Clinical Cancer Research

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ISSN / EISSN : 1078-0432 / 1557-3265
Total articles ≅ 20,246
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Chang Gon Kim, Nam Suk Sim, , Kum-Hee Yun, , Seung Hyun Kim, Wooyeol Baek, , Sang Kyum Kim, , et al.
Abstract:
Purpose: Monotherapy with eribulin or gemcitabine has been found to be moderately effective in treating soft-tissue sarcomas (STS). In this study, we evaluated the efficacy and safety of eribulin-gemcitabine combination therapy for the two most common histologic types of STS, liposarcoma and leiomyosarcoma. Patients and methods: In this non-randomized, multicenter, phase II study, we included patients with progressive disease who had received one or two courses of chemotherapy that included doxorubicin. Patients were administered 1.4 mg/m2 eribulin and 1,000 mg/m2 gemcitabine on days 1 and 8 every 3 weeks. The primary endpoint was progression-free survival rate at 12 weeks (PFSR12wks), with null and alternative hypotheses of PFSR12wks {less than or equal to}20.0% and {greater than or equal to}40.0%, respectively. Exploratory biomarker analyses with next-generation sequencing (NGS) were performed on pretreatment tumor samples. Results: Among the 37 patients included, the overall PFSR12wks was 73.0%, achieving the primary endpoint. The objective response rate, disease control rate, median progression-free survival, and median overall survival were 16.2%, 78.4%, 5.6 months, and 31.9 months, respectively, without differences according to histologic type. New safety signals and treatment-related deaths were not documented. NGS-based transcriptome analysis revealed that functional enrichment in the transforming growth factor-ß pathway was mostly associated with a poor outcome, whereas single genetic alterations largely failed to predict treatment outcome. Conclusions: Eribulin-gemcitabine combination therapy showed promising activity and an acceptable safety profile in patients with liposarcoma or leiomyosarcoma. Gene expression profiling with pathway enrichment analysis would have possibilities to have predictive value for survival outcome, necessitating further investigation to confirm.
Chiara Monfrini, Federico Stella, Vanessa Aragona, Martina Magni, Silva Ljevar, Cristina Vella, Eugenio Fardella, Annalisa Chiappella, Francesca Nanetti, Martina Pennisi, et al.
Abstract:
Background: In clinical trials, the expansion and persistence of CAR-T cells correlate with therapeutic efficacy. However, properties of CAR-T cells that enable their in vivo proliferation have still to be consistently defined and the role of CAR-T bag content has never been investigated in a real life setting. Experimental Design: Residual cells obtained after washing 61 anti-CD19 CAR-T product bags were analysed to identify tisagenlecleucel/Tisa-cel and axicabtagene ciloleucel/Axi-cel phenotypic features associated with post-infusion CAR-T cell in vivo expansion and with response and survival. Results: While Tisa-cel was characterized by a significant enrichment in CAR+CD4+ T cells with central memory (P<0.005) and effector (P<0.005) phenotypes and lower rates of CAR+CD8+ with effector memory (P<0.005) and naive-like (P<0.05) phenotypes as compared to Axi-cel, the two products displayed similar expansion kinetics. In vivo CAR-T cell expansion was influenced by the presence of CAR-T with a CD8+ T central memory signature (P<0.005) in both Tisa-cel and Axi-cel infusion products and was positively associated with response and progression-free survival (P<0.05). Conclusions: Our data indicate that despite the great heterogeneity of Tisa-cel and Axi-cel products, the differentiation status of the infused cells mediates CAR-T cell in vivo proliferation that is necessary for anti tumor response.
, Tharu M. Fernando, Rebecca Bowen, Katarzyna J. Jerzak, Xinni Song, , Frances Boyle, Steven McCune, Anne Armstrong, Catherine Shannon, et al.
