Inhibition of Galectin-9 sensitizes tumors to anthracycline treatment via inducing antitumor immunity.

Anthracyclines are a class of conventionally and routinely used first-line chemotherapy drugs for cancer treatment. In addition to the direct cytotoxic effects, increasing evidence indicates that the efficacy of the drugs also depends on immunomodulatory effects with unknown mechanisms. Galectin-9 (Gal-9), a member of the ß-galactoside-binding protein family, has been demonstrated to induce T-cell death and promote immunosuppression in the tumor microenvironment. Here, we asked whether anthracycline-mediated immunomodulatory activity might be related to Gal-9. We found that combining doxorubicin with anti-Gal-9 therapy significantly inhibited tumor growth and prolonged overall survival in immune-competent syngeneic mouse models. Moreover, Gal-9 expression was increased in response to doxorubicin in various human and murine cancer cell lines. Mechanistically, doxorubicin induced tumoral Gal-9 by activating the STING/interferon ß pathway. Clinically, Gal-9 and p-STING levels were elevated in the tumor tissues of breast cancer patients treated with anthracyclines. Our study demonstrates Gal-9 upregulation in response to anthracyclines as a novel mechanism mediating immune escape and suggests targeting Gal-9 in combination with anthracyclines as a promising therapeutic strategy for cancer treatment.

Venetoclax in combination with nucleoside analogs in acute myelogenous leukemia.

PURPOSE OF REVIEW: Venetoclax in combination with nucleoside analogs such as hypomethylating agents (HMA) and low-dose cytarabine (LDAC) has led to unprecedented response and survival outcomes in patients with acute myeloid leukemia (AML). This has spurred the development of regimens combining venetoclax with other nucleoside analogs with distinct mechanisms of action. Here, we review older and newer nucleoside analogs, the rationale for their combination with venetoclax, and clinical evidence for the combination when available. RECENT FINDINGS: Venetoclax with HMA prolonged survival in a phase 3 study. Additionally, biologic correlates of response and resistance to venetoclax with HMA have been identified. The addition of venetoclax to standard intensive regimens containing higher doses of cytarabine and purine nucleoside analogs are safe and induce very high rates of remission and measurable residual disease negativity (MRD) negativity in newly diagnosed and relapsed/refractory AML. Investigational nucleoside analogs aim to improve upon the safety, bioavailability, or efficacy of approved venetoclax combinations and are currently being evaluated in clinical studies. SUMMARY: The development of venetoclax with HMA has transformed care for elderly adults with AML and opened the door for novel combinations of venetoclax with other nucleoside analogs. Further clinical studies are needed to see if these novel combinations further improve outcomes in AML particularly for patients with high-risk disease.

A Clinical Review of the Different Strategies to Minimize Hemorrhagic Cystitis Associated with the Use of Post-Transplantation Cyclophosphamide in an Allogeneic Transplant.

Post-transplantation cyclophosphamide (PTCy) has improved hematopoietic stem cell transplantation outcomes for patients with major HLA disparities. Although PTCy in combination with calcineurin inhibitors is a successful graft-versus-host disease regimen, giving high doses of cyclophosphamide may cause hemorrhagic cystitis (HC). The strategies used to prevent HC are adapted from published data in the pre-transplantation conditioning setting. However, there is no consensus on what the optimal strategy is to prevent PTCy-associated HC. This review provides a summary of the different preventative strategies used in this setting. Based on the results published in current literature, hyperhydration is an effective preventative strategy, but it may cause fluid overload and other complications. Additionally, mesna at least 100% of the PTCy dose should be administered as a continuous infusion or frequent intermittent bolus infusion. More comparative studies between these strategies are needed to provide a definitive solution for preventing HC associated with PTCy.

High-Risk Mantle Cell Lymphoma in the Era of Novel Agents.

PURPOSE OF REVIEW: Mantle cell lymphoma (MCL) is a heterogenous disease with a variety of morphologic and genetic features, some of which are associated with high risk disease. Here we critically analyze the current state of the understanding of MCL's biology and its implications in therapy, with a focus on chemotherapy-free and targeted therapy regimens. RECENT FINDINGS: Mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin's lymphoma, defined by a hallmark chromosomal translocation t(11;14) which leads to constitutive expression of cyclin D1. Recent discoveries in the biology of MCL have identified a number of factors, including TP53 mutations and complex karyotype, that lead to unresponsiveness to traditional chemoimmunotherapy and poor outcomes. Bruton tyrosine kinase inhibitors, BH3-mimetics and other novel agents thwart survival of the neoplastic B-cells in a manner independent of high-risk mutations and have shown promising activity in relapsed/refractory MCL. These therapies are being investigated in the frontline setting, while optimal responses to chemotherapy-free regimens, particularly in high-risk disease, might require combination approaches. High-risk MCL does not respond well to chemoimmunotherapy. Targeted agents are highly active in the relapsed refractory setting and show promise in high-risk disease. Novel approaches may soon replace the current standard of care in both relapsed and frontline settings.

Inhibition of c-MET upregulates PD-L1 expression in lung adenocarcinoma.

