Magnus Essand's research projects on cancer immunotherapy
CAR-T cell therapy
Chimeric antigen receptor (CAR) T cell therapy is a complex treatment regimen involving reprogramming of patient-derived T cells ex vivo before returning these cells to the patient. Our research group has both preclinical and clinical projects on CAR-T cells.
CD19 CAR-T cell therapy is today approved for B-cell acute lymphoblastic leukemia and large B-cell lymphoma. It has however become evident that tumors can recur after treatment and then, in many cases lack CD19 expression. This so-called antigen-loss is due to selective pressure induced by the treatment.
Heterogeneity within solid tumors makes it difficult to find an antigen that is uniformly expressed and can be targeted by CAR-T cells. Furthermore, solid tumors exhibit an immunosuppressive microenvironment that dampens the activity of CAR-T cells. To address these issues, we arm CAR-T cells with factors able to revert immune suppression and evoke bystander activation of endogenous tumor antigen-specific T cells. By inducing bystander epitope spreading, the newly activated cytolytic T cells can target also “CAR-target antigen-negative” tumor cells and thereby improve outcome in experimental models.
For hematological malignancies, our main focus is on developing CAR-T cells targeting CD20, that are further armed to counteract antigen-loss. Such CAR-T cells could be used to treat lymphoma patients early in their disease progression, but also patients relapsing from conventional CD19 CAR-T cell therapy. We are currently running a clinical trial with conventional CAR-T cells, and we have recently received a research grant from the Swedish Cancer Society with the aim to take armed CAR-T cells into a first-in-man clinical trial.
For solid tumors our research is so far preclinical in nature and the main focus is on glioblastoma (both for adult and pediatric patients). In a collaborative project recently granted by the Sjöberg Foundation, we try to further equip CAR-T cells with a molecular signature making them adhere to glioblastoma vessels for better uptake in the tumors. We are also developing armed CAR-T cells that target neuroblastoma and prostate cancer.
Oncolytic virus therapy
Immune checkpoint inhibitors can today help many cancer patients with metastatic disease. However, as immune checkpoint inhibitors work by blocking inhibitory signaling in already activated T cells, they are dependent on the presence of T cells in the tumor bed that are directed against tumor-associated antigens. If tumor-infiltrating T cells are lacking, they need to be generated de novo, prior to treatment with checkpoint inhibitors. Oncolytic viruses can induce immunogenic cancer cell death leading to alarm signals for the immune system with activation of anti-tumor T cell responses and thereby pave the way for sequential immune checkpoint blockade.
We are developing viruses/viral vectors armed with factors for recruitment and activation of dendritic cells that can take up antigen from killed tumor cells and cross-present antigenic epitopes to prime cytolytic T cells. For preclinical work we are focusing on glioblastoma and in a collaborative project recently granted by the Knut and Alice Wallenberg Foundation, we try to develop virus/vectors that are encoding factors able to induce tertiary lymphoid structures in the tumor microenvironment for local T cell activation.
Viruses/viral vectors are made specific for recruitment to tumors through virus capsid modification and they are made specific for replication inside tumor cells through insertion of gene regulatory elements. We are also running a clinical trial for neuroendocrine cancer patients with an oncolytic virus developed in house, thanks to crowdfunding and support from the VictoryNET foundation.