Liposomal Paclitaxel Research Articles

Two-Stage Phase II Study of Envafolimab Combined with Endostar and Concurrent Chemoradiotherapy in Treatment of Unresectable Locally Advanced Esophageal Squamous Cell Carcinoma: Preliminary Results of Stage 1

<h3>Purpose/Objective(s)</h3> Concurrent chemoradiotherapy (CRT) is the standard of care for patients with unresectable locally advanced esophageal squamous cell carcinoma (LA-ESCC). In the era of immunotherapy, we performed a single-center, open-label phase II study of CRT combined with endostar (inhibitor of tumor angiogenesis) and envafolimab (PD-L1 checkpoint inhibitor) in patients with LA-ESCC. <h3>Materials/Methods</h3> Treatment-naïve patients with LA-ESCC were enrolled. Radiologists evaluated each patient to exclude the risk of esophageal fistula before enrollment. Involved field radiotherapy at doses of 50.4 Gy (1.8Gy QD), two cycles of paclitaxel liposome (150 mg /m²) and carboplatin (AUC=5) Q4W and 5 cycles of endostar (75mg × 48h, QW) were delivered. Envafolimab at 400 mg subcutaneous injection Q4W was started concurrently with CRT and continued for up to 12 cycles. In Stage 1, the primary endpoint was safety and tolerability. Secondary endpoint was objective response rate and the rate of endoscopic complete remission (EsCR) defined as absence of invasive cells in esophagoscopic biopsy. Responses were assessed by positron emission tomography-computed tomography (PET-CT) at baseline, 12 weeks after the CRT, and computed tomography (CT) at 4 weeks after the CRT, every 12 weeks thereafter. The esophagoscopic examination and biopsy were monitored at baseline, after 41.4 Gy radiation, and 1 month after the CRT To evaluate the efficacy. <h3>Results</h3> Between Sep. 8, 2021 and Nov. 15, 2022, 10 patients were enrolled in Stage-1. Treatment-related adverse events (TRAE) occurred in 9 (90%) patients, the most common of which was fatigue (30%), nausea (40%), thrombocytopenia (20%), leucopenia (60%), acute esophagitis (40%), thyroid dysfunction (10%), and Rash (20%). These occurred predominantly at grade 1 or 2 severity. The most frequent TRAE of grade 3 or worse was leucopenia (40%). No patient had pneumonitis, esophageal fistula. There were no deaths or treatment discontinuations due to serious adverse events. CT scan was completed in 10 patients, esophagoscopic examination biopsy in 9 of them, at 4 weeks after the CRT. All patients had a decrease in target lesion size on CT. The objective response rate was 100%. The pathology report of 8 patients revealed no cancerous cells was observed, resulting in an EsCR rate of 88.9%. <h3>Conclusion</h3> In the stage-1, Envafolimab combined with endostar and CRT was well tolerated with manageable toxicity for unresectable LA-ESCC patients. The preliminary results provide a basis for the ongoing stage 2 study. This trial is registered with ClinicalTrials.gov, number ChiCTR2100051606.

Cancer cell-derived exosomes as the delivery vehicle of paclitaxel to inhibit cancer cell growth

Delivering water-insoluble drugs, such as paclitaxel (PTX), to the tumor site is a challenge. Exosomes are capable of delivering “cargo” to the target site without causing adverse effects, unlike synthetic nanoparticles. Here, we have prepared PTX-loaded exosomes from breast cancer cells. This formulation is further explored for its activity against breast cancer cell lines. Our data indicate that the exosomes are more efficient than free paclitaxel and liposomal paclitaxel in inhibiting the cancer cell growth. The primary reason for this superior activity is determined to be exosomes’ ability to deliver more amount of drug in the cytosol. However, the exact mechanism by which exosomes deliver the drug across the cell membrane still needs to be explored.

ARTISTRY-7: A phase 3, multicenter study of nemvaleukin alfa, a novel engineered cytokine, in combination with pembrolizumab versus chemotherapy in patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer (326)

