Increased numbers of tumor-infiltrating macrophages correlate with poor disease outcome in patients affected by several types of cancer, including breast and prostate carcinomas. The colony stimulating factor 1 receptor (CSF1R) signaling pathway drives the recruitment of tumor-associated macrophages (TAMs) to the neoplastic microenvironment and promotes the differentiation of TAMs toward a pro-tumorigenic phenotype. Twelve clinical trials are currently evaluating agents that target the CSF1/CSF1R signaling pathway as a treatment against multiple malignancies, including breast carcinoma, leukemia, and glioblastoma. The blockade of CSF1R signaling has been shown to greatly decrease the number of macrophages in a tissue-specific manner. However, additional mechanistic insights are needed in order to understand how macrophages are depleted and the global effects of CSF1R inhibition on other tumor-infiltrating immune cells. Using BLZ945, a highly selective small molecule inhibitor of CSF1R, we show that CSF1R inhibition attenuates the turnover rate of TAMs while increasing the number of CD8+ T cells that infiltrate cervical and breast carcinomas. Specifically, we find that BLZ945 decreased the growth of malignant cells in the mouse mammary tumor virus-driven polyomavirus middle T antigen (MMTV-PyMT) model of mammary carcinogenesis. Furthermore, we show that BLZ945 prevents tumor progression in the keratin 14-expressing human papillomavirus type 16 (K14-HPV-16) transgenic model of cervical carcinogenesis. Our results demonstrate that TAMs undergo a constant turnover in a CSF1R-dependent manner, and suggest that continuous inhibition of the CSF1R pathway may be essential to maintain efficacious macrophage depletion as an anticancer therapy.
The ganglioside fucosyl-GM1 (FucGM1) is a tumor-associated antigen expressed in a large percentage of human small cell lung cancer (SCLC) tumors, but absent in most normal adult tissues, making it a promising target in immuno-oncology. This study was undertaken to evaluate the preclinical efficacy of BMS-986012, a novel, nonfucosylated, fully human IgG1 antibody that binds specifically to FucGM1. The antitumor activity of BMS-986012 was evaluated in assays using SCLC cells and in mouse xenograft and syngeneic tumor models, with and without chemotherapeutic agents and checkpoint inhibitors. BMS-986012 showed a high binding affinity for FcγRIIIa (CD16), which resulted in enhanced antibody-dependent cellular cytotoxicity (ADCC) against FucGM1-expressing tumor cell lines. BMS-986012-mediated tumor cell killing was also observed in complement-dependent cytotoxicity (CDC) and antibody-dependent cellular phagocytosis (ADCP) assays. In several mouse SCLC models, BMS-986012 demonstrated efficacy and was well tolerated. In the DMS79 xenograft model, tumor regression was achieved with BMS-986012 doses of 0.3 mg/kg and greater; antitumor activity was enhanced when BMS-986012 was combined with standard-of-care cisplatin or etoposide. In a syngeneic model, tumors derived from a genetically engineered model of SCLC were treated with BMS-986012 or anti-FucGM1 with a mouse IgG2a Fc and their responses evaluated; when BMS-986012 was combined with anti-PD-1 or anti-CD137 antibody, therapeutic responses significantly improved. Single-agent BMS-986012 demonstrated robust antitumor activity, with the addition of chemotherapeutic or immunomodulatory agents further inhibiting SCLC growth in the same models. These preclinical data supported evaluation of BMS-986012 in a phase I clinical trial of patients with relapsed, refractory SCLC. .
10032 Background: Pediatric acute myeloid leukemia (AML) is a rare disease with roughly 500 cases diagnosed in the United States each year and has had minimal improvement in clinical outcomes over recent decades. Novel treatment development to improve outcomes may be enhanced with an accompanying test for predicting treatment response. We previously demonstrated that an ex vivo drug sensitivity assay (DSA) can predict clinical response in myelodysplastic syndrome. Here we investigated the use of the DSA in pediatric AML patients, including a subset participating in a clinical trial of atovaquone. Atovaquone is an FDA-approved anti-parasitic drug that was associated with lower relapse rates in adult AML patients. Adding atovaquone and other standard of care combination treatments into the DSA, we investigated whether the assay, performed on pre-induction samples, correlated with measures of clinical response. Methods: We assayed pre-induction blood or bone marrow samples from 22 de novo pediatric AML patients diagnosed at Texas Children’s between 5/2015 and 10/2020 who consented to research (82% enrolled in clinical trial identifier NCT03568994). We subsetted this analysis to patients who received ADE (Cytarabine, Daunorubicin, Etoposide) (n = 20) induction, with the majority additionally receiving atovaquone (n = 16). For the DSA, samples were incubated with up to 25 compounds, including the treatment drug combinations and each of the compounds individually. After incubation, changes in tumor blast populations were assessed by flow cytometry. For each drug condition, drug sensitivity was calculated based on the number of blasts remaining after treatment. After quality control, downstream analyses were limited to 13 samples. Clinical response data, including minimal residual disease (MRD) percentage by flow cytometry and one year relapse-free survival, were correlated with the drug sensitivity results. Results: For the de novo subset analysis, we observed correlations between ex vivo drug sensitivity with both MRD percentage (r = 0.63) and one year relapse-free survival (RFS1, AUC = 0.92). The 3 patients with lowest ex vivo sensitivity had the highest MRD percentages (mean 21%). 2 of the 3 patients who did not achieve one year relapse-free survival had the lowest ex vivo sensitivity. Drug combination sensitivity correlated more with MRD and RFS1 than the single agents alone (single agent mean MRD r = 0.39). Conclusions: In our cohort, ex vivo DSA for ADE and atovaquone in pediatric AML cases correlated with both MRD and one year relapse-free survival. This suggests that clinical response in pediatric AML may be assessed prior to treatment using a DSA. This study also suggests that the DSA can be used to test drug combinations, and thus may be used for investigating novel treatment combinations. Further development of the DSA may benefit treatment decisions and prioritization of drug development.
<p>4 suppl tables on FucGM1 expression in lung cancer, binding, and mouse PK</p>
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