Three questions to Romana Gugenberger, Chief Medical and Scientific Officer

1.   Despite novel immune-therapies against cancer there are still non-responders and relapses. Why is that?

Romana Gugenberger:  Tumors are heterogeneous. Additionally, tumors are not static but evolve. Once a response with a treatment such as an immune checkpoint therapy has been achieved, clinicians  may face a relapse due to a loss of antigens against which the drug was directed to. One needs to keep this in mind when applying one-target and one-pathway approaches with known immune checkpoint blockade or chimeric antigen receptor T cells (CAR T cells). Moreover, the immune tumor microenvironment (TME) represents a hurdle. A substantial advance came from the understanding of the role of the TME in the modulation of anticancer immune responses. Our team  has been working to develop means to overcome the TME barriers and find approaches for T cells to be delivered to the tumor cells and destroy them. In the meantime, there is evidence that not only T cells are involved, but also other immune cell types such as natural killer cells (NK), B cells, antigen presenting cells (APC). It is fascinating to imagine that with Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b), the invIOs team may be able to reverse nonimmunogenic “cold” into “hot” tumors being infiltrated by T cells one day. We have been intensively working at invIOs to deliver a novel therapeutic approach for solid and hematological cancers.

2.   There are currently many approaches in immune-oncology. Why is invIOs cell therapy platform targeting Cbl-b so special?

Romana Gugenberger:  In context of tumors, Cbl-b acts as a brake on the immune system. I believe that Cbl-b, the novel immune checkpoint inhibitor, is a rough diamond. The discovery of immune checkpoint molecules Programmed cell death-1 (PD-1), its ligand PD-L1 and cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4) led to the 2018 Nobel prize in Physiology or Medicine being awarded to Drs. Allison and Honjo. This resulted in an unprecedented development of novel therapies based on monoclonal antibodies, while Cbl-b is still waiting to move into the main focus. Cbl-b is definitely not an easy target, as it is found within cells. But silencing Cbl-b has been shown to mobilize T and NK cells to destroy tumor cells in many preclinical studies and animal models. It was APEIRON, now invIOs, that first showed in clinical studies that Cbl-b silencing could re-activate immune cells in patients with advanced tumors. The trials used the proprietary small interfering RNA (siRNA) method to silence Cbl-b in patient-derived peripheral blood mononuclear cells (PBMCs) (project APN401). This led to signs of efficacy by detection of cytokine release patterns. And the therapy was safe and well tolerated. We hope that Cbl-b will be further proven to be key in stimulating various anti-tumor active immune cells in patients. Beside PBMC, possible further platform starting materials include tumor-infiltrating lymphocytes (TIL) (project INV441), in which the Cbl-b target possesses additional features such as to override the PD-1/PD-L1 pathways. This would  lead to powerful antitumor immune responses as have been described as characteristic of “hot” tumors.

3.    Is Cbl-b a friend or foe of known immune check point inhibitors such as PD-1/PD-L1?

Romana Gugenberger: Definitely friend! Immune checkpoint therapies are widely indicated in a variety of cancer types. Immune checkpoint blockade has dramatically improved survival
and quality of life for patients. However, not all patients benefit, and only few predictors of response and toxicity currently exist. It makes sense to add other agonistic or inhibitory checkpoints to improve tumor-related outcomes. While Cbl-b potentially has efficacy against various cancer types as a monotherapy, it could be an interesting combination partner in cancer therapy as well. These combinations can be explored in clinical studies in the future. Combining immune checkpoint blockade with silencing Cbl-b could increase and prolong responses with anti-PD-1/-PD-L1 approaches. Utilizing Cbl-b inhibition in context of a novel adoptive cell therapy (project APN401) is currently being tested in a  Phase 1b open-label, multi-center, dose escalation and expansion study  in patients with advanced solid cancers.