Ascierto PA, Del Vecchio M, Mandalá M et al. Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. 2020;21:1465–77.
Bentebibel S-E, Hurwitz ME, Bernatchez C et al. A first-in-human study and biomarker analysis of NKTR-214, a novel IL2rβγ-biased cytokine, in patients with advanced or metastatic solid tumors. Cancer Discov 2019;9:711–21.
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Harnessing therapy resistant tumor microenvironment with lipid nanoparticles carrying miR-199b-5p and miR-204-5p to potentiate MAPKi in BRAF-mutant metastatic melanoma
Luigi Fattore1, V. Campani2, E. Marra3, G. Cafaro4, D. Liguoro5, C.F. Ruggiero6, V. Castaldo5, L. Aurisicchio3, P.A. Ascierto6, G. De Rosa2, R. Mancini5, G. Ciliberto7
1Department of Research, Advanced Diagnostics and Technological Innovation, Translational Research Area, IRCCS Regina Elena National Cancer Institute, Rome, Italy; 2 Department of Pharmacy, University of Naples Federico II, Naples, Italy; 3 Takis s.r.l., Rome, Italy; 4 Preclinical Models and New Therapeutic Agents Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy; 5 Department of Molecular and Clinical Medicine, University of Roma “Sapienza”, Rome, Italy; 6 Istituto Nazionale Tumori IRCCS, "Fondazione G. Pascale", Naples, Italy; 7 Scientific Directorate, IRCSS Regina Elena National Cancer Institute, Rome, Italy
Correspondence: Luigi Fattore (Email address: email@example.com)
Journal of Translational Medicine 2022; 20(1): 2
Background: The efficacy of BRAF + MEK inhibitors for melanoma patients harboring BRAF mutations is limited by drug resistance; from here, the need to identify additional therapeutic approaches. Towards this goal, our group has demonstrated that microRNAs act as facilitators or antagonists of this phenomenon. This has both diagnostic and therapeutic implications; here, we have addressed the latters. Our nanotechnology approach, aimed to overcome the biopharmaceutical issues of the use of miRNAs in therapy, i.e. their rapid degradation in bloodstream and the poor intracellular uptake, has been to use lipid nanoparticles (LNPs) carrying the oncosuppressive miR-204-5p and miR-199b-5p for in vitro and in vivo efficacy studies.
Material and Methods: BRAF-mutant melanoma cell lines, namely M14 and A375, and their MAPKi-resistant counterparts have been subjected to: a) RNA-seq experiments and b) treatments using LNPs carrying miR-204-5p and miR-199b-5p. Gene Set Enrichment Analysis (GSEA) has been interrogated to identify the molecular pathways/genes affected by these miRNAs. Elisa assays have been used to assess the levels of cytokines in media coming from LNP-treated or not MAPKi-resistant cells. CD1 nude mice have been injected with M14 and A375 cells and treated with BRAFi + MEKi in the presence or not of LNPs to assess the efficacy of these combinatorial regimens.
Results: Starting from RNA-seq of two BRAF-mutant melanoma models rendered resistant to MAPKi in vitro implemented with GSEA bioinformatics analyses, we identified the molecular pathways/genes affected by oncosuppressive miR-204-5p and miR-199b-5p. They mostly rewire the alteration of cytokines and chemokines responsible for EMT, hypoxia and extracellular matrix degradation. In particular, we have demonstrated that VEGFa, TGFb1, CCL5 and CXCL2 are aberrantly released by drug resistant melanoma cells and their levels are restored upon LNP stimulation in vitro. According to the capability of these soluble factors to reprogram microenvironment responsible for tumor progression and therapy failure, we observed that cell media coming from resistant cells is able to trigger the migration and polarization of macrophages toward a pro-tumoral M2-type phenotype. Again, this phenomenon was strongly impaired by LNP treatments. Finally, using mouse models xenografted with M14 and A375 cells, we have demonstrated that LNPs carrying miR-204-5p and miR-199b-5p are able to reduce tumor growth as single agents and better when combined with MAPKi.
Conclusions: To our knowledge this is the first study combining LNPs carrying oncosuppressive miRNAs with target therapy in cancer and pave the way to propose them as a novel therapeutic option for BRAF-mutant melanoma patients.