Abstract:
Purpose: Despite promising activity in hematopoietic malignancies, efficacy of the B-cell lymphoma 2 (BCL) inhibitor venetoclax in solid tumors is unknown. We report the prespecified VERONICA primary results, a randomized phase 2 clinical trial evaluating venetoclax and fulvestrant in estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer, post-cyclin-dependent kinase (CDK) 4/6 inhibitor progression. Patients and Methods: Pre-/postmenopausal females {greater than or equal to}18 years were randomized 1:1 to venetoclax (800 mg oral daily) plus fulvestrant (500 mg intramuscular; Cycle 1: Days 1 and 15; subsequent 28-day cycles: Day 1) or fulvestrant alone. The primary endpoint was clinical benefit rate (CBR); secondary endpoints: progression-free survival (PFS), overall survival, and safety. Exploratory biomarker analyses included BCL2 and BCL extra-large (BCLXL) tumor expression, and PIK3CA ctDNA mutational status. Results: At primary analysis (cutoff: August 5, 2020; n = 103), venetoclax did not significantly improve CBR (venetoclax plus fulvestrant: 11.8% [n = 6/51; 95% confidence interval (CI): 4.44-23.87]; fulvestrant: 13.7% [7/51; 5.70-26.26]; risk difference -1.96% [95% CI: -16.86-12.94]). Median PFS was 2.69 months (95% CI: 1.94-3.71) with venetoclax plus fulvestrant versus 1.94 months (1.84-3.55) with fulvestrant (stratified hazard ratio 0.94 [95% CI: 0.61-1.45]; P = 0.7853). Overall survival data were not mature. A non-significant improvement of CBR and PFS was observed in patients whose tumors had strong BCL2 expression (immunohistochemistry 3+), a BCL2/BCLXL Histoscore ratio {greater than or equal to}1, or PIK3CA-wildtype status. Conclusions: Our findings do not indicate clinical utility for venetoclax plus fulvestrant in endocrine therapy-resistant, CDK4/6 inhibitor-refractory metastatic breast tumors, but suggest possible increased dependence on BCLXL in this setting.
Wout De. Mey, , Kris Thielemans, ,
Abstract:
Recent advances in the manufacturing, modification, purification and cellular delivery of ribonucleic acid (RNA) have enabled the development of RNA-based therapeutics for a broad array of applications. The approval of two SARS-CoV-2-targeting mRNA-based vaccines has highlighted the advances of this technology. Offering rapid and straightforward manufacturing, clinical safety and versatility, this paves the way for RNA therapeutics to expand into cancer immunotherapy. Together with ongoing trials on RNA cancer vaccination and cellular therapy, RNA therapeutics could be introduced into clinical practice, possibly stewarding future personalized approaches. In the present review, we discuss recent advances in RNA-based immuno-oncology together with an update on ongoing clinical applications and their current challenges.
, Hsiling Chiu, Vivek S. Chopra, Martino Colombo, Nisha Patel, Maria Ortiz Estevez, Michelle F. Waldman, Remco Loos, Fadi Towfic, Anita K. Gandhi
Abstract:
Purpose: Cereblon (CRBN), a substrate receptor of the E3 ubiquitin ligase complex CRL4CRBN, is the target of the small molecules lenalidomide (Len) and avadomide (Ava). Upon binding of the drugs, Aiolos and Ikaros are recruited to the E3 ligase, ubiquitylated and subsequently degraded. In DLBCL cells, Aiolos and Ikaros are direct transcriptional repressors of interferon stimulated genes (ISG) and degradation of these substrates results in increased ISG protein levels resulting in decreased proliferation and apoptosis. Herein, we aimed to uncover the mechanism(s) Aiolos and Ikaros use to repress ISG transcription and provide a mechanistic rationale for a combination strategy enhance cell autonomous activites of CELMoDs Experimental design: We conducted paired RNAseq with histone modification and Aiolos/Ikaros ChIP-seq to identify genes regulated by these transcription factors and to elucidate correlations to drug sensitivity. We confirmed Aiolos/Ikaros mediated transcriptional complex formation in DLBCL patient samples including those treated with avadomide. Results: In DLBCL, the repression of ISG transcription is accomplished in part through recruitment of large transcriptional complexes such as the nucleosome remodeling and deacetylase (NuRD) which modify the chromatin landscape of these promoters. A rational combination approach of Ava with a specific HDAC inhibitor leads to a significant increase in ISG transcription compared to either single agent, and synergistic antiproliferative activity in DLBCL cell lines. Conclusion: Our results provide a novel role for lineage factors Aiolos and Ikaros in DLBCL as well as further insight into the mechanism(s) of Aiolos and Ikaros mediated transcriptional repression and unique therapeutic combination strategies.
, , Gini F. Fleming, , Manish R. Sharma, Joseph M. Custodio, Iulia Cristina Tudor, Hristina I. Pashova, Stacie Peacock Shepherd, Andreas Grauer, et al.
