We have documented expertise in designing clinical trials, writing clinical protocols, Regulatory agencies related processes (IRB, IBC, FDA, etc.), IND package preparation and submission, and opening the clinical trial for patient accrual.
In order to advance our scientific findings from the lab towards a clinical application, it is crucial that we have high quality, certified and safe reagents for our patients. Therefore we also generate large scale viral vector batches (Oncolytics, Lentiviral and Gamma-Retroviral) in our cGMP Facility at UChicago.
Please check the link below
Life-long CD4 T Cell Receptor-engineered cells for sustained anti-cancer effects
Hematopoietic Progenitor/Stem Cells (HSC) are genetically engineered with an MHC II (CD4) TCR, which after differentiation into T cells, will support Anti-Tumor Cytolytic (CTL) TCR-T Cells for an enhanced Cancer killing activity.
Our engineered HSC will provide a continued supply of anti-cancer T cells, allowing life-long anti-tumor responses.