Nemvaleukin alfa (ALKS 4230) monotherapy in patients with advanced melanoma: ARTISTRY-1
Karl Lewis1, Valentina Boni2,3†, Emiliano Calvo3, Olivier Dumas4, David F. McDermott5, Sang Joon Shin6, Yan Wang7, Yangchun Du7, Lei Sun7, Monali Desai7, Carlos Mayo7, Julie R. Graham7*, Ira Winer8, Piotr Tomczak9
1Department of Medicine, University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA; 2NEXT Oncology Madrid, Hospital Universitario Quirónsalud Madrid, Madrid, Spain; 3START Madrid-CIOCC, Centro Integral Oncológico Clara Campal, Madrid, Spain; 4CHU de Québec-Université Laval, Québec City, QC, Canada; 5Beth Israel Deaconess Medical Center, Boston, MA, USA; 6Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea; 7Alkermes, Inc., Waltham, MA, USA; 8Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA; 9Centrum Medyczne Pratia, Poznan, Poland; †At time of study
Correspondence: Juie R. Graham (Email address: Julie.Graham@Alkermes.com)
Journal of Translational Medicine 2022; 20(1): 3
Background: Despite recent melanoma treatment advances, mucosal melanoma remains particularly difficult to treat with response rates to frontline checkpoint inhibitor (CPI) monotherapy and progression-free survival times of < 10% and ~ 3 months, which are approximately half the figures for cutaneous melanoma. Responses are even worse in CPI-experienced patients. Nemvaleukin alfa (nemvaleukin) is a novel engineered cytokine that selectively binds to the intermediate-affinity IL-2 receptor, preferentially activating and expanding antitumor CD8+ T and NK cells, with minimal expansion of Tregs. Nemvaleukin is being evaluated for treatment of advanced solid tumors, including melanoma, in ARTISTRY-1 (NCT02799095).
Materials and methods: Eligible patients with advanced melanoma (cutaneous, mucosal, uveal, acral) previously treated with a CPI were enrolled into a melanoma-specific cohort of ARTISTRY-1 Part B. Intravenous nemvaleukin (6 µg/kg) was administered for 5 days every cycle (14 days, cycle 1; 21 days, cycle 2 +). If patients had disease progression (after ≥ 2 cycles) or stable disease (after ≥ 4 cycles), they could enroll into Part C to receive nemvaleukin and pembrolizumab. Outcomes presented include antitumor activity (RECIST v1.1), pharmacodynamics, and safety as of August 2021.
Results: Forty-seven patients, all CPI-experienced, with advanced melanoma received nemvaleukin in Part B (≤ 28 cycles). Median age was 66 years (range, 37–80); median prior lines of therapy was 3 (range, 1–6). Of 46 evaluable patients, 33 had stable disease. Partial responses were observed in 4 patients, 2 (1 confirmed) of 6 with mucosal melanoma and 2 (1 confirmed) of 40 with cutaneous melanoma. Nemvaleukin induced robust expansion of CD8+ T and NK cells, with minimal effect on Tregs. Treatment-emergent adverse events (AEs) (> 45%), regardless of causality, were pyrexia (66.0%) and nausea (51.1%). Grade ≥ 3 nemvaleukin-related AEs (> 10%) were neutropenia (40.4%) and decreased neutrophil count (17.0%). There were no deaths due to AEs. Three patients had AEs resulting in discontinuation: intestinal obstruction and failure to thrive (both unrelated to treatment) and confusion (related to treatment). Thirteen patients continue monotherapy (Part B) and 22 rolled over to Part C (combination therapy). Of 12 evaluable patients receiving combination therapy, 6 had stable disease, 3 of whom had progression on monotherapy. No additional safety signals were observed.
Conclusions: Nemvaleukin was well tolerated and provided evidence of antitumor activity in CPI-experienced patients with advanced melanoma. The US FDA granted nemvaleukin Orphan Drug and Fast Track designations for mucosal melanoma. A phase 2 study (ARTISTRY-6) is evaluating nemvaleukin in advanced mucosal or cutaneous melanoma.
Trial Registration: ClinicalTrials.gov NCT02799095.
Funding: This study is funded by Alkermes, Inc.
Acknowledgments: The authors would like to thank all the patients who are participating in this study and their families. The study is sponsored by Alkermes, Inc. Medical writing and editorial support was provided by Jennifer Klem, PhD, Parexel International, and funded by Alkermes, Inc.