Abstract:
Purpose: Chemotherapy resistance remains a major problem in many solid tumors, including breast, ovarian, and pancreatic cancer. Glucocorticoids are one potential driver of chemotherapy resistance as they can mediate tumor progression via induction of cell-survival pathways. We investigated whether combining the selective glucocorticoid receptor modulator relacorilant with taxanes can enhance anti-tumor activity. Experimental Design: The effect of relacorilant on paclitaxel efficacy was assessed in OVCAR5 cells in vitro and in the MIA PaCa-2 xenograft. A phase 1 study of patients with advanced solid tumors was conducted to determine the recommended phase 2 dose of relacorilant + nab-paclitaxel. Results: In OVCAR5 cells, relacorilant reversed the deleterious effects of glucocorticoids on paclitaxel efficacy (P<.001). Compared to paclitaxel alone, relacorilant+paclitaxel reduced tumor growth and slowed time to progression in xenograft models (both P<.0001). In the heavily pretreated phase 1 population (median [range] of prior regimens: 3 [1-8], prior taxane in 75.3% [55/73]), 33% (19/57) of response-evaluable patients achieved durable disease control ({greater than or equal to}16 weeks) with relacorilant+nab-paclitaxel and 28.6% (12/42) experienced longer duration of benefit than on prior taxane (up to 6.4x). The most common dose-limiting toxicity of the combination was neutropenia, which was manageable with prophylactic granulocyte-colony stimulating factor. Clinical benefit with relacorilant+nab-paclitaxel was also associated with GR-regulated transcript-level changes in a panel of GR-controlled genes. Conclusions: Preclinical, clinical, and GR-specific pharmacodynamic responses observed demonstrate that selective GR modulation with relacorilant combined with nab-paclitaxel may promote chemotherapy response and is tolerable. Further evaluation of this combination in tumor types responsive to taxanes is ongoing.
John D. Martin, Ryan M. Lanning, Vikash P. Chauhan, Margaret R. Martin, Ahmed S. Mousa, Walid S. Kamoun, , Hang Lee, Triantafyllos Stylianopoulos, Moungi G. Bawendi, et al.
Abstract:
Purpose: The abnormal function of tumor blood vessels causes tissue hypoxia, promoting disease progression and treatment resistance. Although tumor microenvironment normalization strategies can alleviate hypoxia globally, how local oxygen levels change is not known because of inability to longitudinally assess vascular and interstitial oxygen in tumors with sufficient resolution. Understanding the spatial and temporal heterogeneity should help improve the outcome of various normalization strategies. Experimental Design: We developed a multiphoton phosphorescence quenching microscopy system using a low-molecular weight palladium porphyrin probe to measure perfused vessels, oxygen tension and their spatial correlations in vivo in mouse skin, bone marrow, and four different tumor models. Further, we measured the temporal and spatial changes in oxygen and vessel perfusion in tumors in response to anti-VEGFR2 antibody (DC101) and an angiotensin-receptor blocker (losartan). Results: We found that vessel function was highly dependent on tumor type. Although some tumors had vessels with greater oxygen carrying ability than those of normal skin, most tumors had inefficient vessels. Further, inter-vessel heterogeneity in tumors associated with heterogeneous response to DC101 and losartan. Using both vascular and stromal normalizing agents, we show that spatial heterogeneity in oxygen levels persist, even with reductions in mean extravascular hypoxia. Conclusions: High-resolution spatial and temporal responses of tumor vessels to two agents known to improve vascular perfusion globally reveal spatially heterogeneous changes in vessel structure and function. These dynamic vascular changes should be considered in optimizing the dose and schedule of vascular and stromal normalizing strategies to improve the therapeutic outcome.
Mingzhi Zhang, Dan Chen, Xiaorui Fu, Huimin Meng, Feifei Nan, Zhenchang Sun, Hui Yu, Lei Zhang, Ling Li, Xin Li, et al.
Abstract:
Purpose: Since CD7 may represent a potent target for T-lymphoblastic leukemia/lymphoma (T-ALL/LBL) immunotherapy, this study aimed to investigate safety and efficacy of autologous CD7–chimeric antigen receptor (CAR) T cells in patients with relapsed and refractory (R/R) T-ALL/LBL, as well as its manufacturing feasibility. Patients and Methods: Preclinical phase was conducted in NPG mice injected with Luc+ GFP+CCRF-CEM cells. Open-label phase I clinical trial (NCT04004637) enrolled patients with R/R CD7-positive T-ALL/LBL who received autologous CD7-CAR T-cell infusion. Primary endpoint was safety; secondary endpoints included efficacy and pharmacokinetic and pharmacodynamic parameters. Results: CD7 blockade strategy was developed using tandem CD7 nanobody VHH6 coupled with an endoplasmic reticulum/Golgi-retention motif peptide to intracellularly fasten CD7 molecules. In preclinical phase CD7 blockade CAR T cells prevented fratricide and exerted potent cytolytic activity, significantly relieving leukemia progression and prolonged the median survival of mice. In clinical phase, the complete remission (CR) rate was 87.5% (7/8) 3 months after CAR T-cell infusion; 1 patient with leukemia achieved minimal residual disease–negative CR and 1 patient with lymphoma achieved CR for more than 12 months. Majority of patients (87.5%) only had grade 1 or 2 cytokine release syndrome with no T-cell hypoplasia or any neurologic toxicities observed. The median maximum concentration of CAR T cells was 857.2 cells/μL at approximately 12 days and remained detectable up to 270 days. Conclusions: Autologous nanobody-derived fratricide-resistant CD7-CAR T cells demonstrated a promising and durable antitumor response in R/R T-ALL/LBL with tolerable toxicity, warranting further studies in highly aggressive CD7-positive malignancies.
