Accumulating evidence suggests that platelets play a key role in cancer metastatic dissemination through their multilevel interaction with tumor cells. Most crucial is the contribution of platelets ...to the formation and expansion of the early metastatic niche, a protective microenvironment that nurtures the first metastatic cells and is necessary for the establishment of overt metastatic disease. A multitude of mechanisms have been proposed toward this effect. The current review examines the implication of platelets in the three most well-studied mechanisms: (a) the initial preparation of the metastatic microenvironment by the formation of the extracellular matrix (ECM) and the recruitment of granulocytes, (b) the creation of the neovasculature (important for providing the developing tumor with oxygen and nutrients and clearing away the metabolic waste), and (c) the evasion of the immune response by the creation of an immune-suppressive environment around the developing metastases. Finally, the review provides current perspectives on the potential clinical relevance of platelets in cancer progression and their consequent role in cancer therapeutics.
Renal cell carcinoma represents the most common malignancy of the kidney and the majority of cases are categorized as clear cell carcinomas. The elucidation of the specific alterations in key ...molecular and metabolic pathways responsible for cancer development and progression have prompted the rationalization of our classification of this disease and have provided specific targetable molecules implicated in carcinogenesis. Although immunotherapy has been an established option in the treatment of metastatic renal cell cancer for many years, its role has been renewed and upgraded with the implementation of anti-angiogenic agents and immune checkpoint inhibitors in our treatment armamentarium. The future holds promise, as newer agents become available and combination regimens of immunotherapy with anti-angiogenic agents have become the standard of care in the management of metastatic disease and are currently being evaluated in earlier settings. Proper patient selection and individualization of our treatment strategies are of utmost importance in order to provide optimal care to patients suffering from renal cell carcinoma.
Preclinical and clinical data demonstrate synergy between belantamab mafodotin (belamaf) and immunomodulatory drugs with limited overlapping toxicities. We investigated the safety and efficacy of ...belamaf with lenalidomide 25mg on days 1-21 every 28 days and dexamethasone 40mg weekly (belamaf-Rd) in transplant ineligible patients with newly diagnosed multiple myeloma. 36 patients (median age 72.5 years) were randomized to receive belamaf at three different doses (2.5/1.9/1.4 mg/kg) every 8 weeks (q8w). Dosing schedule was extended to every 12 weeks (q12w) to account for ocular toxicity. Most common ≥ Grade (Gr) 3 adverse events were fatigue (n=21, 58.3%), rash (n=6, 16.7%), diarrhea (n=8, 22.2%) and COVID-19 (n=5, 13.9%). Gr 3-4 ocular adverse events (OAEs), comprising of visual acuity decline from baseline and/or keratopathy, were reported in 39/216(18.1%)/ 33/244(13.5%)/ 26/207(12.6%) ophthalmological assessments in cohorts 2.5/1.9/1.4 mg/kg. Importantly, Gr 3-4 keratopathy was identified in 9/216 (4.2%)/ 1/244(0.4%)/ 1/207(0.5%) assessments. Most patients (32/36, 88.9%) were treated in the extended q12w schedule, where dose holds due to OAEs were 40, 33 and 16 in cohorts 2.5/1.9/1.4. Overall, ≥VGPR and ≥CR rates were 83.3% and 52.8%, without significant differences among cohorts. Over a median follow-up of 20.3 months no disease progression was reported; 6 patients discontinued treatment due to infection-related death (n=4 COVID-19, n=2 pneumonia) and 1 patient withdrew consent. Based on toxicity/efficacy balance, the recommended phase 2 dose was 1.9 mg/kg q8w, extended to q12w for toxicity. Belamaf-Rd, with the extended schedule for belamaf, has shown important clinical activity and a significant improvement of OAEs with minimal impact on vision-related functioning in an elderly, non-transplant eligible population.
Lung cancer remains the leading cause of cancer-related death in men and women, despite its constantly declining rates in incidence and mortality in the developed world. The past decade has witnessed ...an unprecedented rise in the development of molecular targeted therapies in various types of tumors. In non-small cell lung cancer (NSCLC), the greatest paradigm shift is the implementation of
and
tyrosine kinase inhibitors in the first line and subsequent lines of therapy, with impressive results. Though less frequent than the molecular alterations in the aforementioned genes, a number of aberrations in potential oncogenic drivers has been discovered, namely mutations in the genes
,
,
,
and
,
and
rearrangements and
,
and
gene amplifications. A great number of clinical trials are currently underway, evaluating agents specifically designed to target these alterations, with mixed results so far. The greatest cumulative benefit offered by these trials is that, despite their success or failure in their objective goals, they have provided us with a better understanding of the complexity of the molecular intracellular processes, necessitating thus the accurate interpretation of the preclinical data in order to appropriately select the patients that may derive benefit from targeted treatment strategies.
