Steven Terry Rosen

Purpose: Systemic immunotherapy is less effective in patients with liver metastases. Immunoembolization could potentially overcome the immunosuppressive tumor microenvironment, but the optimal immunotherapy agent, embolic, and release kinetics are unknown. Methods: A wide range of immunotherapy agents (cytokines, small molecules, and oligonucleotides) were loaded onto various embolics (stabilized lipiodol emulsions, microspheres-in-lipiodol, LC beads, and PLGA microspheres). Drug loading and release kinetics were evaluated in vitro. A pilot study of transarterial immunoembolization was performed in a pig liver tumor model, using extended release lipiodol/CpG-STAT3ASO formulations. CpG-STAT3ASO is a first-in-class dual-function immunotherapy agent that both stimulates the anti-tumor immune response, and counters immunosuppression in immunologically cold tumors. Safety, pharmacokinetics and efficacy were evaluated in pigs. Results: Immunotherapy-loaded embolics released drug with a half-life ranging from days to weeks in vitro, and up to four days in pig liver tumors (depending on the formulation). A stabilized lipiodol emulsion demonstrated 100% burst release (within five minutes after immunoembolization), compared to <1% burst release with microspheres-in-lipiodol. Immunoembolization using lipiodol/CpG-STAT3ASO resulted in decreased size of pig liver tumors, compared to bland embolization. No adverse events were seen, based on clinical, laboratory, and radiographic evaluation, but peritoneal adhesions were observed in association with immunoembolization using microspheres-in-lipiodol. Conclusions: Extended-release immunotherapy-loaded embolics generate sustained intratumoral delivery of immune stimulants. A pilot study of immunoembolization of pig liver tumors showed decreased tumor size, compared to bland embolization, with no autoimmune adverse events.

Vitamin D deficiency is associated with dysregulated alloimmune responses, but the mechanisms by which its active metabolite calcitriol shapes innate lymphoid cell (ILC) development and function remain incompletely understood. Here, we elucidate how calcitriol directs the differentiation of bone marrow (BM) ILC progenitors (ILCPs) into anti-inflammatory ILC3s with therapeutic potential in alloimmune diseases. Using murine vitamin D models, integrated omics, ¹³ C-glucose tracing, humanized mouse models, and clinical samples, we show that calcitriol, through the vitamin D receptor (VDR), selectively promotes the expansion and differentiation of BM ILCPs into IL-10 ⁺ IL-22 ⁺ ILC3s that exert tissue-protective effects in the intestine. Calcitriol-primed BM ILCP cell therapy attenuates intestinal inflammation in an alloimmune setting. Mechanistically, a VDR–SYK axis triggers nuclear translocation of pyruvate kinase M2 (PKM2). Nuclear PKM2 phosphorylates STAT3 at Tyr705, forming a dimerization complex with c-JUN that drives Il10 transcription. Simultaneously, cytosolic PKM2 channels pyruvate into pyruvate carboxylase–mediated mitochondrial anaplerosis, sustaining oxidative phosphorylation while suppressing reverse electron transport-driven mitochondrial ROS production. In human studies, patients with severe alloimmune complications exhibit reduced circulating ILCPs and low serum 25(OH)D levels. Calcitriol-treated human CD117 ⁺ ILCPs efficiently generate IL-10-producing ILCs in vitro and in humanized models, potently suppressing alloreactive T cell responses. Collectively, calcitriol reprograms BM ILCPs via the VDR–SYK–PKM2 axis to generate dual-cytokine IL-10 ⁺ IL-22 ⁺ ILC3s, establishing PKM2 as a key immunometabolic target and supporting calcitriol-primed ILCP-based cell therapy as a promising approach for alloimmune diseases.

Intratumoral injection of immune stimulants could potentially reverse the immunosuppressive tumor microenvironment, but the injected drug rapidly washes out into the systemic circulation. This results in systemic toxicity, and reduced efficacy, potentially requiring daily injections to generate an antitumor immune response. To address this problem, we developed an extended-release hydrogel that retains the immunotherapy agent at the injection site, and releases it over several days, even in highly vascular liver tumors. The extended-release hydrogel is a composite material containing drug-loaded microspheres (for sustained, tunable drug release), embedded in a radiopaque cross-linked hydrogel (for local retention). Using these new intratumoral drug carriers, we demonstrate the ability to safely deliver a wide range of different immunotherapy agents (cytokines, oligonucleotides, small molecules) into pig liver tumors, with no acute systemic toxicity. The microsphere gel reduces burst release by 7.8x (compared to microspheres), and increases half-life by > 15x (compared to hydrogel). Thus, the immunotherapy-loaded microsphere gel enables sustained intratumoral delivery of immune stimulants from a single injection, with low systemic toxicity.