Objectives: ARTISTRY-7 will evaluate the novel engineered cytokine nemvaleukin alfa (nemvaleukin, ALKS 4230) in patients (pts) with gynecologic cancers. Nemvaleukin was designed to selectively bind to the intermediate-affinity IL-2 receptor, preferentially activating and expanding antitumor CD8+ T and NK cells with minimal expansion of Tregs. This selectivity may enhance tumor killing and improve safety/tolerability compared with high-dose IL-2. In clinical studies, nemvaleukin monotherapy and combination with pembrolizumab have shown evidence of clinical benefit in multiple tumor types. In ARTISTRY-1, four responses are observed in pts with ovarian cancer (OC), including one complete response in a pt with platinum-resistant OC and five prior lines of therapy who remains on treatment. Epithelial OC is the 7th most common cause of cancer mortality in women. The standard frontline treatment is platinum-based chemotherapy, to which many pts become resistant or are refractory. There is a high unmet medical need for platinum-resistant OC. Methods: ARTISTRY-7 is a phase III, multicenter, open-label randomized study of nemvaleukin and/or pembrolizumab versus chemotherapy (ClinicalTrials.gov registration forthcoming). Eligible pts included females (>18 y) with histologically confirmed epithelial OC (high-grade serous, endometrioid, clear cell), fallopian tube cancer, or primary peritoneal cancer. Pts must have received >1 prior line of systemic anticancer therapy in the platinum-sensitive setting, ≤5 prior lines in the platinum-resistant setting, and prior bevacizumab, with evidence of radiographic progression on most recent therapy. Primary platinum-refractory disease (progression during first-line platinum-based therapy) or primary platinum resistance (progression <3 months after completion of first-line platinum-based therapy) is exclusionary. Pts must have an ECOG performance status of 0 or 1, an estimated life expectancy of >3 months, and adequate hematologic reserve and hepatic and renal function. Approximately 376 pts will be randomized (3:1:1:3) to receive intravenous nemvaleukin (6 μg/kg) on days 1-5 and pembrolizumab (200 mg) on day 1 of each 21-day cycle, pembrolizumab monotherapy, nemvaleukin monotherapy, or investigator’s choice chemotherapy (pegylated liposomal doxorubicin, paclitaxel, topotecan, or gemcitabine) and stratified according to PD-L1 status, histologic subtype (high-grade vs non-high-grade serous), and chemotherapy (paclitaxel vs other). Pts will continue treatment in the absence of disease progression or intolerable toxicity (maximum 35 cycles for pembrolizumab; nemvaleukin can be continued). Investigator-assessed progression-free survival (RECIST v1.1) in pts treated with nemvaleukin/pembroli- zumab versus chemotherapy (primary endpoint), characterization of antitumor activity of nemvaleukin and pembrolizumab in combination and as monotherapy, safety, HRQOL, and pharmacokinetic/ pharmacodynamic effects will be collected. Objectives: ARTISTRY-7 will evaluate the novel engineered cytokine nemvaleukin alfa (nemvaleukin, ALKS 4230) in patients (pts) with gynecologic cancers. Nemvaleukin was designed to selectively bind to the intermediate-affinity IL-2 receptor, preferentially activating and expanding antitumor CD8+ T and NK cells with minimal expansion of Tregs. This selectivity may enhance tumor killing and improve safety/tolerability compared with high-dose IL-2. In clinical studies, nemvaleukin monotherapy and combination with pembrolizumab have shown evidence of clinical benefit in multiple tumor types. In ARTISTRY-1, four responses are observed in pts with ovarian cancer (OC), including one complete response in a pt with platinum-resistant OC and five prior lines of therapy who remains on treatment. Epithelial OC is the 7th most common cause of cancer mortality in women. The standard frontline treatment is platinum-based chemotherapy, to which many pts become resistant or are refractory. There is a high unmet medical need for platinum-resistant OC. Methods: ARTISTRY-7 is a phase III, multicenter, open-label randomized study of nemvaleukin and/or pembrolizumab versus chemotherapy (ClinicalTrials.gov registration forthcoming). Eligible pts included females (>18 y) with histologically confirmed epithelial OC (high-grade serous, endometrioid, clear cell), fallopian tube cancer, or primary peritoneal cancer. Pts must have received >1 prior line of systemic anticancer therapy in the platinum-sensitive setting, ≤5 prior lines in the platinum-resistant setting, and prior bevacizumab, with evidence of radiographic progression on most recent therapy. Primary platinum-refractory disease (progression during first-line platinum-based therapy) or primary platinum resistance (progression <3 months after completion of first-line platinum-based therapy) is exclusionary. Pts must have an ECOG performance status of 0 or 1, an estimated life expectancy of >3 months, and adequate hematologic reserve and hepatic and renal function. Approximately 376 pts will be randomized (3:1:1:3) to receive intravenous nemvaleukin (6 μg/kg) on days 1-5 and pembrolizumab (200 mg) on day 1 of each 21-day cycle, pembrolizumab monotherapy, nemvaleukin monotherapy, or investigator’s choice chemotherapy (pegylated liposomal doxorubicin, paclitaxel, topotecan, or gemcitabine) and stratified according to PD-L1 status, histologic subtype (high-grade vs non-high-grade serous), and chemotherapy (paclitaxel vs other). Pts will continue treatment in the absence of disease progression or intolerable toxicity (maximum 35 cycles for pembrolizumab; nemvaleukin can be continued). Investigator-assessed progression-free survival (RECIST v1.1) in pts treated with nemvaleukin/pembroli- zumab versus chemotherapy (primary endpoint), characterization of antitumor activity of nemvaleukin and pembrolizumab in combination and as monotherapy, safety, HRQOL, and pharmacokinetic/ pharmacodynamic effects will be collected.

