Akamis Bio Takes On Advanced Solid Tumors

By Erin Harris, Editor-In-Chief, Cell & Gene
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Based in the U.K. and Cambridge, MA, Akamis Bio is a clinical-stage oncology company that has developed a portfolio of solid tumor-targeted T-SIGn (Tumor-Specific Immuno-Gene) therapeutics, which aim to enable a patient’s own immune system to combat cancer. T-SIGn uses intravenously administered, novel viral vectors that can carry payloads of multiple immunotherapeutic proteins to both primary and metastatic solid tumors. I caught up with Akamis Bio’s CEO, Dr. Howard Davis, to better understand T-SIGn, the NG-350A trial, and how T-SIGn may impact CAR-T for solid tumors.

Tell us about Akamis Bio.

Akamis Bio is a clinical-stage oncology company. Our focus is on treating advanced solid tumors with novel, systemically administered viruses that can deliver immuno-modulatory therapeutics directly into tumors to transform the microenvironment and drive robust anti-tumor immune responses. We believe our approach can broaden the potential of immunotherapy by addressing the safety and efficacy challenges of treating solid tumors with I.V. administered, tumor-specific therapeutics that can both generate a potent immune response and avoid systemic toxicity.

We do this with our Tumor-Specific Immuno-Gene (T-SIGn) therapeutics platform, which was built to selectively deliver multiple transgene combinations (cytokines, chemokines, antibodies) for expression by tumor cells. T-SIGn therapeutics are adenoviral vector-based, unique in their ability to be delivered intravenously and reach tumors in compartments that are not accessible by intra-tumoral injection, including both primary and metastatic tumor sites.

Before we discuss Akamis Bio’s T-SIGn (Tumor-Specific Immuno-Gene) therapeutic platform, talk us through some of the biggest challenges facing CAR-T for solid tumors.

Cell therapy and CAR-T are successful in the hematologic cancer space, but there are a number of hurdles in the solid tumor space. These include poor immune cell infiltration of and survival within tumors, the immunosuppressive properties of the tumor microenvironment, and systemic toxicity issues linked to off-target CAR-T cell reactivity.

One key challenge is in understanding whether tumor antigens are enriched enough on the surface of tumor cells or whether expression occurs elsewhere in the body that may lead to on-target / off-tumor effects and/or cytokine release syndrome (CRS). T-SIGn platform therapeutics offer the opportunity to enrich the presence of an antigen on the tumor cell surface. This may allow for a lower dose of cell therapy – or we could potentially have a cell therapy target an agent that doesn’t occur naturally in the body, such as a synthetic protein, that is expressed on the surface of the tumor and could increase the specificity of the cell therapy response.

Not long ago we published data in collaboration with bluebird bio that looked at the combination of our viral vector with their CAR-T and we saw an interesting synergy between the two. With the T-SIGn vector alone, we saw mild control of the growth of the tumor, but when combined with the CAR-T there was robust tumor suppression during the 90 days of the in vivo experiment, controlling tumor growth and shrinking it below the level of detection in the mouse model.

T-SIGn vectors can also carry chemokines​ to improve CAR-T cell trafficking to the tumor, as well as activating cytokines and co-stimulatory ligands​ to enhance CAR-T cell activation and survival. We believe it has the potential to be used in combination with antibody-drug conjugates (ADCs), bispecifics, and radionucleotides to improve the efficacy and/or safety profile of these agents.

Explain T-SIGn (Tumor-Specific Immuno-Gene) platform. What is its purpose and how is it combating disease?

The T-SIGn platform is based on an adenovirus-based vector which was evolved to further enhance the selectivity of the virus for replication in tumor cells. The vector also includes a transgene cassette designed to express a specific gene or combination of genes within a tumor following IV delivery. The virus only replicates within epithelial-derived tumor tissue; there is no replication or transgene expression in healthy epithelial tissue. The T-SIGn platform is armed with a transgene payload and these transgenes are only expressed in solid tumor tissue where the virus can replicate.

Once inside the tumor, these treatments modulate the tumor microenvironment, enabling the local production of potent immuno-therapeutics that drive robust anti-tumor immune responses that can recognize, attack and clear solid tumors. Clinical data has shown evidence of long-lasting immune activation profiles consistent with immuno-therapeutic payload expression and activity.

The systemic delivery of T-SIGn therapeutics also offers other important advantages over direct intra-tumoral injection, with the potential to reach lesions throughout the body, including both primary and metastatic tumor sites, while reducing the complexity of treatment. T-SIGn therapeutics have shown a promising safety profile in multiple clinical studies, with more than 240 patients dosed across clinical studies to date.

Explain the progression of the NG-350A trial.

NG-350A, our lead program, is a Phase 1 immuno-stimulatory tumor gene therapy driving intra-tumoral expression of a CD40 agonist. Our data thus far has shown a consistent safety profile and promising pharmacokinetics/pharmacodynamics, paving the way for a Ph1b expansion cohort. The viral vector carries a transgene cassette encoding a full-length monoclonal antibody (Ab) to CD40. The antibody activates the dendritic pathway, triggering antigen presentation in the draining lymph nodes of the tumor that then recruits the immune system to the tumor site where it recognizes the antigens being presented and attacks the tumor locally.

One of the key limitations around systemically delivered Ab to CD40 has been liver toxicity; as you increase the dose of the Ab systemically, dose limiting toxicities have been observed. With T-SIGn, we express the CD40 agonist Ab locally in the tumor and therefore, we are able to achieve intratumoral levels that are much higher than what could be achieved following systemic administration of the Ab.

NG-350A is being investigated as both a monotherapy and in combination with checkpoint inhibitors. We completed a Phase 1a study in patients with metastatic or advanced epithelial tumors, which showed consistent safety and tolerability with none of the dose limiting adverse events (AEs) typically seen with systemic CD40 agonists.

We have a second ongoing study evaluating the safety, tolerability, and preliminary efficacy of NG-350A in combination with pembrolizumab in patients with advanced or metastatic epithelial tumors. We have completed enrollment for a final single-cycle dose cohort and our safety data supports multi-cycle combo dosing. The outcome of that study will enable us to proceed into an expansion cohort, which we plan to initiate in the first half of next year. Our partners at the PICI and the Cancer Research Institute are also running a Phase 1b study of NG-350A in combination with two different agents in patients with previously untreated metastatic pancreatic adenocarcinoma. This study is conducted by the PICI and the Cancer Research Institute. We anticipate data from that study next year.

How might T-SIGn impact CAR-T?

Akamis Bio is not a cell therapy company, but we are focused on developing our versatile T-SIGn platform to treat a variety of solid tumors both as stand-alone monotherapy, as well as in combination with other immuno-oncology modalities like CAR-T.

CAR-T cell therapies, of course, have been immensely successful in the treatment of hematologic cancers and the industry has met the demand for these therapies in the past several years. However, challenges have become apparent for CAR-T, particularly when it comes to treating solid tumors. I believe the future of CAR-T relies on developing ways to address known challenges in solid tumors by either: 1) "heating up" a cold tumor by expressing cytokines or chemokines that help a CAR-T traffic directly to the solid tumor site, or 2) enriching the antigen presence on the surface of the targeted tumor cell. These are two areas where we believe Akamis Bio’s T-SIGn therapeutics can have a significant impact on the potential of CAR-T in the solid tumor space.