delolimogene mupadenorepvec (LOAd703)

Combining LOAd703 with nab-paclitaxel plus gemcitabine in patients with advanced pancreatic ductal adenocarcinoma was feasible and safe. To build upon this novel chemoimmunotherapeutic approach, arm 2 of LOKON001, which combines LOAd703, nab-paclitaxel plus gemcitabine, and atezolizumab, is ongoing.

P1/2, N=46, Active, not recruiting, Lokon Pharma AB | Trial completion date: Dec 2024 --> Aug 2024 | Trial primary completion date: Dec 2023 --> Aug 2023

In the LOKON002 phase I/II clinical trial (NCT03225989), therapy with LOAd703 (delolimogene mupadenorepvec) is investigated in combination with gemcitabine-based chemotherapy in patients with advanced cancer. In conclusion, LOAd703 therapy in combination with chemotherapy generated an inflamed tumor microenvironment in tumors that are normally seen as immunologically “cold”. Hence, LOAd703 may be able to prime tumors for immune checkpoint inhibitors or other immunotherapies, such as adoptive T or NK cell transfer.

Partial response (PR) was achieved in two patients with pancreatic cancer treated at the highest LOAd703 dose level in combination with gemcitabine and nab-paclitaxel. No association between adverse events and response was identified. Anti-adenoviral antibody levels (IgG), which increased in all patients, could not be related to indices of clinical benefit.Based on the safety of LOAd703 at all dose levels studied, as well as evidence of objective clinical activity in patients with advanced pancreatic cancer, further disease-directed studies of intratumoral administration of LOAd703 are warranted.

We are also performing multiplex analysis of proteomic changes in infected tumor cells using the OLINK® TARGET 96 assay. Finally, we willconfirm the effect of LOAd703 in vivo in a murine xenograft model for STS.

Ovarian cancer is commonly treated with debulking surgery, followed by a combination of a taxane and a platinum-based chemotherapy. This effect was confirmed in vivo, in which the combination therapy had a better tumor control than the other treatment groups. A clinical trial is ongoing to confirm the effect of adding LOAd703 to different treatment regimes in ovarian cancer (NCT03225989).

Funded by: Pharmaceutical/Biotech Company. Combining intratumoral injections of LOAd703 with standard nPG chemotherapy was safe and feasible. The target response rate at the highest dose level was met, and treatment-emergent immune responses were observed. A follow-up clinical trial combining LOAd703, nPG, and the anti-PDL-1 inhibitor atezolizumab is underway.

Here we have evaluated the anti-tumor effects of trimerized membrane-bound (TMZ)-CD40L-armed LOAd700 and TMZ-CD40L/4-1BBL-armed LOAd703 in a variety of solid tumors to understand the underlying tumor modulating mechanisms. Upregulation of cell surface calreticulin as well as the death receptors TRAIL-R1 and -R2 indicated generation of a more immunogenic phenotype of cancer cells. Thus, our findings suggest that CD40L-armed LOAd viruses could be inducers of apoptosis and immunogenic cell death in a variety of cancer types with an augmented effect in cancer cells expressing the CD40 receptor.

LOAd703, encoding trimerized (TMZ)-CD40L and 4-1BBL, is under clinical investigation in solid tumors...The addition of the immunosuppressing cytokines did not affect LOAd732 capacity to expand the antigen-specific T cells.In conclusion, LOAd732 infected DCs express activation markers and co-stimulatory molecules and produce cytokines necessary for the initiation of an immune response. Moreover the DCs are functional and can expand antigen-specific T cells and protect them from TGF-β and IL-10 suppression.

Herein, we investigated whether the adenoviral gene vehicle mLOAd703 carrying both DC- and T cell-activating genes can lead to inflammation in a B16-CD46 model and thereby overcome resistance to checkpoint inhibition therapy...This response was even more pronounced after combining the virus with checkpoint therapy, in particular with anti-PD-L1 and anti-TIM-3, leading to further reduced tumor growth in injected lesions. Moreover, anti-PD-L1 combination also facilitated abscopal responses in non-injected lesions.

The exosomes from CD40L/4-1BBL-expressing tumor cells, or the viruses themselves, could stimulate robust dendritic cell (DC) activation with an enhanced level of major histocompatibility complex (MHC) and costimulatory molecules. Hence, exosomes after OV infection can locally activate immune responses at the tumor site and encounter immune cells such as DCs.

To investigate the role of exosomes derived from OV-treated tumors, human melanoma Mel526 cells were infected by delolimogene mupadenorepvec -LOAd703 - which is an adenoviral serotype 5/35 OV armed with costimulatory molecules CD40L and 4-1BBL...In conclusion, tumor-derived exosomes released by OV-infected tumor cells can cargo the immunostimulatory transgenes expressed by the OVs and are then converted from immunosuppressive to immune activating exosomes as shown by their capacity to activate immune cells such as dendritic cells. Exosomes that cargo immunostimulatory transgenes from OV-infected tumor cells may support the systemic immunity gained by OVs after local intratumoral delivery.

In addition, LOAd703-infected lymphoma cells upregulated the secretion of several chemokines (CXCL10, CCL17, CCL22, CCL3, CCL4) essential for immune cell homing, leading to enhanced CAR T-cell migration. In conclusion, immunostimulatory LOAd703 therapy is an intriguing approach to induce anti-lymphoma immune responses and to improve CAR T-cell therapy in B-cell lymphoma.

The abscopal effect was further increased by combining mLOAd703 with anti-PD-1 or anti-PD-L1. LOAd703 (i.t.) is currently in clinical development with and without PD-L1.

Further, LOAd viruses are armed with human immunostimulatory transgenes: trimerized membrane-bound CD40L (LOAd700, LOAd703) and 4-1BBL (LOAd703). This was most prominent with LOAd703. In conclusion, LOAd viruses are of interest for MM therapy.

P1/2; N=120; Not yet recruiting; Sponsor: Hoffmann-La Roche