Nasal Administration of Novel Recombinant Protozoan Strain Prevents Metastatic Melanoma in the Lung

When administered via mucosal administration, human interleukin-15 (IL-15) and IL receptor alpha (IL-15Rα)-secreting protozoan Neospora caninum (N. caninum) fused to the sushi domain of IL-15 receptor (NC1-IL-15hRec) could be a non-invasive, effective, and safe immunotherapeutic approach for metastatic melanoma, according to the results of a recent study published in BMJ.

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IL-15 is more stable when bound to the high affinity receptor IL-15Rα. Once genetically engineered to the N. caninum protozoan, this novel strain improves T cell survival and activation, enhancing the effector responses of natural killer (NK) cells that target tumors and cluster of differentiation 8 (CD8+) cells.

“Our combinatory approach…administered intranasally could meet all criteria for a highly effective, multi-mechanism strategy for elimination of lung metastases with a much-needed low toxicity thanks to local delivery,” the study authors wrote in the recent article.

Melanoma is the deadliest form of skin cancer, accounting for 65% of skin cancer mortality, primarily because of metastases, later diagnoses, and therapy resistance. Metastases are the primary cause of mortality for many cancer types, and in melanoma, 85% of late-stage patients develop metastases in the lungs.

N. caninum is an obligate intracellular protozoan non-pathogenic for humans that has exhibited high anticancer and antitumor properties. Investigators previously showed that engineering a strain that can safely and effectively secrete IL-15 can block the growth of tumors and metastases. Investigators conducted a new study to assess the efficacy of N. caninum administered intranasally in a syngeneic mouse model (C57BL6) of animals infected with B16F10 melanoma lung metastases.

The team observed that treatment involves multiple immune cell activation pathways to stimulate antitumor B cell activity and kill tumors via interleukin-12 (IL-12). The novel protozoan intranasal treatment was also associated with a strong increase of immune cells within the lung, particularly NK cells, CD8+T cells, and macrophages. Further, the model showed that N. caninum lowered the expression of genes that code for proteins, which facilitate tumor growth in the lungs.

“Several studies have shown that inhibiting those proteins and their interactions could lead to the development of new anticancer therapeutics,” the study authors wrote in the article.

Traditionally, IL-15 monotherapy is effective for advanced cancers but associated with high toxicity. Inhaling IL-15 has been shown to prevent lung metastases in dogs with melanoma. Other human trials suggest IL inhalation also creates response rates with no major adverse events (AEs).

The current study expands on these studies to show that inhaling IL-15 with a protozoan reduces systemic toxicity associated with IL-15. However, effective treatment of refractory tumors may require strategies that combine N. caninum treatment with other genetically engineered oncolytic agents.

“Combination of this armed protozoa (IL-15/IL-15Rα-secreting N. caninum) with an intranasal route could reinforce the existing therapeutic arsenal against cancer and narrow the spectrum of incurable cancers,” the study authors wrote in the article.

Reference

Battistoni A, Lantier L, Tommaso A, et al. Nasal administration of recombinant Neospora caninum secreting IL-15/IL-15Rα inhibits metastatic melanoma development in lung. Journal for ImmunoTherapy of Cancer. 2023; doi: 10.1136/jitc-2023-006683