, Ronald Tutrone, Christopher Pieczonka, K. Gary. Barnette, Robert H. Getzenberg, Domingo Rodriguez, Mitchell S. Steiner, Daniel R. Saltzstein, Mario A. Eisenberger, Emmanuel S. Antonarakis
Abstract:
Purpose: Sabizabulin, an oral cytoskeleton disruptor, was tested in a phase Ib/II clinical study in men with metastatic castration-resistant prostate cancer (mCRPC). Patients and Methods: The phase Ib portion utilized a 3+3 design with escalating daily oral doses of 4.5–81 mg and increasing schedule in 39 patients with mCRPC treated with one or more androgen receptor–targeting agents. Prior taxane chemotherapy was allowed. The phase II portion tested a daily dose of 63 mg in 41 patients with no prior chemotherapy. Efficacy was assessed using PCWG3 and RECIST 1.1 criteria. Results: The MTD was not defined in the phase Ib and the recommended phase II dose was set at 63 mg/day. The most common adverse events (>10% frequency) at the 63 mg oral daily dosing (combined phase Ib/II data) were predominantly grade 1–2 events. Grade ≥3 events included diarrhea (7.4%), fatigue (5.6%), and alanine aminotransferase/aspartate aminotransferase elevations (5.6% and 3.7%, respectively). Neurotoxicity and neutropenia were not observed. Preliminary efficacy data in patients treated with ≥1 continuous cycle of 63 mg or higher included objective response rate in 6 of 29 (20.7%) patients with measurable disease (1 complete, 5 partial) and 14 of 48 (29.2%) patients had PSA declines. The Kaplan–Meier median radiographic progression-free survival was estimated to be 11.4 months (n = 55). Durable responses lasting >2.75 years were observed. Conclusions: This clinical trial demonstrated that chronic oral daily dosing of sabizabulin has a favorable safety profile with preliminary antitumor activity. These data support the ongoing phase III VERACITY trial of sabizabulin in men with mCRPC.
Lawrence P. Andrews, Anthony R. Cillo, Lilit Karapetyan, , ,
Abstract:
Immunotherapy targeting co-inhibitory receptors has been highly successful in treating a wide variety of malignancies, however only a subset of patients exhibits durable responses. The first FDA-approved immunotherapeutics targeting co-inhibitory receptors PD1 and CTLA4, alone or in combination, significantly improved survival but were also accompanied by substantial toxicity in combination. The third FDA-approved immune checkpoint inhibitor targets LAG3, a co-inhibitory receptor expressed on activated CD4+ and CD8+ T cells, especially in settings of long-term antigenic stimulation, such as chronic viral infection or cancer. Mechanistically, LAG3 expression limits both the expansion of activated T cells and the size of the memory pool, suggesting that LAG3 may be a promising target for immunotherapy. Importantly, the mechanism(s) by which LAG3 contributes to CD8+ T cell exhaustion may be distinct from those governed by PD1, indicating that the combination of anti-LAG3 and anti-PD1 may synergistically enhance antitumor immunity. Clinical studies evaluating the role of anti-LAG3 in combination with anti-PD1 are underway, and recent phase III trial results in metastatic melanoma demonstrate both the efficacy and safety of this combination. Further ongoing clinical trials are evaluating this combination across multiple tumor types and the adjuvant setting, with accompanying translational and biomarker-focused studies designed to elucidate the molecular pathways that lead to improved antitumor T cell responses following dual blockade of PD1 and LAG3. Overall, LAG3 plays an important role in limiting T cell activation and has now become part of the repertoire of combinatorial immunotherapeutics available for the treatment of metastatic melanoma.
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