Clinical feasibility and treatment outcomes with unselected autologous tumor-infiltrating lymphocyte therapy in patients with advanced cutaneous melanoma
Robert E Hawkins,1,2,3* Yizhou Jiang,1 Paul C Lorigan,2 Fiona C Thistlethwaite,2,3 Manon Pillai,2 Martine Thomas,1 Natalia Kirillova,1 John S Bridgeman,1 Gray Kueberuwa,1 Ryan D Guest,1 Zachary J Roberts1
1Instil Bio, Inc., Dallas, TX, USA; 2Department of Medical Oncology, The Christie, NHS Foundation Trust, Manchester, United Kingdom; 3Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom
Correspondence: Robert Hawkins (Email address: Robert.Hawkins@instilbio.com)
Journal of Translational Medicine 2022; 20(1): 4
Background: Patients with advanced melanoma who relapse following immune checkpoint inhibition or targeted therapy have limited treatment options and poor outcomes. The intrinsic antitumor activity and broad T-cell receptor repertoire of unselected autologous tumor-infiltrating lymphocytes (TILs) may provide advantages over other treatments in solid tumors, including checkpoint inhibitor–refractory melanoma.
Material and methods: This is a retrospective analysis of a single-center experience of TILs for patients with advanced cutaneous melanoma and no standard of care treatment options. Unselected autologous TILs derived from digested tumors were manufactured under a Medicines and Healthcare Products Regulatory Agency Manufacturing Specials license. Patients received lymphodepleting chemotherapy (cyclophosphamide, fludarabine [Cy/Flu]), followed by TIL infusion and post-TIL high-dose IL-2 on a compassionate use basis. Efficacy was investigator assessed by CT/MRI for 15 patients per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (RECIST-evaluable group); 6 additional patients were followed using standard imaging techniques (e.g., CT, PET) and clinical monitoring but did not have quantitative tumor burden measurements (non-RECIST–evaluable group). Clinically significant adverse events (AEs) post-TIL infusion were reported. Data cutoff was December 31, 2019.
Results:: Between October 2011 and August 2019, 21 patients were treated with Cy/Flu, TILs, and high-dose IL-2. All patients had high-risk metastatic disease—33% had stage IV M1d, the median number of disease sites was 4, and patients received an average of 3 prior therapies (any checkpoint inhibitor, 91%; PD-1 inhibitor [PD-1i], 57%; BRAFi, 52%; MEKi, 24%). With a median follow-up of 52.2 months, the overall response rate in RECIST-evaluable patients (n = 15) was 53% (complete response rate, 13%); the disease control rate was 73%. Additional durable responses were observed in the non-RECIST–evaluable group (n = 6). Responses were generally consistent across subgroups, including age, number of disease sites, tumor burden, brain metastases, number of prior therapies, and prior PD-1i, BRAFi, and MEKi. For all treated patients, the median overall survival was 21.3 months. AEs were generally self-limited and consistent with Cy/Flu and high-dose IL-2. Common any-grade AEs (≥ 30% of patients) were thrombocytopenia (62%), pyrexia (57%), and rigors (43%); no treatment-related deaths were observed.
Conclusions: The high response rate observed in this series highlights the successful bench-to-bedside application of unselected autologous TILs to address unmet medical need in advanced melanoma. Use of tumor digests as starting material for manufacturing of TILs demonstrates the feasibility of this approach. A multicenter phase 2 trial of this therapy in advanced melanoma is currently enrolling (DELTA-1; NCT05050006).
Phase 3 randomized trial comparing tebentafusp with investigator’s choice in first line metastatic uveal melanoma
Sophie Piperno-Neumann1, Jessica C. Hassel2, Piotr Rutkowski3*, Jean-Francois Baurain4, Marcus O. Butler5, Max Schlaak6, Ryan J. Sullivan7, Sebastian Ochsenreither8, Reinhard Dummer9, John M. Kirkwood10, Anthony, M. Joshua11, Joseph J. Sacco12, Alexander N. Shoushtari13, Marlana Orloff14, Richard D. Carvajal15, Omid Hamid16, Shaad E. Abdullah17, Chris Holland17, Howard Goodall17, Paul Nathan18
1Institut Curie, Paris, France; 2University Hospital Heidelberg, Heidelberg, Germany; 3Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland; 4Medical Oncology Department, King Albert II Cancer Institute, Cliniques Universitaires Saint-Luc, Brussels, Belgium; 5Princess Margaret Cancer Centre, Toronto, ON, Canada; 6Department of Dermatology and Allergy, University Hospital, Munich, Germany; 7Massachusetts General Hospital, Boston, MA, United States; 8Charité-Universitätsmedizin Berlin, Berlin, Germany; 9University Hospital of Zürich, Zurich, Switzerland; 10University of Pittsburgh Medical Center, Pittsburgh, PA, United States; 11Saint Vincent's Hospital, Sydney, Australia; 12The Clatterbridge Cancer Centre, Wirral, United Kingdom; 13Memorial Sloan-Kettering Cancer Center, New York, NY, United States; 14Thomas Jefferson University Hospitals, Philadelphia, PA, United States; 15Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, United States; 16The Angeles Clinic and Research Institute, A Cedars Sinai Affiliate, Los Angeles, CA, United States; 17Immunocore Ltd, Abingdon, United Kingdom; 18Mount Vernon Cancer Centre, Northwood, United Kingdom
Correspondence: Piotr Rutkowski (Email address: Piotr.Rutkowski@pib-nio.pl)
Journal of Translational Medicine 2022; 20(1): 5
Background: Metastatic uveal melanoma (mUM) has a poor prognosis with a 1-yr OS rate of 52%. No systemic treatment has proven an OS benefit in randomized trials. Tebentafusp (tebe), a bispecific consisting of an affinity-enhanced T cell receptor fused to an anti-CD3 effector that can redirect T cells to target gp100 + cells, has shown promising activity in previously treated mUM pts. Here, we report the primary analysis of overall survival (OS) in the intention-to-treat population (ITT) of a Ph3 trial of tebe vs. investigator’s choice (IC) as first line (1L) therapy in pts with mUM [NCT03070392].