Cost-effectiveness of management strategies for patients with recurrent ovarian cancer and inoperable malignant bowel obstruction (078)

Objectives: Patients with recurrent platinum-resistant ovarian cancer often present with inoperable malignant bowel obstruction from large burden abdominal disease. End-of-life interventions such as total parenteral nutrition (TPN) and chemotherapy may modestly improve survival but may also result in a worsened quality of life (QOL) and high cost. We aimed to describe the relative cost-effectiveness of these interventions to inform clinical decision-making. Methods: Four strategies, including home hospice, TPN alone, chemotherapy alone, and TPN+chemotherapy, for management of platinum-resistant recurrent ovarian cancer with inoperable malignant bowel obstruction and gastrostomy tube, were compared using a simple decision model. Chemotherapy regimens modeled included standard monotherapies (liposomal doxorubicin, pacli-taxel, gemcitabine, or topotecan). An alternative scenario assumed a higher cost novel therapy (pembrolizumab). Costs and rates of blood transfusion ($451,15%) and granulocyte colony-stimulating factor ($3079, 9.6%) were incorporated into standard chemotherapy costs. Median survival and rates of hospitalization were obtained from the detailed literature review: hospice (survival 38 days, 6% hospitalization), chemotherapy (42 days, 24%), TPN (55 days, 24%), and TPN+chemotherapy (74 days, 43%). End-of-life QOL-related utilities (0.08 for end-stage with bowel obstruction; 0.07 for additional hospitalization) were incorporated. Outcomes included the average cost of strategy and incremental cost-effectiveness ratios (ICERs) in US dollars per quality-adjusted life-year (QALY) gained. Multiple one-way sensitivity analyses performed on utilities, costs, probability of hospitalization, and expected survival time (Figure 1). Results: TPN+chemotherapy was the most costly strategy ($33,099) in the base case scenario and was associated with the highest QALYs (0.016). The lowest cost strategy was standard chemotherapy alone (cost $7,078, QALYs 0.009), which dominated home hospice ($8,666, QALYs 0.008) due to lower cost and slightly higher QALYs. The TPN alone strategy (cost $21,025, QALYs 0.012) was dominated by a combination of other strategies. The ICER of TPN+chemotherapy was $3.8 million/QALY compared to chemotherapy alone. In the novel therapy scenario, hospice was the least costly strategy, novel therapy alone was dominated, and TPN+novel therapy had an ICER of $11 million/QALY compared to the next less costly strategy. The model’s results were stable to multiple one-way sensitivity analyses. Objectives: Patients with recurrent platinum-resistant ovarian cancer often present with inoperable malignant bowel obstruction from large burden abdominal disease. End-of-life interventions such as total parenteral nutrition (TPN) and chemotherapy may modestly improve survival but may also result in a worsened quality of life (QOL) and high cost. We aimed to describe the relative cost-effectiveness of these interventions to inform clinical decision-making. Methods: Four strategies, including home hospice, TPN alone, chemotherapy alone, and TPN+chemotherapy, for management of platinum-resistant recurrent ovarian cancer with inoperable malignant bowel obstruction and gastrostomy tube, were compared using a simple decision model. Chemotherapy regimens modeled included standard monotherapies (liposomal doxorubicin, pacli-taxel, gemcitabine, or topotecan). An alternative scenario assumed a higher cost novel therapy (pembrolizumab). Costs and rates of blood transfusion ($451,15%) and granulocyte colony-stimulating factor ($3079, 9.6%) were incorporated into standard chemotherapy costs. Median survival and rates of hospitalization were obtained from the detailed literature review: hospice (survival 38 days, 6% hospitalization), chemotherapy (42 days, 24%), TPN (55 days, 24%), and TPN+chemotherapy (74 days, 43%). End-of-life QOL-related utilities (0.08 for end-stage with bowel obstruction; 0.07 for additional hospitalization) were incorporated. Outcomes included the average cost of strategy and incremental cost-effectiveness ratios (ICERs) in US dollars per quality-adjusted life-year (QALY) gained. Multiple one-way sensitivity analyses performed on utilities, costs, probability of hospitalization, and expected survival time (Figure 1). Results: TPN+chemotherapy was the most costly strategy ($33,099) in the base case scenario and was associated with the highest QALYs (0.016). The lowest cost strategy was standard chemotherapy alone (cost $7,078, QALYs 0.009), which dominated home hospice ($8,666, QALYs 0.008) due to lower cost and slightly higher QALYs. The TPN alone strategy (cost $21,025, QALYs 0.012) was dominated by a combination of other strategies. The ICER of TPN+chemotherapy was $3.8 million/QALY compared to chemotherapy alone. In the novel therapy scenario, hospice was the least costly strategy, novel therapy alone was dominated, and TPN+novel therapy had an ICER of $11 million/QALY compared to the next less costly strategy. The model’s results were stable to multiple one-way sensitivity analyses.

