invIOs Advances siRNA-Transfected Cell Therapy APN401 into Phase 1b for Solid Tumors with 24-Hour Turnaround Enabling Outpatient Infusion; Extends Platform to CAR-T Development

APN401 is developed based on invIOs' EPiC platform, utilizing siRNA to transfect autologous peripheral blood mononuclear cells (PBMCs) for the silencing of Cbl-b., which plays a key role in suppressing anti-cancer immune responses. By blocking Cbl-b, it is possible to overcome the immunosuppressive tumor microenvironment (TME) and enhance the killing of tumor cells, as well as induce prolonged anti-tumor immune cell memory.

siRNA Belongs to the RNAi Series in Gene SilencingsiRNA belongs to the RNA interference (RNAi) series in gene silencing. It is a class of short double-stranded RNA molecules that can bind with proteins in the body to form RNA-induced silencing complexes (RISC). These complexes specifically bind to homologous regions of exogenous gene-expressed mRNA and cleave the mRNA at the binding site. The cleaved, broken mRNA will degrade, thereby blocking post-transcriptional gene silencing mechanisms of corresponding gene expression. As a novel gene silencing technology, it has been widely used in the development of targeted drugs due to its high efficiency, high specificity, and low toxicity.

At the 2023 AACR Annual Meeting, invIOs presented updated clinical data on APN401 for the treatment of solid tumors: metastatic appendiceal cancer patients and squamous cell carcinoma of the head and neck who had received multiple lines of therapy achievedDisease stability lasting up to 6 months. Notably,Cbl-b silenced autologous PBMCs can be manufactured and infused back into the patient within approximately 24 hours, and are expected to support outpatient treatment.。

invIOs' EPiC Platform is an immune cell enhancement platform used for the development of personalized cell therapies. The platform is based on a closed manufacturing system, enabling rapid processing of cells. Based on this platform, invIOs has also developed INV441, a TIL therapy that uses siRNA to silence Cbl-b, thereby activating cellular anti-tumor immunity and enhancing tumor-killing capabilities.

Previously, invIOs collaborated with the Medical University of Innsbruck to jointly develop a novel CAR-T cell therapy for lung cancer using the EPiC platform. This research also received funding from FFG. Reportedly, this collaboration also focuses on the modification of Cbl-b to enhance the efficacy of CAR-T therapy in solid tumors.

It can be seen that the invIOs pipeline under research is all centered around Cbl-b. Cbl-b is an E3 ubiquitin ligase that has been identified as a key inhibitor in suppressing T-cell activation in the absence of CD28 co-stimulation. It inhibits the transcriptional activity of T-cells and promotes immune tolerance in both adaptive and innate immunity.Studies have shown that Cbl-b is expressed in all leukocyte subsets and regulates some immune cell signaling pathways, significantly limiting their anti-tumor effects.。

In T cells, Cbl-b mediates CD28 co-stimulation and attenuates TCR-induced activation, thereby influencing the threshold for T cell activation; in NK cells, Cbl-b functions downstream of TAM receptors, reducing cytokine production and weakening target cell killing; in Treg cells, Cbl-b can promote the formation of an inhibitory tumor microenvironment; in dendritic cells, Cbl-b affects changes in their cytokine expression profile, preventing the initiation of CD8+ T cell expansion. Currently, most drugs targeting Cbl-b are small molecule inhibitors, with only a few companies leveraging this strategy to develop innovative macromolecular drugs.

Phio Pharmaceuticals CorpDevelopment of INTASYL™ Technology Platform: A Self-Delivering RNAi Technology Platform. INTASYL™ is a hybrid oligonucleotide compound featuring a single-stranded phosphorothioate region, a short double-stranded region, and includes various nuclease-stabilizing and hydrophobic chemical modifications. These chemical modifications provide stability, effective cellular uptake, and reduced inflammatory response; simultaneously, they enable INTASYL™ compounds to be self-delivering without the need for delivery mechanisms or technologies—cells can automatically absorb INTASYL™ without carriers. INTASYL™ can not only inhibit extracellular targets (TIGIT) but also intracellular targets (Cbl-b) that antibodies cannot address.

In May this year, Phio Pharmaceuticals presented clinical data related to INTASYL™ at the 2023 American Society of Gene & Cell Therapy (ASGCT) Annual Meeting. The data showed:Using INTASYL™ TIGIT and CBL-B can enhance the anti-tumor response of NK cells, leading to the development of more effective cell therapies for cancer treatment.。

In August, Phio Pharmaceuticals announced the completion of the first patient dosing in a clinical trial conducted in collaboration with AgonOx and Providence Cancer Institute. This first-in-human trial aims to evaluate the safety and potential for enhanced therapeutic benefits of AgonOx’s AGX148 “double-positive” (DP) CD8 tumor-infiltrating lymphocytes (TIL), both as a monotherapy and in combination with Phio’s PD-1 silencing PH-762, in patients with melanoma and other advanced solid tumors.

The technical approach and overall product development of invIOs GmbH are relatively "niche." Using siRNA to silence Cbl-b improves safety compared to some products that utilize viral transfection. As for efficacy, the currently published data suggests it is acceptable, but more clinical data is still needed for support.

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