Non-small cell lung cancer (NSCLC) patients with c-MET dysregulation may benefit from c-MET inhibitors therapy as inhibition of c-MET activity has emerged as a therapeutic approach against this disease. Although several c-MET inhibitors have been evaluated in multiple clinical trials in lung cancer, their benefits so far have been modest. Thus, furthering our understanding of the mechanisms contributing to the lack of success of c-MET inhibitors in clinical trials is essential toward the development of rational and effective combination strategies. Here we show that exposure of NCSLC cell lines to c-MET inhibitor tivantinib increases their expression of PD-L1, which in turn causes cells to become more resistant to T-cell killing. Mechanistically, inhibition of c-MET suppresses p-GSK3ß, leading to the stabilization of PD-L1 similar to that observed in liver cancer cells. Collectively, our findings suggest a potential crosstalk between c-MET inhibition and immune escape and provide a rationale for the combination therapy of c-MET inhibitors and immune checkpoint blockade in NSCLC.

MET Inhibitors Promote Liver Tumor Evasion of the Immune Response by Stabilizing PDL1.

BACKGROUND & AIMS: Inhibitors of MET have not produced satisfactory outcomes in trials of patients with liver cancer. We investigated the mechanisms of liver tumor resistance to MET inhibitors in mice. METHODS: We tested the effects of MET inhibitors tivantinib and capmatinib in the mouse hepatocellular carcinoma (HCC) cell line HCA-1 and in immune-competent and immunodeficient mice with subcutaneous tumors grown from this cell line. Tumors were collected from mice and tumor cells were analyzed by time-of-flight mass cytometry. We used short hairpin RNAs to weaken expression of MET in Hep3B, SK-HEP-1, HA59T, and HA22T liver cancer cell lines and analyzed cells by immunoblot, immunofluorescence, and immunoprecipitation assays. Mass spectrometry was used to assess interactions between MET and glycogen synthase kinase 3ß (GSK3B), and GSK3B phosphorylation, in liver cancer cell lines. C57/BL6 mice with orthotopic tumors grown from Hep1-6 cells were given combinations of capmatinib or tivantinib and antibodies against programmed cell death 1 (PDCD1; also called PD1); tumors were collected and analyzed by immunofluorescence. We analyzed 268 HCCsamples in a tissue microarray by immunohistochemistry. RESULTS: Exposure of liver cancer cell lines to MET inhibitors increased their expression of PD ligand 1 (PDL1) and inactivated cocultured T cells. MET phosphorylated and activated GSK3B at tyrosine 56, which decreased the expression of PDL1 by liver cancer cells. In orthotopic tumors grown in immune-competent mice, MET inhibitors decreased the antitumor activity of T cells. However, addition of anti-PD1 decreased orthotopic tumor growth and prolonged survival of mice compared with anti-PD1 or MET inhibitors alone. Tissue microarray analysis of HCC samples showed an inverse correlation between levels of MET and PDL1 and a positive correlation between levels of MET and phosphorylated GSK3B. CONCLUSIONS: In studies of liver cancer cell lines and mice with orthotopic tumors, MET mediated phosphorylation and activated GSK3B, leading to decreased expression of PDL1. Combined with a MET inhibitor, anti-PD1 and anti-PDL1 produced additive effect to slow growth of HCCs in mice.

Chronic myeloid leukemia among patients with a history of prior malignancies: A tale of dual survivorship.

BACKGROUND: Some patients with chronic myeloid leukemia (CML) have a history of previous malignancies. To the authors' knowledge, outcomes for CML diagnosed in these patients have not been well described. The current study was conducted to determine the outcome of patients with CML and a history of prior malignancies. METHODS: The current study included patients who were enrolled in clinical trials of tyrosine kinase inhibitors as initial therapy for CML in chronic phase from July 2000 to January 2014. RESULTS: Of the 630 patients with CML who were treated with frontline tyrosine kinase inhibitors, 626 had a known prior malignancy status. Of these, 45 patients (7%) had a prior malignancy other than nonmelanoma skin cancer whereas 17 patients (3%) had a history of nonmelanoma skin cancers alone. Characteristics of CML were similar between the patients with no prior malignancy, those with a prior malignancy, and those with nonmelanoma skin cancer. Patients with a prior malignancy were found to have an older median age compared with the other 2 groups. The most common prior malignancies were nonmelanoma skin cancer in 20 patients, breast cancer in 11 patients, melanoma in 7 patients, prostate cancer in 6 patients, and colorectal cancer in 5 patients. With regard to CML, the event-free survival, transformation-free survival, and failure-free survival rates were found to be similar between the groups. There was a statistically significantly decreased survival in the group with a prior malignancy versus the group with no prior malignancy versus the group with nonmelanoma skin cancer. In a multivariate analysis, advanced age and an elevated creatinine level were found to be associated with worse survival after a diagnosis of CML. CONCLUSIONS: Patients with CML with a history of prior malignancies appear to have the same excellent outcome as patients with no prior malignancies. In the few instances in which concomitant therapy for other malignancies was required during therapy with tyrosine kinase inhibitors, this was able to be accomplished without significant toxicity. Cancer 2017;123:609-616. © 2016 American Cancer Society.