A facile method for anti-cancer drug encapsulation into polymersomes with a core-satellite structure

Polymersomes possess the self-assembly vesicular structure similar to liposomes. Although a variety of comparisons between polymersomes and liposomes in the aspects of physical properties, preparation and applications have been elaborated in many studies, few focus on their differences in drug encapsulation, delivery and release in vitro and in vivo. In the present work, we have provided a modified direct hydration method to encapsulate anti-cancer drug paclitaxel (PTX) into PEG-b-PCL constituted polymersomes (PTX@PS). In addition to advantages including narrow particle size distribution, high colloid stability and moderate drug-loading efficiency, we find that the loaded drug aggregate in small clusters and reside through the polymersome membrane, representing a unique core-satellite structure which might facilitate the sustained drug release. Compared with commercial liposomal PTX formulation (Lipusu®), PTX@PS exhibited superb tumor cell killing ability underlain by multiple pro-apoptotic mechanisms. Moreover, endocytic process of PTX@PS significantly inhibits drug transporter P-gp expression which could be largely activated by free drug diffusion. In glioma mice models, it has also confirmed that PTX@PS remarkably eradicate tumors, which renders polymersomes as a promising alternative to liposomes as drug carriers in clinic.

Co-Delivery of 5-Fluorouracil and Paclitaxel in Mitochondria-Targeted KLA-Modified Liposomes to Improve Triple-Negative Breast Cancer Treatment.

In this research, KLA-modified liposomes co-loaded with 5-fluorouracil and paclitaxel (KLA-5-FU/PTX Lps) were developed, and their antitumor activity against triple-negative breast cancer (TNBC) was evaluated. KLA-5-FU/PTX Lps were prepared using the thin-film dispersion method, and their in vitro anticancer efficacy was assessed in human breast cancer cells (MDA-MB-231). An MDA-MB-231 tumor-bearing mouse model was also established to evaluate their antitumor efficacy in vivo. KLA-5-FU/PTX Lps showed enhanced cytotoxicity against MDA-MB-231 cells, improved drug delivery to mitochondria, and induced mitochondria-mediated apoptosis. The modified liposomes also showed favorable antitumor activity in vivo due to their strong ability to target tumors and mitochondria. The liposomes showed no obvious systemic toxicity. Our results suggest that KLA-5-FU/PTX Lps are a promising system with which to target the delivery of antitumor drugs to mitochondria as a treatment for TNBC.

Artificial reconstruction for a thymoma invading superior vena cava

Artificial reconstruction for a thymoma invading superior vena cava

Abstract CT148: A phase 1b dose-escalation study of ZN-c3, a WEE1 inhibitor, in combination with chemotherapy (CT) in subjects with platinum-resistant or refractory ovarian, peritoneal, or fallopian tube cancer

Abstract Background: ZN-c3 is a novel, selective, and orally bioavailable WEE1 inhibitor that has demonstrated significant antitumor activity in in-vitro and in-vivo models. Combining ZN-c3 with CT may inhibit repair of CT-induced DNA damage and provide therapeutic benefit in patients with platinum-resistant or refractory ovarian, peritoneal, or fallopian tube cancer. Methods: This Phase 1b, open-label, multicenter study is assessing ZN-c3 plus pegylated liposomal doxorubicin (PLD), carboplatin, paclitaxel, or gemcitabine in adult women with high-grade serous epithelial ovarian, peritoneal, or fallopian tube carcinoma who have received 1-2 prior regimens/lines of therapy in the metastatic setting and are refractory or resistant to platinum-based therapy. The primary objective is to investigate the safety and tolerability of ZN-c3 in combination with chemotherapy including identification of the MTD/RP2D. Secondary endpoints include estimates of clinical activity of ZN-c3 in combination with chemotherapy. Treatment is given in repeated 21- or 28-day cycles with once-daily ZN-c3 until disease progression or unacceptable toxicity. Results: As of the cutoff date of Oct 28, 2021, based on interim data, a total of 25 subjects (all dose levels, all chemotherapy cohorts) had measurable disease at baseline and at least 1 post-baseline radiological assessment. Of those, 6/25 (24%) had a partial response (1 confirmed and 5 unconfirmed), 14/25 (56%) had stable disease (6 ongoing), and 5/25 (20%) had radiological progressive disease (80% disease control rate defined as complete response, partial response, and stable disease). In the ZN-c3 plus carboplatin cohort (cutoff date Jan 5, 2022), 4/10 (40%) had a partial response (2 confirmed and 2 unconfirmed), 4/10 (40%) had stable disease, and 2/10 (20%) had radiological progressive disease (80% disease control rate). As of the cutoff date of Oct 28, 2021, 41 subjects were evaluable for safety (i.e., received at least 1 dose of ZN-c3). Adverse events (≥20% all Grade in any treatment group) were (all Grade/≥ Grade 3) [n(%)]: nausea 22 (53.7%)/3 (7.3%), neutropenia 21 (51.2%)/14 (34.1%), thrombocytopenia 14 (34.1%)/7 (17.1%), anemia 10 (24.4%)/4 (9.8%), diarrhea 10 (24.4%)/1 (2.4%), fatigue 10 (24.4%)/1 (2.4%), vomiting 10 (24.4%)/4 (9.8%), leukopenia 8 (19.5%)/3 (7.3%), abdominal pain 7 (17.1%)/3 (7.3%), hypoalbuminemia 6 (14.6%)/1 (2.4%), alanine aminotransferase increased 5 (12.2%)/3 (7.3%), and hypomagnesemia 5 (12.2%)/1 (2.4%). The study is ongoing including combination dose-finding (NCT04516447). Conclusions: ZN-c3, combined with CT, appears to be well-tolerated and is demonstrating clinical activity in patients with platinum-resistant or refractory ovarian, peritoneal, or fallopian tube cancer. Citation Format: Anes Pasic, Gary Richardson, Zivko Vranjes, Tarek Meniawy, Jennifer Rodriquez, Lukas Makris, Soamnauth Misir, Philippe Pultar, Dimitris Voliotis, Siqing Fu. A phase 1b dose-escalation study of ZN-c3, a WEE1 inhibitor, in combination with chemotherapy (CT) in subjects with platinum-resistant or refractory ovarian, peritoneal, or fallopian tube cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT148.

