A paracrine circuit of IL-1ß/IL-1R1 between myeloid and tumor cells drives genotype-dependent glioblastoma progression.

Monocytes and monocyte-derived macrophages (MDMs) from blood circulation infiltrate glioblastoma (GBM) and promote growth. Here, we show that PDGFB-driven GBM cells induce the expression of the potent proinflammatory cytokine IL-1ß in MDM, which engages IL-1R1 in tumor cells, activates the NF-κB pathway, and subsequently leads to induction of monocyte chemoattractant proteins (MCPs). Thus, a feedforward paracrine circuit of IL-1ß/IL-1R1 between tumors and MDM creates an interdependence driving PDGFB-driven GBM progression. Genetic loss or locally antagonizing IL-1ß/IL-1R1 leads to reduced MDM infiltration, diminished tumor growth, and reduced exhausted CD8+ T cells and thereby extends the survival of tumor-bearing mice. In contrast to IL-1ß, IL-1α exhibits antitumor effects. Genetic deletion of Il1a/b is associated with decreased recruitment of lymphoid cells and loss-of-interferon signaling in various immune populations and subsets of malignant cells and is associated with decreased survival time of PDGFB-driven tumor-bearing mice. In contrast to PDGFB-driven GBM, Nf1-silenced tumors have a constitutively active NF-κB pathway, which drives the expression of MCPs to recruit monocytes into tumors. These results indicate local antagonism of IL-1ß could be considered as an effective therapy specifically for proneural GBM.

Keeping Myeloma in Check: The Past, Present and Future of Immunotherapy in Multiple Myeloma.

Multiple myeloma is an incurable disease of malignant plasma cells and an ideal target for modern immune therapy. The unique plasma cell biology maintained in multiple myeloma, coupled with its hematological nature and unique bone marrow microenvironment, provide an opportunity to design specifically targeted immunotherapies that selectively kill transformed cells with limited on-target off-tumor effects. Broadly defined, immune therapy is the utilization of the immune system and immune agents to treat a disease. In the context of multiple myeloma, immune therapy can be subdivided into four main categories: immune modulatory imide drugs, targeted antibodies, adoptive cell transfer therapies, and vaccines. In recent years, advances in all four of these categories have led to improved therapies with enhanced antitumor activity and specificity. In IMiDs, modified chemical structures have been developed that improve drug potency while reducing dose limiting side effects. Targeted antibody therapies have resulted from the development of new selectively expressed targets as well as the development of antibody drug conjugates and bispecific antibodies. Adoptive cell therapies, particularly CAR-T therapies, have been enhanced through improvements in the manufacturing process, as well as through the development of CAR constructs that enhance CAR-T activation and provide protection from a suppressive immune microenvironment. This review will first cover in-class breakthrough therapies for each of these categories, as well as therapies currently utilized in the clinic. Additionally, this review will explore up and coming therapeutics in the preclinical and clinical trial stage.

BCL2 Family Inhibitors in the Biology and Treatment of Multiple Myeloma.

Although much progress has been made in the treatment of multiple myeloma, the majority of patients fail to be cured and require numerous lines of therapy. Inhibitors of the BCL2 family represent an exciting new class of drugs with a novel mechanism of action that are likely to have activity as single agents and in combination with existing myeloma therapies. The BCL2 proteins are oncogenes that promote cell survival and are frequently upregulated in multiple myeloma, making them attractive targets. Venetoclax, a BCL2 specific inhibitor, is furthest along in development and has shown promising results in a subset of myeloma characterized by the t(11;14) translocation. Combining venetoclax with proteasome inhibitors and monoclonal antibodies has improved responses in a broader group of patients, but has come at the expense of a toxicity safety signal that requires additional follow-up. MCL1 inhibitors are likely to be effective in a broader range of patients and are currently in early clinical trials. This review will cover much of what is known about the biology of these drugs, biomarkers that predict response, mechanisms of resistance, and unanswered questions as they pertain to multiple myeloma.

Design of BET Inhibitor Bottlebrush Prodrugs with Superior Efficacy and Devoid of Systemic Toxicities.

Prodrugs engineered for preferential activation in diseased versus normal tissues offer immense potential to improve the therapeutic indexes (TIs) of preclinical and clinical-stage active pharmaceutical ingredients that either cannot be developed otherwise or whose efficacy or tolerability it is highly desirable to improve. Such approaches, however, often suffer from trial-and-error design, precluding predictive synthesis and optimization. Here, using bromodomain and extra-terminal (BET) protein inhibitors (BETi)-a class of epigenetic regulators with proven anticancer potential but clinical development hindered in large part by narrow TIs-we introduce a macromolecular prodrug platform that overcomes these challenges. Through tuning of traceless linkers appended to a "bottlebrush prodrug" scaffold, we demonstrate correlation of in vitro prodrug activation kinetics with in vivo tumor pharmacokinetics, enabling the predictive design of novel BETi prodrugs with enhanced antitumor efficacies and devoid of dose-limiting toxicities in a syngeneic triple-negative breast cancer murine model. This work may have immediate clinical implications, introducing a platform for predictive prodrug design and potentially overcoming hurdles in drug development.

Reduction of liver fibrosis by rationally designed macromolecular telmisartan prodrugs.

At present there are no drugs for the treatment of chronic liver fibrosis that have been approved by the Food and Drug administration of the United States. Telmisartan, a small-molecule antihypertensive drug, displays antifibrotic activity, but its clinical use is limited because it causes systemic hypotension. Here, we report the scalable and convergent synthesis of macromolecular telmisartan prodrugs optimized for preferential release in diseased liver tissue. We optimized the release of active telmisartan in fibrotic liver to be depot-like (that is, a constant therapeutic concentration) through the molecular design of telmisartan brush-arm star polymers, and show that these lead to improved efficacy and to the avoidance of dose-limiting hypotension in both metabolically and chemically induced mouse models of hepatic fibrosis, as determined by histopathology, enzyme levels in the liver, intact-tissue protein markers, hepatocyte necrosis protection, and gene-expression analyses. In rats and dogs, the prodrugs are retained long-term in liver tissue and have a well-tolerated safety profile. Our findings support the further development of telmisartan prodrugs that enable infrequent dosing in the treatment of liver fibrosis.

Publisher Correction: Reduction of liver fibrosis by rationally designed macromolecular telmisartan prodrugs.

In the version of this Article originally published, the author Peter Blume-Jensen was not denoted as a corresponding author; this has now been amended and the author's email address has been added. The 'Correspondence and requests for materials' statement was similarly affected and has now been updated with the author's initials 'P.B-J.'