Abstract
Background
PD-L1, an immune checkpoint protein, is an important biomarker for monitoring cancer patients during the administration of cancer immunotherapy. Droplet digital PCR (ddPCR), is a ...highly sensitive and accurate tool for the quantification of cancer biomarkers in liquid biopsy. We report the development and analytical validation of a novel duplex RT-ddPCR assay for the simultaneous quantification of PD-L1 and hypoxanthine phosphoribosyltransferase (HPRT) (used as reference gene) transcripts in circulating tumor cells (CTCs).
Methods
RT-ddPCR experimental conditions were first optimized and the assay was analytically validated using synthetic standards and the BB49 and SCC47 cancer cell lines. The developed assay was further applied in 71 peripheral blood (PB) samples from head and neck squamous cell carcinoma (HNSCC) patients and 20 PB samples from healthy donors. PD-L1 and HPRT transcripts were quantified in cDNAs derived from CTCs isolated by a size-dependent microfluidic device. The developed RT-ddPCR assay was directly compared to RT-qPCR using 71 identical patient cDNA samples.
Results
Analytical sensitivity was 0.64 copies/μL, while estimation of intra- and interassay variation revealed a high reproducibility (within-run CV%:4.7–23%; between-run CV%:13%). Using the developed RT-ddPCR assay 33/71(46.5%) HNSCC patients’ samples were found positive for PD-L1 expression in CTCs, while by using RT-qPCR fewer samples (23/71, 32.4%) were positive (concordance: 55/71, 77.5%).
Conclusions
The developed RT-ddPCR assay for PD-L1 in CTCs is highly sensitive, specific, and reproducible; additionally, it offers improved diagnostic sensitivity over RT-qPCR. The clinical utility of the assay should be prospectively evaluated for the real-time monitoring of CTCs of cancer patients under immunotherapy.
7530 Background: Ocular adverse events (OAEs, best corrected visual acuity BCVA change from baseline and keratopathy) are common with belantamab mafodotin (belamaf; GSK2857916) and often necessitate ...an ophthalmic exam to guide dosing. Herein, we evaluate a novel approach for belamaf dose modifications in transplant ineligible patients (pts) with newly diagnosed MM, treated with an extended schedule of belamaf with lenalidomide and dexamethasone (Rd) in the BelaRd study. Methods: BelaRd (NCT04808037) is an ongoing, phase 1/2 study of 2 Parts. Part 1 established the recommended phase 2 dose (RP2D) of 1.9 mg/kg q8w, extended to q12w to account for OAEs. Part 2 assesses the safety/efficacy of RP2D in Groups A and B, of 15 pts each, and evaluates two sets of guidelines for OAE management. In Group A, dosing is determined by an ophthalmic exam performed by a certified ophthalmologist; in Group B it is determined by the pts’ responses in the Vision Related Anamnestic (VRA) tool and the presence of ≥Grade (Gr) 3 OAEs. VRA is a patient-reported questionnaire capturing ocular symptoms and their impact on activities of daily living (ADL). Herein, we present the OAEs and preliminary efficacy results after 205 ophthalmic and VRA assessments for all Part 2 pts (cut-off date 05/10/2023). Results: By the cut-off date, the median belamaf administrations and number of cycles reached were 3.0/3.0 and 8.0/7.0 for Groups A and B, respectively. The respective rates of Gr2 and ≥Gr3 BCVA change from baseline were 34.6%/24.2% and 6.4%/0.0%, while a meaningful BCVA decline (Snellen score <20/50) and ≥3 lines drop in the better-seeing eye was recorded in 11.0%/7.2% ophthalmological assessments; no ≥Gr3 keratopathy was observed. Among 110/94 VRA assessments, ocular symptoms and ADL impairment, manifesting for ≥50% of the time in the last 24 hours prior to belamaf administration (substantial time), were noted in 6.4%/10.6% and 3.6%/7.4%. Of note, VRA captured a “substantial time” response in 86% of assessments with ≥Gr3 OAEs. Finally, for the response-evaluable pts, at a median follow-up of 7.7 months, ORR was 93.3%/85.7% in Groups A and B (PR/VGPR/CR: 26.7%/53.3%/13.3%; 21.4%/64.3%/0.0%) and the median time to first response was ~ 1 month. Conclusions: The VRA tool was safe and effective in informing belamaf dose modifications. Future analyses will determine if VRA may effectively eliminate the need for an ophthalmic exam prior to belamaf dosing. Clinical trial information: NCT04808037 . Table: see text
PDF