Liposomal formulations for lung cancer treatment in the last two decades: a systematic review.

Lung cancer is the leading cause of cancer mortality worldwide. To improve the therapeutic outcomes, drug delivery systems, and particularly liposomes, have been widely investigated. Therefore, this review analyzed systematically the literature to inquire about the safety and efficacy of liposomal formulations in lung cancer treatment. Three electronic databases (PubMed, Web of Science and Cochrane CENTRAL) were systematically searched until May 2020. Clinical trials containing information about the effects of liposomal formulations in lung cancer patients were considered eligible. Twenty two selected studies present different treatment options for both small and non-small-cell lung cancers. After compiling and analyzing all the published information, we verified that combination of liposomal cisplatin and paclitaxel led to a statistically significant improvement of the evaluated outcomes. Moreover, tecemotide, a liposome-based immunotherapy, demonstrated lower toxicity compared to control groups. Evidences that other subgroups could benefit from this formulation were also provided. This systematic review (registration number CRD42021246587) demonstrates that liposomal formulations are promising alternatives to overcome limitations of traditional cancer therapy. However, larger, longer, randomized and double-blinded clinical trials, selecting their patients' cohort considering more responsive subgroups would be beneficial to strengthen the scientific and clinical evidence of the results herein reported.

ROSELLA: A phase 3 study of relacorilant in combination with nab-paclitaxel versus investigator’s choice in advanced, platinum-resistant, high-grade epithelial ovarian, primary peritoneal, or fallopian-tube cancer.

TPS5620 Background: Chemotherapy resistance is a major concern in the treatment of advanced platinum-resistant and platinum-refractory ovarian cancer. One mechanism of resistance is driven by cortisol, which can suppress the apoptotic pathways that chemotherapy agents rely upon, eg, suppression of BCL2 and FOXO3a pathways. Preclinical and clinical data indicate that glucocorticoid receptor (GR) antagonism may reverse the anti-apoptotic effects of cortisol, thereby restoring the efficacy of cytotoxic agents. Relacorilant is a selective GR modulator that has shown promise in overcoming resistance when combined with taxanes (particularly nab-paclitaxel) in preclinical models (Greenstein &amp; Hunt 2021) and early-phase clinical studies (Munster et al. 2019) in various solid tumors. A randomized, controlled phase 2 study of relacorilant + nab-paclitaxel found clinically meaningful improvements in progression-free survival (PFS) and duration of response (DOR) without increased side effect burden in patients with recurrent, platinum-refractory and platinum-resistant ovarian cancer (Colombo et al. 2021). The aim of this phase 3 study is to confirm these phase 2 findings in a larger patient population. Methods: ROSELLA (EudraCT 2022-000662-18, NCT pending) is a phase 3, randomized, 2-arm, open-label, multicenter study of relacorilant + nab-paclitaxel compared to investigator’s choice of chemotherapy agents in patients with confirmed high-grade serous epithelial ovarian, primary peritoneal, or fallopian tube cancer. The trial is being conducted at multiple sites in North America and Europe and has a planned enrollment of 360 patients. Patients are randomized 1:1 to either relacorilant (150 mg the day before, day of, and day after nab-paclitaxel infusion) + nab-paclitaxel (80 mg/m2 on days 1, 8, and 15 of each 28-day cycle) or investigator’s choice of chemotherapy (liposomal doxorubicin, paclitaxel, topotecan, or nab-paclitaxel). Randomization is stratified by prior lines of therapy (1 vs &gt; 1), region of world (North America vs Europe), and prior bevacizumab (yes/no). Adult female patients with platinum-resistant disease (progression within 6 months of completion of platinum-containing therapy), excluding patients with primary platinum refractory disease, who have received 1–3 lines of prior systemic anticancer therapy and at least 1 prior line of platinum therapy are being enrolled. Life expectancy ≥3 months, adequate organ function, and ECOG performance status of 0 or 1 are required. The primary study endpoint is PFS by blinded independent central review. Key secondary endpoints include overall survival, PFS by investigator, overall response rate, best overall response, DOR, clinical benefit rate, safety, quality of life, CA-125, pharmacodynamics, and pharmacokinetics. Clinical trial information: 2022-000662-18.

