A phase 1b study of zilovertamab in combination with paclitaxel for locally advanced/unresectable or metastatic Her2-negative breast cancer.

BACKGROUND: Zilovertamab is a humanized monoclonal antibody targeting ROR1, an onco-embryonic antigen expressed by malignant cells of a variety of solid tumors, including breast cancer. A prior phase 1 study showed that zilovertamab was well tolerated and effective in inhibiting ROR1-signaling, which leads to activation of ERK1/2, NF-κB, and NRF2 target genes. This phase 1b study evaluated the safety and tolerability of zilovertamab with paclitaxel in patients with advanced breast cancer. PATIENTS AND METHODS: Eligible patients had locally advanced, unresectable, or metastatic HER2- breast cancer with Eastern Cooperative Group performance status of 0-2 and without prior taxane therapy in the advanced setting. Study treatment included 600 mg of zilovertamab administered intravenously (IV) on Days 1 and 15 of Cycle 1 and then Day 1 of each 28-day cycle along with paclitaxel weekly at 80 mg/m2 IV. RESULTS: Study patients had received a median of 4 prior therapies (endocrine therapy + chemotherapy) for locally advanced, unresectable, or metastatic disease. No patient discontinued therapy due to toxicity ascribed to zilovertamab. Adverse events were consistent with the known safety profile of paclitaxel. Of 16 patients, 6 (38%) had a partial response, and 6/16 (38%) patients had stable disease as best tumor response. CONCLUSION: The combination of zilovertamab and paclitaxel was safe and well tolerated in heavily pre-treated advanced breast cancer patients. Further evaluation of ROR1 targeting in breast cancer patients with zilovertamab is warranted. TRIAL REGISTRATION: NCT02776917. Registered on ClinicalTrials.gov on 05/17/2016.

The Inflammatory Effects of Dietary Lipids Regulate Growth of Parasites during Visceral Leishmaniasis.

Visceral leishmaniasis is a potentially fatal disease caused by the protozoon Leishmania donovani or L. infantum (Li). Although previous studies revealed that high lipid intake reduces parasite burdens in Leishmania donovani-infected mice, the specific contributions of dietary lipids to Li-associated pathogenesis are not known. To address this, we evaluated parasite growth, liver pathology, and transcriptomic signatures in Li-infected BALB/c mice fed either a control, high-fat, high-cholesterol, or high-fat-high-cholesterol diet. Using quantitative PCR (qPCR), we observed significantly reduced liver parasite burdens in mice fed the high-fat-high-cholesterol diet compared to mice fed the control diet. In contrast to the liver, parasite expansion occurred earlier in the spleens of mice fed the experimental diets. Histological examination revealed an intense inflammatory cell infiltrate in livers predominantly composed of neutrophils caused by the high-fat-high-cholesterol diet specifically. After 8 weeks of infection (12 weeks of diet), Illumina microarrays revealed significantly increased expression of transcripts belonging to immune- and angiogenesis-related pathways in livers of both uninfected and Li-infected mice fed the high-fat-high-cholesterol diet. These data suggest that increased fat and cholesterol intake prior to Li infection leads to a hepatic inflammatory environment and thus reduces the parasite burden in the liver. Defining inflammatory signatures as well as pathology in the liver may reveal opportunities to modify the therapeutic approach to Li infection. IMPORTANCE Leishmaniasis is a spectrum of diseases caused by Leishmania species protozoa that is most common in warm climates, coinciding with impoverished regions. Visceral leishmaniasis is a potentially fatal disease in which parasites infect reticuloendothelial organs and cause progressive wasting and immunocompromise. The distribution and demographics of visceral leishmaniasis have changed over recent years, coinciding with modernizing societies and the increased availability of Western diets rich in lipid content. We report here that increased dietary fat and cholesterol intake affected disease pathogenesis by increasing inflammation and reducing localized parasite burdens in the liver. These diet-induced changes in disease pathogenesis might explain in part the changing epidemiology of visceral leishmaniasis. A relationship between diet and inflammatory responses may occur in leishmaniasis and other microbial or immune-mediated diseases, possibly revealing opportunities to modify the therapeutic approach to microbial infections.

Epidemiological and Experimental Evidence for Sex-Dependent Differences in the Outcome of Leishmania infantum Infection.

Leishmania infantum causes visceral leishmaniasis (VL) in Brazil. We previously observed that VL is more common in males than females living in endemic neighborhoods, despite similar exposure. Using a larger sample, we document that VL is more common in males than females, but only after puberty. BALB/c and C57BL/6 mouse models confirmed that there is a biological basis for male susceptibility to symptomatic VL, showing higher parasite burdens in males than females. Female C57BL/6 mice generated more antigen-induced cytokines associated with curative responses (interferon-γ, interleukin [IL]-1ß). Males expressed higher levels of IL-10 and tumor necrosis factor, which are linked to exacerbated disease. Different parasite lines entered or survived at a higher rate in macrophages of male- than female-origin. These results suggest that males are inherently more susceptible to L. infantum than females and that mice are a valid model to study this sex-dependent difference.