Altamira Therapeutics Announces Significant Enhancement of Immune Checkpoint Inhibition Therapy in Combination With Zbtb46 mRNA Delivered With SemaPhore Nanoparticles in Animal Tumor Models

Altamira Therapeutics Ltd. recently announced the publication of a peer-reviewed article in Nature Immunology highlighting the important role of the Zbtb46 gene in the control of tumor growth and demonstrating a significant reduction in tumor growth in vivo through treatment with Zbtb46 mRNA delivered with Altamira’s SemaPhore nanoparticle technology. The treatment effect was potentiated when combined with anti-PD1 immune checkpoint inhibition, inducing long-term remission and promoting immunological memory. The research was conducted by a group around Professor Kyunghee Choi of the Pathology & Immunology Department of Washington University School of Medicine (St. Louis, MO).

“Immune checkpoint inhibitors such as Keytruda or Opdivo have shown remarkable efficacy in treating a broad range of solid tumors, but unfortunately a large number of patients are unable to benefit from them due to an immunosuppressive tumor microenvironment,” said Samuel Wickline, MD, Altamira’s Chief Scientific Adviser and a co-author of the publication. “The study from the Choi Lab shows impressive results from boosting Zbtb46 expression with tumor vessel normalization and enhanced antitumor immunity. Administration of Zbtb46 mRNA nanoparticles appears to provide the right conditions for anti-PD1 treatments to work in a substantially larger cancer population, helping to control tumor growth, induce long-term remission and promote immunological memory. The exciting results with Zbtb46 mRNA nanoparticles are just another great example highlighting the potential of the SemaPhore platform for delivering mRNA therapeutics to non-hepatic tissues.”

The research group studied the role of the Zbtb46 (Zinc finger and BTB domain-containing protein 46) gene in the progression of solid tumors and in tumor angiogenesis and anti-tumor immunity. Cancers require the formation of new blood vessels (tumor angiogenesis) to grow and metastasize, supplying their cells with a supportive microenvironment rich with oxygen and nutrients. In addition, the newly formed vasculature within the tumor microenvironment may block the infiltration of T cells, thus suppressing an appropriate immune response and preventing the killing of cancer cells. The researchers found that downregulation of Zbtb46 resulted in a pro-tumor microenvironment, including dysfunctional vasculature and immunosuppressive cell accumulation. In contrast, enforced Zbtb46 expression mitigated the pro-tumor microenvironment features and restricted tumor growth. These findings suggest that ZBTB46 is a critical factor for angiogenesis and immunosuppressive conditions in the tumor microenvironment and could be a promising target for cancer treatment.

In a next step, the group tested the systemic delivery of Zbtb46 mRNA with SemaPhore nanoparticles in mouse models of sarcoma and metastatic breast cancer to boost Zbtb46 expression. The treatment resulted in sustained Zbtb46 expression, a restored immunostimulatory tumor microenvironment and a highly significant reduction in tumor growth (p<0.0001). Further, the Zbtb46 mRNA nanoparticle treatment was combined with an immune checkpoint inhibitor (anti-PD1) treatment, which resulted in even better outcomes. The authors reported: “Remarkably, Zbtb46 nanoparticles induced dramatic anti-PD1 response in both anti-PD1-responsive [sarcoma] and anti-PD1-refractory [breast cancer] tumor models, generating long-term complete remission of tumor in many of the treated animals.” Extended monotherapy with Zbtb46 nanoparticles produced complete remission even in mice refractory to anti-PD1 treatment. Addition of a VEGF inhibitor to the combination therapy further enhanced the treatment response. Mice whose sarcoma was eliminated through treatment did not develop fresh cancers following repeated challenge, indicating the development of a protective immunological memory.

SemaPhore is a versatile platform designed to enable safe and effective delivery of mRNA into target cells, using systemic or local administration. It is based on a proprietary 21 amino acid peptide that can engage any type of RNA in rapid self-assembly into a polyplex. The polyplex has a size, charge, and other physical features that allow it to escape hepatic clearance and thus to reach target tissues other than the liver. SemaPhore protects the RNA payload from degradation in the circulation and allows for rapid and effective cell entrance. Efficient delivery and positive treatment outcomes have been demonstrated in multiple murine models of disease so far.

Altamira Therapeutics (Nasdaq: CYTO) is developing and supplying peptide-based nanoparticle technologies for efficient RNA delivery to extrahepatic tissues (OligoPhore/SemaPhore platforms). The company currently has two flagship siRNA programs using its proprietary delivery technology: AM-401 for KRAS driven cancer and AM-411 for rheumatoid arthritis, both in preclinical development beyond in vivo proof of concept. The versatile delivery platform is also suited for mRNA and other RNA modalities and made available to pharma or biotech companies through out-licensing. In addition, Altamira holds a 49% stake (with additional economic rights) in Altamira Medica AG, which holds its commercial-stage legacy asset Bentrio, an OTC nasal spray for allergic rhinitis. Further, the Company is in the process of partnering / divesting its inner ear legacy assets. Founded in 2003, Altamira is headquartered in Hamilton, Bermuda, with its main operations in Basel, Switzerland. For more information, visit https://altamiratherapeutics.com/