ARTISTRY-7: A phase 3, multicenter study of nemvaleukin alfa in combination with pembrolizumab versus chemotherapy in patients (pts) with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer.

TPS5609 Background: ARTISTRY-7 will evaluate the novel engineered cytokine nemvaleukin alfa (nemvaleukin, ALKS 4230) in pts with gynecologic cancers. Epithelial ovarian cancer (OC) is the 7th most common cause of cancer mortality in women. OC is an area of high unmet need, as many pts become resistant or refractory to frontline platinum-based chemotherapy. Nemvaleukin was designed to selectively bind to the intermediate-affinity interleukin-2 (IL-2) receptor, preferentially activating and expanding antitumor CD8+ T and NK cells with minimal expansion of Tregs. This selectivity may provide enhanced tumor killing and improved safety/tolerability compared with high-dose IL-2. In clinical studies, nemvaleukin, as monotherapy and in combination with pembrolizumab, has shown evidence of clinical benefit in multiple tumor types, including OC. In ARTISTRY-1, 4 responses were observed in pts with OC, including 2 complete responses, 1 in a pt with platinum-resistant OC and 5 prior lines of therapy, and 2 partial responses. Methods: ARTISTRY-7 is a phase 3, multicenter, open-label randomized study of nemvaleukin and/or pembrolizumab vs chemotherapy. Eligible pts are women (≥18 y) with histologically confirmed epithelial OC (high-grade serous, endometrioid, clear cell), fallopian tube cancer, or primary peritoneal cancer. Pts must have received ≥1 prior line of systemic therapy in the platinum-sensitive setting, ≤5 prior lines in the platinum-resistant setting, and prior bevacizumab, with radiographic progression on most recent therapy. Primary platinum-refractory disease (progression on first-line platinum therapy) or primary platinum resistance (progression &lt; 3 months after completion of first-line platinum therapy) is exclusionary. Pts must have ECOG performance status of 0 or 1, estimated life expectancy of ≥3 months, and adequate hematologic reserve and hepatic and renal function. Approximately 376 pts will be randomized (3:1:1:3) to receive nemvaleukin 6 μg/kg IV on days 1-5 and pembrolizumab 200 mg IV on day 1 of each 21-day cycle, pembrolizumab monotherapy, nemvaleukin monotherapy, or chemotherapy (pegylated liposomal doxorubicin, paclitaxel, topotecan, or gemcitabine) and stratified according to PD-L1 status, histologic subtype (high-grade vs non–high-grade serous), and chemotherapy (paclitaxel vs other). Pts will continue treatment until disease progression or intolerable toxicity (maximum 35 cycles for pembrolizumab; nemvaleukin can be continued). The primary endpoint is investigator-assessed PFS (RECIST v1.1) in the nemvaleukin/pembrolizumab vs chemotherapy group. Secondary/exploratory endpoints include overall survival, other antitumor measures, safety, health-related quality of life, and pharmacokinetic/pharmacodynamic effects. Clinical trial information: NCT05092360.

Cisplatin and paclitaxel-loaded liposomes induced cervical cancer (HeLa) cell death with multiple copies of human papillomavirus by apoptosis and decreased their cytotoxic effect on non-tumor cells

In the research and development of new anticancer treatments, nanotechnology is a powerful tool in the fight against cancer. Considering that cancer is a global health problem, we co-encapsulated cisplatin (CP) and paclitaxel (PTX) in liposomes and evaluated their cytotoxicity in fibroblasts (NIH3T3) and HeLa cells containing multiple copies of human papillomavirus 18 (HeLa-HPV18). CP and PTX were successfully encapsulated into liposomes with a particle size distribution <180 nm, poly dispersion index (PDI) < 0.2, spherical morphology, high negative zeta potential, and encapsulation efficiency of 59% (CP), 88% (PTX) and 57% + 87% (CP + PTX). FTIR suggests that the drugs were successfully encapsulated in liposomes. The liposomes ensured a higher cytotoxic effect on HeLa-HPV18 cells and a smaller cytotoxic effect on NIH3T3 cells when the drugs were encapsulated. In addition, combined treatment with CP and PTX encapsulated in liposomes ensured a synergic effect between the drugs, inducing cell death by apoptosis.

