Magnus Essand's research projects on gene, cell and immunotherapy of cancer
Oncolytic virus therapy
The viruses we develop are genetically engineered to selectively kill tumor cells and induce a potent and adequate anti-tumor immune response. Virus infectivity is altered through genetic modification of the virus capsid or glycoproteins to favor infection of tumors cells. Virus replication is altered by introduction of regulatory elements, such as promoter and/or microRNA target sequences into the virus genome to specifically engage virus activity to tumor cells.
Immunogenic cancer cell death, caused by oncolytic viruses, can reduce immune suppression in the tumor microenvironment and provoke an adaptive anti-tumor immune response and thereby pave the way for sequential checkpoint blockade using for example anti-PD1 antibodies. We are in detail studying immunogenic cell death caused by adenovirus, Semliki Forest virus (SFV) and vaccinia virus.
Various immune stimulatory genes are incorporated in the virus genomes to enhance the capacity of the oncolytic virus to control the anti-tumor immune attack. We are specifically interested in Helicobacter pylori neutrophil-activating protein (HP-NAP) as a transgene in viruses for Th1-directed immune activation.
Adenoviruses developed in the lab have been brought into clinical trial. At the moment a recombinant neurotropic SFV is being developed for experimental treatment of glioblastoma, a deadly brain cancer affecting both adults and children.
CAR T-cell immunotherapy
The T-cells we develop are genetically engineered to express a chimeric antigen receptor (CAR) that can recognize antigens expressed by tumor cells. While CD19 CAR T-cell therapy works well for leukemias, solid tumors are far more challenging since unique and homogenously expressed target antigens are lacking. Therefore CAR T-cell therapy of solid tumors must be able to spare normal tissues expressing low levels of the target antigen recognized by the CAR but also be able to induce bystander immunity in the tumor microenvironment to kill also tumor cells that do not express the antigen recognized by the CAR.
Solid tumors exhibit an immunosuppressive microenvironment that dampens the activity of CAR T-cells. Therefore, the transgenes included in the CAR T-cells should be able to revert immune suppression. We are focusing on CAR T-cells targeting PSCA on prostate cancer cells, GD2 on neuroblastoma and CD19 on B-cell leukemia and lymphoma.
CAR T-cell therapy is a complex procedure including isolation of T-cells from patients blood, genetic modification of the T cells to express the CAR molecule, expansion of the CAR-engineered T cells to large numbers before adoptive transfer back to the patients. We are trying to improve all steps, thereby developing new and better viral vectors for efficient transfer of CAR transgenes to T-cells.
We are also developing optimized protocols to expand the engineered T cells to make them resistant to oxidative stress and immunosuppressive factor that they will meet once they have been transferred back to the patients.
Allogeneic DC cancer vaccines
Patient-derived DCs modified ex vivo with tumor-associated antigens have been evaluated as therapeutic cancer vaccines with some success. It has however become clear that ex vivo-modified DCs are short-lived when re-injected and do not migrate to draining lymph nodes. The therapeutic effect obtained from administration of ex vivo-modified DCs, with respect to functionality and maturation characteristics, appears to come from resident tissue (bystander) DCs that take up material from dying injected ex vivo-modified DCs and bring it to lymph nodes for antigen presentation to naïve T-cells and B-cells.
We therefore investigate if allogeneic DCs (DCs from a different individual) can be used instead. The logistics would be simplified and costs significantly reduced. Importantly, the HLA mismatch will most likely act as a strong adjuvant both for activation of NK-cells and T-cells.
We perform both efficacy studies of DC vaccines and mechanistic studies to evaluate which cell types are attracted and activated in response to allogeneic DCs. We use real-time intravital confocal microscopy imaging to study these events. We also investigate whether the therapeutic effect can be improved if the allogeneic DCs are combined with viruses secreting HP-NAP, IL-1b and other immune modulators.