Programmed death‐1 (PD‐1) blockade offers a survival advantage over antibody‐drug conjugate (ADC) treatment in classic Hodgkin lymphoma (cHL). As such, an updated pharmacoeconomic analysis of these different therapeutic strategies is indicated. This study therefore assessed the cost‐effectiveness of nivolumab combined with doxorubicin, vinblastine, and dacarbazine (N‐AVD) to that of brentuximab vedotin with AVD (BV‐AVD). A three‐state Markov model was developed to assess lifetime costs and efficacy for N‐AVD and BV‐ACVD regimens as treatments for adolescent and adult cHL patients from the perspectives of payers in China and the USA, using respective willingness to pay (WTP) thresholds of $37,608 and $150,000 per quality‐adjusted life year (QALY). Primary analytical outcomes included direct medical costs, lifetime efficacy, incremental cost‐effectiveness ratio (ICERs), and incremental net health benefit (INHB). Model stability was tested through sensitivity and subgroup analyses. N‐AVD treatment yielded 1.41–2.01 and 1.06–1.39 QALYs over BV‐AVD for cHL patients in the USA and China, respectively. Incremental healthcare costs for first‐line N‐AVD treatment were −$746,249 to $393,009 and −$109,358 to $292,324 compared to BV‐AVD treatment, for corresponding ICERs of –$432,098/QALY to $288,541/QALY and −$79,173/QALY to $275,376/QALY in the USA and China, respectively. Sensitivity analyses suggested that the utility of progression‐free survival had an influence on the results of these cost‐effectiveness analyses. N‐AVD and BV‐AVD are cost‐effective approaches to treating patients with cHL in both the USA and China. N‐AVD and BV‐AVD may respectively be best suited to use as treatments for adolescents and elderly individuals.

Modern drug development remains among the most capital-intensive and failure-prone processes in global innovation. Fewer than 5% of molecules entering human trials achieve FDA approval, yet the biotechnology ecosystem persists and even thrives. In this article, the authors trace the full arc from molecular discovery to market launch through the lens of private market investment. Advances in genomics, structure-based design, artificial intelligence, and adaptive regulation are transforming the economics of biopharma innovation. The analysis in this article highlights the paradox of resilience: while most drug candidates fail, diversified biotech firms and their private market backers continue to generate value through portfolio optionality, milestone-linked financing, and strategic exits. Through venture capital, growth equity, and royalty-linked financing structures, private market investors now function as both risk absorbers and innovation accelerants, turning biological volatility into an enduring data-driven asset class within alternative investments.

Fig S1. SF3B1 mutant CLL samples had pervasive changes in 3’ splice site. Fig S2. Omics analyses identify widespread post-transcriptional upregulation of splicing factors in CLL. Fig S3. Abundance of spliceosome complexes and RNA-binding proteins are associated with clinical outcomes in CLL. Fig S4. METTL3 is consistently upregulated along with differential m6A modification on transcripts of RNA splicing process in CLL. Fig S5. KO or pharmacological inhibition of METTL3 impacts cell growth. Fig S6. KO or pharmacological inhibition of METTL3 impacts apoptosis, cell cycle, and splicing factor abundance. Fig S7. Splicing factors are either direct or indirect targets of METTL3. Fig S8. Validation of association between m6A and splicing factor abundance using dCasRx-METTL3.

Table S1 shows CLL sample information; Table S2 shows protein expression detected in CLL and normal B cells using TMT proteomics; Table S3 shows top 150 transcripts with highest m6A density in B cells; Table S4 shows sequences of shRNAs, sgRNAs, and primers used in our study; Table S5 shows cellular pathways enriched in our study.

Selective targeting of the functionally exhausted malignant T cells in cutaneous T-cell lymphoma (CTCL) and distinct cells within the tumor microenvironment (TME) via programmed cell death 1/programmed cell death ligand 1 blockade (durvalumab) may restore an antitumor immune response. The oral immunomodulator lenalidomide, which has activity in CTCL, may enhance durvalumab immune checkpoint blockade. Our phase 1/2 clinical trial of durvalumab and lenalidomide in patients with refractory/advanced CTCL sought to assess the safety and tolerability and to identify the maximum tolerated dose and recommended phase 2 dose (RP2D) of lenalidomide plus fixed-dose durvalumab. Secondary and tertiary objectives were to investigate the efficacy and effects on the TME. Thirteen patients were evaluable for toxicities and 12 for dose decisions and response. No serious adverse events (AEs) or dose-limiting toxicities (DLTs) were observed during cycles 1 to 3 (DLT evaluation period), and dose level 3 was identified as the RP2D. The most frequent AEs were tumor flare, fatigue, neutropenia, and leukopenia. Three patients developed grade 1 or 2 autoimmune thyroiditis that resolved with treatment. Best overall and skin response rates were 58.3% (95% confidence interval (95% CI), 27.7-84.8%) and 75% (95% CI: 42.8-94.5%), respectively. The median cycles of treatment were 11, and the median duration of response was 25.5 months. The combination showed clinical activity with 7 partial responses and 4 stable disease. Potentially predictive immune signatures were downregulation of -α signaling via NF-κB, interferon gamma, and phosphoinositide 3 kinase-AKT-mammalian target of rapamycin signaling pathways in responders and upregulation of MYC targets and proinflammatory pathways in nonresponders. Profiling of immune cell compositions revealed changes in individual immune cell clusters based on treatment response. This trial was registered at www.ClinicalTrials.gov as #NCT03011814.