Construction of gastric cancer patient-derived organoids and their utilization in a comparative study of clinically used paclitaxel nanoformulations

BackgroundGastric cancer (GC) is a highly heterogeneous disease with many different histological and molecular subtypes. Due to their reduced systemic adverse effects, nanoformulation agents have attracted increasing attention for use in the treatment of GC patients in the clinic. To improve therapeutic outcomes, it is vitally necessary to provide individual medication references and guidance for use of these nanoformulations, and patient-derived organoids (PDOs) are promising models through which to achieve this goal.ResultsUsing an improved enzymatic digestion process, we succeeded in constructing GC PDOs from surgically resected tumor tissues and endoscopic biopsies from GC patients; these PDOs closely recapitulated the histopathological and genomic features of the corresponding primary tumors. Next, we chose two representative paclitaxel (PTX) nanoformulations for comparative study and found that liposomal PTX outperformed albumin-bound PTX in killing GC PDOs at both the transcriptome and cellular levels. Our results further showed that the different distributions of liposomal PTX and albumin-bound PTX in PDOs played an essential role in the distinct mechanisms through which they kill PDOs. Finally, we constructed patient-derived xenografts model in which we verified the above distinct therapeutic outcomes via an intratumoral administration route.ConclusionsThis study demonstrates that GC PDOs are reliable tools for predicting nanoformulation efficacy.Graphical

Interpatient Heterogeneity in Drug Response and Protein Biomarker Expression of Recurrent Ovarian Cancer.

Simple SummaryRecurrent ovarian-cancer patients face low 5-year survival rates despite chemotherapy. Oncologists may choose from a variety of guideline-recommended second-line therapeutic options without knowing which one works best. Thus, therapy alterations and adjustments are often required. We analyzed the response that 30 tumor lesions had to certain treatments in our patient-derived ovarian-cancer spheroid model. In addition, we characterized samples by immunohistochemical staining for new druggable molecular targets. Our results might help in tailoring future therapies for individual patients with recurrent ovarian cancer.Recurrent ovarian-cancer patients face low 5-year survival rates despite chemotherapy. A variety of guideline-recommended second-line therapies are available, but they frequently result in trial-and-error treatment. Alterations and adjustments are common in the treatment of recurrent ovarian cancer. The drug response of 30 lesions obtained from 22 relapsed ovarian cancer patients to different chemotherapeutic and molecular agents was analyzed with the patient-derived ovarian-cancer spheroid model. The profile of druggable biomarkers was immunohistochemically assessed. The second-line combination therapy of carboplatin with gemcitabine was significantly superior to the combination of carboplatin with PEGylated liposomal doxorubicin (p < 0.0001) or paclitaxel (p = 0.0007). Except for treosulfan, all nonplatinum treatments tested showed a lesser effect on tumor spheroids compared to that of platinum-based therapies. Treosulfan showed the highest efficacy of all nonplatinum agents, with significant advantage over vinorelbine (p < 0.0001) and topotecan (p < 0.0001), the next best agents. The comparative testing of a variety of treatment options in the ovarian-cancer spheroid model resulted in the identification of more effective regimens for 30% of patients compared to guideline-recommended therapies. Recurrent cancers obtained from different patients revealed profound interpatient heterogeneity in the expression pattern of druggable protein biomarkers. In contrast, different lesions obtained from the same patient revealed a similar drug response and biomarker expression profile. Biological heterogeneity observed in recurrent ovarian cancers might explain the strong differences in the clinical drug response of these patients. Preclinical drug testing and biomarker profiling in the ovarian-cancer spheroid model might help in optimizing treatment management for individual patients.

The Basic Study of Liposome in Temperature-Sensitive Gel at Body Temperature for Treatment of Peritoneal Dissemination

Peritoneal dissemination is a disease that is difficult to treat surgically because it is widely scattered and proliferates in the abdominal cavity. It is a challenge that even if the drug is administered directly into the abdominal cavity, it rapidly disappears from the abdominal cavity, and the therapeutic effect is not optimal, as expected. In this study, for a liposomal paclitaxel in temperature-sensitive gel that is a suspension before administration and a gel after intraperitoneal administration, the antitumor effect of this formulation was evaluated. Temperature-sensitive gels were prepared using methylcellulose, sodium citrate, and macrogol 4000 and mixed with liposomal paclitaxel. Liposomal paclitaxel containing temperature-sensitive gel in the body was administered into the peritoneal cavity of a mouse model of peritoneal dissemination; the number of cells was significantly reduced compared to a paclitaxel solution of liposomal paclitaxel. These results showed that the liposome in temperature-sensitive gel inhibited cell proliferation in the abdominal cavity. This formulation can be administered easily at room temperature, and it gels and remains in the abdominal cavity for a long period, resulting in a more substantial effect than the existing drug.

Nanoparticle albumin-bound paclitaxel is superior to liposomal paclitaxel in the neoadjuvant treatment of breast cancer.

Aim: The present study aimed to retrospectively compare the efficacy and safety between liposomal paclitaxel (Lps-P) and nanoparticle albumin-bound paclitaxel (Nab-P) in neoadjuvant systemic treatment (NST) of breast cancer. Materials & methods: Two hundred thirty-five patients who were diagnosed with invasive breast cancer and then received dose-dense NST with epirubicin and cyclophosphamide followed by paclitaxel were enrolled. Results: Nab-P has an advantage in improving the total and axillary-only pathologic complete response rate over Lps-P. Although Nab-P can cause a higher incidence and severity of peripheral sensory neuropathy (PSN), most symptoms are temporary and reversible. In the Lps-P group, the proportion of patients with residual irreversible PSN is larger. Conclusion: Nab-P might be superior to Lps-P in NST of breast cancer.

