Inhaled recombinant human IL-15 in dogs with naturally occurring pulmonary metastases from osteosarcoma or melanoma: a phase 1 study of clinical activity and correlates of response

Abstract

PurposeAlthough recombinant human interleukin-15 (rhIL-15) has generated much excitement as an immunotherapeutic agent for cancer, activity in human clinical trials has been modest to date, in part due to the risks of toxicity with significant dose escalation. Since pulmonary metastases are a major site of distant failure in human and dog cancers, we sought to investigate inhaled rhIL-15 in dogs with naturally occurring lung metastases from osteosarcoma (OSA) or melanoma. We hypothesized a favorable benefit/risk profile given the concentrated delivery to the lungs with decreased systemic exposure.Experimental designWe performed a phase I trial of inhaled rhIL-15 in dogs with gross pulmonary metastases using a traditional 3+3 cohort design. A starting dose of 10 µg twice daily × 14 days was used based on human, non-human primate, and murine studies. Safety, dose-limiting toxicities (DLT), and maximum tolerated dose (MTD) were the primary objectives, while response rates, progression-free and overall survival (OS), and pharmacokinetic and immune correlative analyses were secondary.ResultsFrom October 2018 to December 2020, we enrolled 21 dogs with 18 dogs reaching the 28-day response assessment to be evaluable. At dose level 5 (70 μg), we observed two DLTs, thereby establishing 50 µg twice daily × 14 days as the MTD and recommended phase 2 dose. Among 18 evaluable dogs, we observed one complete response >1 year, one partial response with resolution of multiple target lesions, and five stable disease for an overall clinical benefit rate of 39%. Plasma rhIL-15 quantitation revealed detectable and sustained rhIL-15 concentrations between 1-hour and 6 hour postnebulization. Decreased pretreatment lymphocyte counts were significantly associated with clinical benefit. Cytotoxicity assays of banked peripheral blood mononuclear cells revealed significant increases in peak cytotoxicity against canine melanoma and OSA targets that correlated with OS.ConclusionsIn this first-in-dog clinical trial of inhaled rhIL-15 in dogs with advanced metastatic disease, we observed promising clinical activity when administered as a monotherapy for only 14 days. These data have significant clinical and biological implications for both dogs and humans with refractory lung metastases and support exploration of combinatorial therapies using inhaled rhIL-15.

Nasal administration of recombinantNeospora caninumsecreting IL-15/IL-15Rα inhibits metastatic melanoma development in lung

“… 45 46 Interestingly, a recent study investigated an alternative route of administration, through an inhaled IL-15 therapeutic protocol, leading to improved protection against lung metastasis in dogs with naturally occurring osteosarcoma or melanoma with a clinical benefit rate of 39%. 47 Inhaled cytokine therapy offers the benefit of local delivery and passive addressing of immunotherapy to the lungs, a frequent site of metastatic disease, while limiting systemic exposure and potential toxicity with most administered agent restricted at the tumor site. Inhaled IL-2 has also been used in human cancer trials with response rates of approximately 15% with no major side effects observed.…”

Improved characterization and translation of NK cells for canine immunotherapy

“…At the completion of trial, among 21 dogs total, we observed a 39% clinical benefit rate (31). Cytotoxicity of patient PBMCs against osteosarcoma (OSA) and melanoma (M5) targets significantly increased from pre-to post-therapy and maximal cytotoxicity was significantly correlated with patient survival (31). The finding of increased peripheral blood cytotoxicity across the entire cohort post-treatment suggests that tumor cell death is occurring, but only leading to improved survival in certain patients.…”

“…RNA sequencing of patient PBMCs offers preliminary evidence that the activating/inhibitory balance may be patient specific, since principal component analysis (PCA) variance was driven largely by two dogs that responded to treatment (17). At the completion of trial, among 21 dogs total, we observed a 39% clinical benefit rate (31). Cytotoxicity of patient PBMCs against osteosarcoma (OSA) and melanoma (M5) targets significantly increased from pre-to post-therapy and maximal cytotoxicity was significantly correlated with patient survival (31).…”

“…Immunotherapies can also stimulate endogenous NK cells through cytokines that are responsible for the activation, migration, and expansion of NK cells in vivo . Our group also completed a first-in-dog dose escalation trial in dogs with pulmonary metastatic melanoma and osteosarcoma using inhaled recombinant human IL-15 to stimulate NK cells in the lung at metastasis sites ( 31 ). Seven of the initial enrollees were also analyzed in a preliminary assessment of peripheral NK cells using flow cytometry and RNA sequencing ( 17 , 22 ).…”

A single-cell transcriptomic study reveals immune suppressive cancer cell-immune cell interactions in the triple negative canine breast cancers

“…Multiple mechanisms are assumed to be involved in the immune suppressive tumor microenvironment in dogs, including in ltration of immune suppressive cells 10,11 and expression of immune checkpoints that suppress T cell activity [5][6][7][12][13][14] . Different types of immune modulatory therapies applied to dogs have shown that the tumor immune environment (TiME) among the cancer-immune cycle is the rate-limiting step for immune evasion and effective cancer immunotherapy [5][6][7]12,15,16 . However, little information is available regarding the composition of the tumor microenvironment, its interaction with the tumor in the context of its microenvironment, and tumor antigens in dogs 17 .…”