Magnus Essand's research projects on cancer immunotherapy

CAR-T cell immunotherapy

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.

Hematological malignancies

CD19-directed CAR-T cell therapies are today approved for B-cell acute lymphoblastic leukemia and B-cell lymphomas. Treatment is effective but many patients relapse after treatment and the recurrent tumour is then often negative for CD19 expression. This so-called antigen-loss is probably due to selective pressure induced by the treatment. Our main focus is on developing CAR-T cells targeting CD20, that are armed with the Neutrophil-Activating Protein (NAP), derived from Helicobacter pylori, to counteract antigen-loss. Such CAR20(NAP)-T cells are currently entering clinical evaluation for patients who not eligible to receive approved CD19 CAR-T cell products and patients relapsing from approved CD19 CAR-T cell treatment.

Glioblastoma

Antigen heterogeneity within solid tumours, such as glioblastoma, makes it difficult to develop CAR-T cells that target and kill all tumour cells within a tumour. Furthermore, these tumours exhibit an immunosuppressive microenvironment that dampens the activity of CAR-T cells. We have developed CAR-T cells directed against IL13Ra2, an antigen commonly expressed by glioblastoma. IL13Ra2 expression is however heterogenous. By arming IL13Ra2-directed CAR-T cells with NAP we have shown in animal models that we are able to evoke bystander activation of endogenous tumour antigen-specific T cells that can target also “CAR-target antigen-negative” tumour cells and thereby improve outcome in experimental models.

Oncolytic viruses

Oncolytic viruses can induce immunogenic cancer cell death releasing endogenous alarm signals for the immune system leading to activation of anti-tumour T cell responses. They can therefore pave the way for effective immune checkpoint blockade and other immunotherapies.

We are developing oncolytic viruses armed with factors for recruitment and activation of dendritic cells that upon activation can take up tumour antigen from killed tumor cells and cross-present antigenic epitopes to prime cytolytic T cells.

Neuroendocrine Cancer

A recombinant oncolytic adenovirus, called AdVince, was developed in the lab. The virus capsid was modified for increased uptake in tumour cells and neuroendocrine virus replication is ensured by a specific promoter and microRNA target sequences in the virus genome. AdVince is currently being evaluated in patients with neuroendocrine cancer patients at Uppsala University Hospital.

Glioblastoma

Semliki Forest virus (SFV) is a neurotropic virus that is being evaluated as an oncolytic agent in preclinical glioblastoma models. We restrict virus activity by insertion of microRNA target sequences in the virus genome and arm the virus with transgenes able to induce antitumoral immunity.

Viral vectors to improve cancer immunotherapy

We are developing tumor vessel-targeted adeno-associated viral (AAV) vectors encoding LIGHT and other factors able to transform tumor-associated endothelial cells into high endothelial venules (HEVs) for improved T cell recruitment into tumors and to induce antigen-presenting niches in the tumor microenvironment to sustain the activity of antigen-specific T cells.

This work is being carried out together with Anna Dimberg and her research group. The focus is on glioblastoma and the AAV vectors are made specific for targeting tumor vessels through virus capsid modification. We are now entering the phase of scaling up vector production to bridge the cap to clinical trials.