Tumor-permeable smart liposomes by modulating the tumor microenvironment to improve the chemotherapy

Low levels of accumulation and permeability in tumors are two primary reasons for the limited efficacy of conventional antineoplastic nanodrugs. In the present study, based on an original corosolic acid liposome (CALP) carrier with the functions of cell penetration, tumor permeability and anti-inflammation developed by our previous work, a versatile PTX/CALP was achieved by CALP loading paclitaxel (PTX). Compared to conventional PTX liposomes (PTX/LP) prepared by cholesterol and phospholipid, PTX/CALP exhibited extremely increasing cellular uptake and cytotoxicity in vitro, and in vivo enhancing the accumulation and permeability of tumor, thus significantly improving the antitumor efficacy. Further evidence indicated that PTX/CALP conspicuously promoted the recruitment of CD8+ T cells as well as reduced the infiltration of regulatory T cells and M2 macrophages into tumor by inducing enhanced immunogenic cell death (ICD) and down-regulating the inflammation level. Therefore, the improvement of efficacy was also attributed to the superiorities of PTX/CALP in modulating the inflammatory and immunosuppressive tumor microenvironment. Overall, the smart PTX liposomes based on the multi-functional CALP carrier without any modification could overcome the harsh tumor biological barriers, enhance the induction of ICD and then achieve satisfactory efficacy, suggesting its promising potentials in industrial transfer and clinical application.

Neoadjuvant chemotherapy with liposomal paclitaxel plus platinum for locally advanced esophageal squamous cell cancer: Results from a retrospective study.

BackgroundThis study analyzed the efficacy and safety of neoadjuvant chemotherapy with liposomal paclitaxel plus platinum in patients with locally advanced resectable esophageal squamous cell carcinoma (ESCC).MethodsThe data of patients with locally advanced resectable ESCC (staging cT2N + M0, cT3‐4aNanyM0, IA‐IVA) who received preoperative chemotherapy with liposomal paclitaxel plus platinum (cisplatin, nedaplatin or carboplatin) in HuanXing Cancer Hospital from July 2018 to October 2019 were collected. The primary endpoint of this study was R0 resection rate, and secondary endpoints were pathological complete response (pCR) rate, 1‐ and 2‐year overall survival (OS) rate, 1‐year and 18‐month disease‐free survival (DFS) rate, and safety.ResultsA total of 32 eligible patients were included in this study. All patients received neoadjuvant chemotherapy and surgery. The R0 resection rate was 93.8%, the pCR rate was 12.5%, and down‐staging was achieved in 14 patients (47.8%). Median follow‐up was 31.0 months (95% confidence interval [CI] 30.1–31.9 months). The 1‐ and 2‐year OS rates were 96.9% and 78.1%, and the 1‐year and 18‐month DFS rates were 86.7% and 76.7%, respectively. The median DFS and OS were not reached. The incidence rate of neoadjuvant chemotherapy related grade 3–4 adverse events was 21.9%, including neutropenia (21.9%) and leukopenia (9.4%).ConclusionsThe results of this study suggest that liposomal paclitaxel combined with platinum as neoadjuvant chemotherapy can provide satisfactory R0 resection rate and survival rate, and significant tumor down‐staging effect for patients with locally advanced resectable ESCC, with safety profile.

Engineering Lipusu with lysophosphatidylcholine for improved tumor cellular uptake and anticancer efficacy.

Liposomes have been developed as drug delivery carriers to enhance the antitumor efficiency of therapeutic agents. Lipusu® (Lip), a paclitaxel (PTX) liposome, has been widely used in the treatment of breast cancer. Compared with PTX, Lip could change the biodistribution and reduce the systemic toxicity. However, there was no positive effect on the entry of PTX into tumor cells, and thus the therapeutic effect was not significantly improved. Therefore, it is meaningful to engineer Lip for improving tumor cellular uptake efficiency. Here, lysophosphatidylcholine (LPC)-engineered Lip (LPC-Lip) was constructed via inserting single chain lipid tails into liposomal lipid bilayers, which was realized by simple incubation. Compared with Lip, the better cellular uptake of liposomes modified with LPC resulted in enhanced cytotoxic activity of LPC-Lip in 4T1 cells. Furthermore, stronger tumor growth inhibition was observed in LPC-Lip treated 4T1 tumor-bearing mice without significant side effects. In conclusion, by modulating the lipid composition of Lip, the antitumor efficacy can be improved, and LPC engineered Lip may serve as a promising formulation of PTX for future cancer therapy.

S1‐Guideline Cutaneous Angiosarcomas – Update 2021

S1‐Guideline Cutaneous Angiosarcomas – Update 2021