Advances from immuno-oncology (IO) are changing the standard of care of many types of cancer, and the paradigm of cancer treatments and drug development is being rewritten on a regular basis. Moreover, an unprecedented number of new investigational agents and companies are entering the field of IO. As such, it has become challenging for oncology physicians conducting clinical trials, industry veterans developing IO drugs, and even regulators reviewing novel IO agents to keep track of the rapidly evolving landscape. To help the key stake holders in the field understand the latest IO landscape, we sought to present an unbiased, neutral, scientifically curated, and timely updated analysis of all the current IO agents in clinical development and the clinical trials testing these agents. We based our analyses on information collected from numerous trusted and publicly available sources. We have developed two databases. One database tracks 2004 IO agents (940 in clinical stage and 1064 in preclinical stage) against 303 targets, from 864 companies; the other tracks 3042 active clinical trials of these agents with a target enrollment of 577 076 patients. This report provides key analyses of these data. Furthermore, we will discuss a number of important and actionable trends in the current IO landscape: a large number of companies developing agents against the same IO targets; a rapid increase in the number of anti-PD-1/L1 combination studies, many of which are testing the same combinations and following inefficient patterns; and a significant increase in the number of small, investigator-initiated studies. For each of the findings, we speculate the causes and discuss a few initiatives that aim to address some of these challenges. Finally, by making these landscape analyses available, we aspire to inform the cancer community as they seek to strive for efficiencies and innovation while avoiding duplication.

Inflammation is a key feature of atherosclerosis and a target for therapy. Statins have potent anti-inflammatory properties but these cannot be fully exploited with oral statin therapy due to low systemic bioavailability. Here we present an injectable reconstituted high-density lipoprotein (rHDL) nanoparticle carrier vehicle that delivers statins to atherosclerotic plaques. We demonstrate the anti-inflammatory effect of statin-rHDL in vitro and show this effect is mediated through inhibition of the mevalonate pathway. We also apply statin-rHDL nanoparticles in vivo in an apolipoprotein E-knockout mouse model of atherosclerosis and show they accumulate in atherosclerotic lesions where they directly affect plaque macrophages. Finally we demonstrate that a three-month low-dose statin-rHDL treatment regimen inhibits plaque inflammation progression, while a one-week high-dose regimen markedly decreases inflammation in advanced atherosclerotic plaques. Statin-rHDL represents a novel potent atherosclerosis nanotherapy that directly affects plaque inflammation.

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Tumor-associated macrophages (TAMs) are increasingly investigated in cancer immunology and are considered a promising target for better and tailored treatment of malignant growth. Although TAMs also have high diagnostic and prognostic value, TAM imaging still remains largely unexplored. Here, we describe the development of reconstituted high-density lipoprotein (rHDL)–facilitated TAM PET imaging in a breast cancer model. Methods Radiolabeled rHDL nanoparticles incorporating the long-lived positron-emitting nuclide 89Zr were developed using 2 different approaches. The nanoparticles were composed of phospholipids and apolipoprotein A-I (apoA-I) in a 2.5:1 weight ratio. 89Zr was complexed with deferoxamine (also known as desferrioxamine B, desferoxamine B), conjugated either to a phospholipid or to apoA-I to generate 89Zr-PL-HDL and 89Zr-AI-HDL, respectively. In vivo evaluation was performed in an orthotopic mouse model of breast cancer and included pharmacokinetic analysis, biodistribution studies, and PET imaging. Ex vivo histologic analysis of tumor tissues to assess regional distribution of 89Zr radioactivity was also performed. Fluorescent analogs of the radiolabeled agents were used to determine cell-targeting specificity using flow cytometry. Results The phospholipid- and apoA-I–labeled rHDL were produced at 79% ± 13% (n = 6) and 94% ± 6% (n = 6) radiochemical yield, respectively, with excellent radiochemical purity (>99%). Intravenous administration of both probes resulted in high tumor radioactivity accumulation (16.5 ± 2.8 and 8.6 ± 1.3 percentage injected dose per gram for apoA-I– and phospholipid-labeled rHDL, respectively) at 24 h after injection. Histologic analysis showed good colocalization of radioactivity with TAM-rich areas in tumor sections. Flow cytometry revealed high specificity of rHDL for TAMs, which had the highest uptake per cell (6.8-fold higher than tumor cells for both DiO@Zr-PL-HDL and DiO@Zr-AI-HDL) and accounted for 40.7% and 39.5% of the total cellular DiO@Zr-PL-HDL and DiO@Zr-AI-HDL in tumors, respectively. Conclusion We have developed 89Zr-labeled TAM imaging agents based on the natural nanoparticle rHDL. In an orthotopic mouse model of breast cancer, we have demonstrated their specificity for macrophages, a result that was corroborated by flow cytometry. Quantitative macrophage PET imaging with our 89Zr-rHDL imaging agents could be valuable for noninvasive monitoring of TAM immunology and targeted treatment.