Exosomes to the rescue in cancer

Codiak demonstrates potential of engineered exosomes to stimulate targeted, antitumor immunity

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Exosomes to the rescue in cancer

CAMBRIDGE, Mass.—Believed to be the first-ever company to have led preclinical trials of engineered exosomes, clinical-stage biopharmaceutical Codiak Biosciences Inc. recently unveiled the results from multiple studies demonstrating the potential of Codiak’s precision exosomes to direct pharmacological payloads to specific cells—and achieve enhanced immune mediated antitumor activity with an expanded safety margin. 

Codiak unveiled its results in November at the 35th Annual Meeting of the Society for Immunotherapy of Cancer (SITC), describing the exosomes' action as extracellular vesicles that act like the body’s FedEx delivery trucks to carry messages between cells to stimulate targeted, integrated anti-tumor immunity in IL-12 and STING—well-validated, yet historically elusive, immuno-oncology pathways.

Codiak’s engEx platform can engineer exosomes with distinct properties, load them with various types of therapeutic molecules, and alter tropism so they reach specific cellular targets such as cancer and infectious diseases. The company believes that exosomes may serve as a valuable therapeutic because of their ability to selectively transport a wide variety of therapeutic payloads to cells, opening the door to a broad potential in treating diseases that have evaded other approaches.

“These data provide further in-vivo evidence that we can effectively harness the inherent biology of exosomes to improve the therapeutic window for selectively delivering potent drug molecules to engage promising targets that have eluded other approaches,” says Douglas E. Williams, Codiak's president and CEO. 

At the time he spoke with DDN, he expected to see results from the healthy volunteer portion of the company’s exoIL-12 study by the end of 2020, and safety, biomarker and preliminary efficacy data from both the exoIL-12 and exoSTING programs by the middle of 2021.

Codiak’s exoIL-12 candidate is an exosome therapeutic engineered to display active IL-12 on the surface of the exosome using the exosomal protein, PTGFRN, as a scaffold protein, designed to facilitate potent local pharmacology at the injection site. By limiting systemic exposure of IL-12 and associated toxicity, Codiak hopes to enhance the therapeutic index with exoIL-12, delivering a more robust tumor response, dose control and an improved safety profile.

Codiak intends to focus development of exoIL-12 on tumors that have, in previous clinical testing, shown clinical responses to IL-12 used as a monotherapy. This includes cutaneous T cell lymphoma (CTCL), melanoma, Merkel cell carcinoma, Kaposi sarcoma, glioblastoma multiforme and triple negative breast cancer.

Among the preclinical findings, Codiac researchers found that tumor-retained pharmacology and superior in-vivo efficacy of exoIL-12 widens the therapeutic window.

The current studies extend observations from previous presentations demonstrating tumor retention and increased tumor growth inhibition across multiple mouse models. Additionally, these data demonstrate significant remodeling of the tumor microenvironment and confirm tissue-retained pharmacology in non-human primate models, thereby widening the therapeutic window for this potent cytokine. 

Among the data presented at SITC 2020, Codiak reported that exoIL-12 was ~100 fold more potent in tumor growth inhibition than recombinant IL-12 (rIL-12), with complete responses observed in 63 percent of mice treated with exoIL-12 compared to 0 percent in mice treated with an equivalent dose of rIL-12. In addition, exoIL-12 showed dramatic change in the tumor microenvironment, triggering a ~8-fold increase in cytotoxic T-cell infiltration and ~150-fold increase in M1 macrophage recruitment. In non-human primates, exoIL-12 showed tissue-localized pharmacology, local induction of IFNg and a lack of systemic exposure.

In multiple in-vitro and in-vivo studies, the engEx Platform was found to affect cellular tropism and boost payload delivery, with Codiak noting in a press release that exosomes engineered to display several types of targeting domains on the surface demonstrated greater association with the target cell types—including dendritic cells, T cells and B cells—in vitro and in vivo. Preliminary in-vivo data showed that intra-tumorally administered anti-Clec9A exosomes reduced the required STING agonist dose by 10-fold and led to greater immune responses against tumor-associated antigens compared to untargeted controls.

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