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B-cell maturation antigen (BCMA)-targeting immunotherapies (e.g., chimeric antigen receptor T cells (CAR-T) and bispecific antibodies (BsAbs)) have achieved remarkable clinical responses in patients with relapsed and/or refractory multiple myeloma (RRMM). Their use is accompanied by exaggerated immune responses related to T-cell activation and cytokine elevations leading to cytokine release syndrome (CRS) in some patients, which can be potentially life-threatening. However, systematic evaluation of the risk of CRS with BCMA-targeting BsAb and CAR-T therapies, and comparisons across different routes of BsAb administration (intravenous (i.v.) vs. subcutaneous (s.c.)) have not previously been conducted. This study utilized a meta-analysis approach to compare the CRS profile in BCMA-targeting CAR-T vs. BsAb immunotherapies administered either i.v. or s.c. in patients with RRMM. A total of 36 studies including 1,560 patients with RRMM treated with BCMA-targeting CAR-T and BsAb therapies were included in the analysis. The current analysis suggests that compared with BsAbs, CAR-T therapies were associated with higher CRS incidences (88% vs. 59%), higher rates of grade ≥ 3 CRS (7% vs. 2%), longer CRS duration (5 vs. 2 days), and more prevalent tocilizumab use (44% vs. 25%). The proportion of CRS grade ≥ 3 may also be lower (0% vs. 4%) for BsAb therapies administered via the s.c. (3 studies, n = 311) vs. i.v. (5 studies, n = 338) route. This meta-analysis suggests that different types of BCMA-targeting immunotherapies and administration routes could result in a range of CRS incidence and severity that should be considered while evaluating the benefit-risk profiles of these therapies.

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Exposure-response (E-R) analyses are an integral component of understanding the benefit/risk profile of novel oncology therapeutics. These analyses are typically conducted using data from the treatment arm to characterize the relationship between drug exposure (low vs. high) and efficacy or safety outcomes. For example, outcomes of patients with lower exposure in the treatment arm (e.g., Q1) might be compared to outcomes of those with higher drug exposure (Q2, Q3, and Q4). Outcomes from the lowest exposure quartile may be also compared to the control arm to evaluate whether the Q1 subgroup derived clinical benefit. However, the sample size and the distribution of patient baseline characteristics and disease risk factors are not balanced in such a comparison (Q1 vs. control), which may bias the analysis and causal interpretation of clinical benefit in the Q1 subgroup. Herein, we report the use of case-control matching to account for this bias and better understand the E-R relationship for avelumab in urothelial carcinoma, a PD-L1 inhibitor approved for the treatment of several cancers. Data from JAVELIN-100 was utilized which is a phase III study of avelumab in first-line maintenance treatment in patients with urothelial carcinoma; this clinical study demonstrated superiority of avelumab versus best-supportive care leading to approval in the United States, Europe, and other countries. A post hoc case-control matching method was implemented to compare the efficacy outcome between Q1 avelumab subgroup and matched patients extracted from the control arm with similar baseline characteristics, which showed a clinically relevant difference in overall survival in favor of the Q1 avelumab subgroup. This analysis demonstrates the importance of accounting for imbalance in important baseline covariates when comparing efficacy outcomes between subgroups within the treatment arm versus the control arm.

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Oncology therapies shifted from chemotherapy to molecularly targeted agents and finally to the era of immune-oncology agents. In contrast to cytotoxic agents, molecularly targeted agents are more selective, exhibit a wider therapeutic window, and may maximally modulate tumor growth at doses lower than the maximum tolerated dose (MTD). However, first-in-patient oncology studies for molecularly targeted agents continued to evaluate escalating doses using limited number of patients per dose cohort assessing dose-limiting toxicities to identify the MTD which is commonly selected for further development adopting a 'more is better' approach that led to several post-marketing requirement (PMR) studies to evaluate alternative, typically lower, doses or dosing frequencies to optimize the benefit-risk profile. In this review, post-marketing dose optimization efforts were reviewed including those required by a regulatory pathway or voluntarily conducted by the sponsor to improve efficacy, safety, or method of administration. Lessons learned and future implications from this deep dive review are discussed considering the evolving regulatory landscape on dose optimization for oncology compounds.

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Chemotherapy faces challenges, including poor aqueous solubility of the drugs, and cardiotoxicity. Micellar drug delivery systems (DDS) are used to encapsulate anticancer drugs for better therapeutic effects, however, with poor loading content. Herein, we synthesized a micellar DDS using γ-benzyloxy substituted poly(ε-caprolactone) as the hydrophobic block and coloaded anticancer doxorubicin (Dox) and antioxidant quercetin (Que). γ-Substituted oligo(ethylene) glycol (OEG) poly(ε-caprolactone)s were used as hydrophilic blocks to make the polymers thermoresponsive. Variation of the OEG chain allowed the tunability of the lower critical solution temperature. Moreover, drug loading and release were studied. Thermodynamic stability, size, and morphology were determined by fluorescence measurements, dynamic light scattering, and transmission electron microscopy. Combination loading demonstrated improved loading of Dox and Que. Biological studies were performed using HepG2 human liver cancer and H9c2 rat heart cells. The use of biodegradable, biocompatible, and thermoresponsive polymers along with the coloading approach is a good strategy in developing DDSs.

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Regenerative medicine aims to engineer tissue constructs that can recapitulate the functional and structural properties of native organs. Most novel regenerative therapies are based on the recreation of a three-dimensional environment that can provide essential guidance for cell organization, survival, and function, which leads to adequate tissue growth. The primary motivation in the use of conductive nanomaterials in tissue engineering has been to develop biomimetic scaffolds to recapitulate the electrical properties of the natural extracellular matrix, something often overlooked in numerous tissue engineering materials to date. In this review article, we focus on the use of electroconductive nanobiomaterials for different biomedical applications, particularly, very recent advancements for cardiovascular, neural, bone, and muscle tissue regeneration. Moreover, this review highlights how electroconductive nanobiomaterials can facilitate cell to cell crosstalk (i.e., for cell growth, migration, proliferation, and differentiation) in different tissues. Thoughts on what the field needs for future growth are also provided.