Research projects on immuno-oncology
Localized immunotherapy, from AdCD40L to locally administrated anti-CD40 therapy
We have initiated a series of novel locally applied immunotherapies in which we aim to revert the immunosuppressive milieu created by the tumour. Therapies include the use of adenovectors expressing CD40L, monoclonal antibodies targeting molecules on immune cells and Toll-like receptor agonists.
Our pioneering studies with AdCD40L immunotherapy of bladder cancer and melanoma led to the IMCAN project together with Alligator Bioscience, in which we have extensively studied how lower doses of anti-CD40 and anti-CTLA-4 can be used to optimize bladder cancer treatment.
Improving the activation of T cells
Immune activation can be hampered by two major immune checkpoint regulators (CTLA-4 and PD-1). In order to ensure proper and sustained T cell activation one can use antibodies that block these two receptors. In addition to the local therapy projects, we have also combined synthetic DNA sequences (CpG) with CTLA-4 or PD-1 blockade to examine if a combination strategy could improve therapy further.
Single and combination strategies were assessed in an experimental bladder cancer model. CTLA-4 blockade alone prolonged survival of mice. When anti-CTLA-4 or anti-PD-1 antibodies were combined with CpG, survival was enhanced and elevated levels of activated T cells were found in treated mice.
We believe that this strategy can be used to further improve immunotherapy for patients with aggressive bladder cancer or other solid tumours.
Antibodies and CpG can improve the activation of T cells
Tumour cell debris is taken up by antigen-presenting cells (APC) and is sequentially presented to the T cell. To improve T cell activation the inhibiting receptors (CTLA-4) on the T cell can be blocked using antibodies. One can also further improve the activation of the antigen-presenting cell by the use of small synthetic DNA sequences (CpG). This can also lead to improved antigen presentation and in the end a better T cell response.
A new generation of therapeutic cancer vaccines
For the last years we have pursued a track of research aiming to improve T cell priming/activation by facilitating the delivery of synthetic long peptides (SLPs) into dendritic cells (DCs) via Fc receptors (FcR) The SLPs are overlapping ~20-30 long amino acid sequences spanning tumour or pathogen related antigens (Ags) and can be used to trigger T cell responses in conjunction with adjuvants.
SLPs have the advantage, over short single peptides, to span a whole tumour associated protein. They include a plethora of CD4 and CD8 T cell epitopes for various HLA alleles. Importantly, they require processing by antigen-presenting cells (APCs) and will therefore not directly interact with MHC class I on non-APCs, thus lowering the risk of T cell anergy.
SLPs have successfully been assessed by our collaborators in Leiden in a clinical trial for high-grade vulvar intraepithelial neoplasia using long peptides spanning the E6 and E7 oncoproteins, but the work demonstrates that improvements are needed to cure larger lesions.
Improving T cell response
To improve therapeutic vaccines we and others have shown that one needs to achieve both improved targeting of antigen material to DCs and improved maturation of DCs
Our work to improve SLP vaccination has led to the discovery that a B cell epitope (a hapten/Ag), when coupled to SLPs, can facilitate Ag-SLP uptake. The idea is that circulating antibodies will bind the hapten and immune complexes will form that can subsequently interact with Fc receptors, which will lead to Ag-SLP uptake, processing and presentation to T cells.
The subsequent T cell response will be improved as the DCs are loaded with significantly more Ag-SLP due to immune complex mediated uptake. Additionally, DCs are activated by the FcR interaction, enabling up-regulation of CD80/CD86 as well as cytokines, which is crucially important for optimal T cell activation.
We are currently investigating this novel vaccine in a human blood loop system to establish how the immune complexes behave in the presence of intact human blood components. Via funding from Bio-X (Vinnova) we are now preparing a clinical grade batch of a prostate cancer vaccine based on long peptides, with the aim to progress to a clinical trial in 2017.
Myeloid cells in the tumour microenvironment
We are collaborating with both industrial and academic partners in the TIMCC network (EU Marie Curie ITN grant to Associate professor Mangsbo and Associate professor Anna Dimberg). Our previous data in this area demonstrate that we can affect myeloid cells by our well known AdCD40L therapy.
Herein we are further exploring how this recruitment and modulation of myeloid cells occur in response to immunotherapy and how the vasculature can affect this. This is an exciting project that will continue until the end of 2016.