<p>This dataset provides a comprehensive analysis of the Fcγ receptor binding kinetics and Fc-mediated functions of botensilimab compared to other approved anti-CTLA-4 antibodies. These results highlight the unique Fc-mediated properties of botensilimab, particularly its enhanced engagement of activating Fcγ receptors without inducing complement-dependent cytotoxicity. This data further provides mechanistic insights into botensilimab's potential for enhanced immune modulation and anti-tumor efficacy.</p>
Abstract Conventional immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) elicit durable survival but primarily in patients with immune-inflamed tumors. Although the mechanisms underlying response to anti–CTLA-4 remain poorly understood, Fc-gamma receptor (FcγR) IIIA coengagement seems critical for activity, potentially explaining the modest clinical benefits of approved anti–CTLA-4 antibodies. We demonstrate that anti–CTLA-4 engineered for enhanced FcγR affinity leverages FcγR-dependent mechanisms to potentiate T-cell responsiveness, reduce intratumoral regulatory T cells, and enhance antigen-presenting cell activation. Fc-enhanced anti–CTLA-4 promoted superior efficacy in mouse models and remodeled innate and adaptive immunity versus conventional anti–CTLA-4. These findings extend to patients treated with botensilimab, an Fc-enhanced anti–CTLA-4 antibody, with clinical activity across multiple poorly immunogenic and ICI treatment–refractory cancers. Efficacy was independent of tumor neoantigen burden or FCGR3A genotype. However, FCGR2A and FCGR3A expression emerged as potential response biomarkers. These data highlight the therapeutic potential of Fc-enhanced anti–CTLA-4 antibodies in cancers unresponsive to conventional ICI therapy. Significance: This study reveals that Fc-enhanced anti–CTLA-4 harnesses novel mechanisms to overcome the limitations of conventional anti–CTLA-4, effectively treating poorly immunogenic and treatment-refractory cancers. Our findings support the development of a new class of immuno-oncology agents, capable of extending clinical benefit to patients with cancers resistant to current immunotherapies.
<div>Purpose:<p>To assess the preclinical efficacy, clinical safety and efficacy, and MTD of palbociclib plus nab-paclitaxel in patients with advanced pancreatic ductal adenocarcinoma (PDAC).</p>Experimental Design:<p>Preclinical activity was tested in patient-derived xenograft (PDX) models of PDAC. In the open-label, phase I clinical study, the dose-escalation cohort received oral palbociclib initially at 75 mg/day (range, 50‒125 mg/day; modified 3+3 design; 3/1 schedule); intravenous nab-paclitaxel was administered weekly for 3 weeks/28-day cycle at 100‒125 mg/m<sup>2</sup>. The modified dose–regimen cohorts received palbociclib 75 mg/day (3/1 schedule or continuously) plus nab-paclitaxel (biweekly 125 or 100 mg/m<sup>2</sup>, respectively). The prespecified efficacy threshold was 12-month survival probability of ≥65% at the MTD.</p>Results:<p>Palbociclib plus nab-paclitaxel was more effective than gemcitabine plus nab-paclitaxel in three of four PDX models tested; the combination was not inferior to paclitaxel plus gemcitabine. In the clinical trial, 76 patients (80% received prior treatment for advanced disease) were enrolled. Four dose-limiting toxicities were observed [mucositis (<i>n</i> = 1), neutropenia (<i>n</i> = 2), febrile neutropenia (<i>n</i> = 1)]. The MTD was palbociclib 100 mg for 21 of every 28 days and nab-paclitaxel 125 mg/m<sup>2</sup> weekly for 3 weeks in a 28-day cycle. Among all patients, the most common all-causality any-grade adverse events were neutropenia (76.3%), asthenia/fatigue (52.6%), nausea (42.1%), and anemia (40.8%). At the MTD (<i>n</i> = 27), the 12-month survival probability was 50% (95% confidence interval, 29.9–67.2).</p>Conclusions:<p>This study showed the tolerability and antitumor activity of palbociclib plus nab-paclitaxel treatment in patients with PDAC; however, the prespecified efficacy threshold was not met.</p>Trial Registration:<p>Pfizer Inc (NCT02501902)</p>Significance:<p>In this article, the combination of palbociclib, a CDK4/6 inhibitor, and nab-paclitaxel in advanced pancreatic cancer evaluates an important drug combination using translational science. In addition, the work presented combines preclinical and clinical data along with pharmacokinetic and pharmacodynamic assessments to find alternative treatments for this patient population.</p></div>
Supplementary Table S3 from A Preclinical and Phase Ib Study of Palbociclib plus Nab-Paclitaxel in Patients with Metastatic Adenocarcinoma of the Pancreas
Melanoma characteristically grows within the epidermis along the dermal-epidermal junction, sometimes extending outward up to several centimeters beyond the foci of invasive tumors. Although follicular involvement by malignant melanoma is widely recognized, to the authors' knowledge no previously published data address this phenomenon.To examine the growth characteristics of in situ melanomas in relation to the hair follicle microanatomy, the authors analyzed 100 cases of primary cutaneous melanomas (61 in situ and 39 invasive melanomas with significant in situ components) obtained from pathology clinical archives.Eighty-two (82%) cases of melanoma in situ demonstrated tumor cells within >or=1 hair follicles. Of those, 57 (69.5%) cases demonstrated the tumor cells only within the infundibulum. Extension of the tumor cells down to the isthmus was observed in 24 cases (29.3%). In only 1 exceptional case (1%) were tumor cells detected beneath the level of the hair follicle bulge.The authors postulate that a physiologic barrier restricts the intraepithelial spread of melanoma tumor cells at or beyond the level of the stem cell niche in the hair follicle bulge. Although the nature of this barrier remains to be elucidated, the distinct biologic characteristics of the hair follicle bulge may provide clues to understanding this phenomenon.