Material and methods: In this randomized, open-label, Ph3 trial, 1L HLA-A*02:01 + pts with mUM were randomized 2:1 to receive tebe or IC of pembrolizumab, ipilimumab or dacarbazine, stratified by LDH. The primary endpoint was OS, defined as the time from randomization to death from any cause. Dual primary objectives were to evaluate 1) OS in the ITT population by comparing all tebe-randomized pts to all IC-randomized pts; and 2) OS in tebentafusp-treated patients with rash during week 1 versus all IC-treated patients. Secondary endpoints included safety and RECIST-defined overall response rate, progression free survival and disease control rate. Here we present the OS in the ITT population. The study was unblinded by an independent data monitoring committee at the first pre-specified interim analysis. This analysis was conducted on the first interim analysis (data extracted Nov 2020).
Results: 378 pts were randomized to tebe (252) or IC, including pembrolizumab (103), ipilimumab (15) or dacarbazine (7). Tebe significantly prolonged OS compared to IC (HR 0.51; 95% CI 0.36–0.71; P < 0.0001) in the ITT population, with estimated 1-yr OS rate of 73.2% (95% CI 66.3–78.9) vs 57.5% (95% CI 47.0–66.6), respectively.
Most common TRAEs were skin-related (gp100+ melanocytes) or cytokine-mediated (T cell activation) and included pyrexia, pruritus, and rash. These AEs decreased in frequency and severity after initial 3-4 doses and were generally manageable with standard interventions. In the tebe arm, the rate of treatment discontinuation due to TRAEs was low (<4%), and there were no treatment-related deaths.
Conclusions: In 1L treatment of mUM pts, tebe monotherapy significantly improved OS compared to IC; the first investigational therapy to improve OS in pts with mUM. Tebe had a predictable and manageable AE profile with a low rate of related discontinuation. Tebe is the first TCR therapeutic to demonstrate an OS benefit.
Trial registration: NCT03070392.
©AACR. Original forum for presentation; Piperno-Neumann S, Hassel JC, Rutkowski P, et al. Abstract CT002: Phase 3 randomized trial comparing tebentafusp with investigator's choice in first line metastatic uveal melanoma. Cancer Res July 1 2021 (81) (13 Supplement) CT002; https://doi.org/10.1158/1538-7445.AM2021-CT002
Mechanistic insights into the role of B cells in radioiodine therapy of differentiated thyroid cancer associated with type 2 diabetes mellitus
Adina E Stanciu1,*, Madalina Bolovan1, Anca Zamfirescu2, Marcel M Stanciu3, Marieta E Panait4
1Department of Carcinogenesis and Molecular Biology, Institute of Oncology” Prof.Dr.Alex.Trestioreanu” Bucharest, Romania; 2Department of Radionuclide Terapy, Institute of Oncology” Prof.Dr.Alex.Trestioreanu” Bucharest, Romania; 3University Politehnica of Bucharest, omania; 4Department of Cancer Biology, Institute of Oncology” Prof. Dr. Alex.Trestioreanu” Bucharest, Romania
Correspondence: Adina E. Stanciu (Email address: firstname.lastname@example.org)
Journal of Translational Medicine 2022; 20(1): 6
Background: The prevalence of type 2 diabetes mellitus (T2DM) is significantly increased in women with differentiated thyroid cancer (DTC) and influences overall survival. T2DM is characterized by a progressive status of chronic, low-grade inflammation with an altered number and function of immune cells, both innate and acquired immunity . Tumor necrosis factor receptor 2 (TNFR2) expression is linked to tolerogenic immune reactions and cells with suppressor function, including a subset of T-regulatory cells . Ablative radiotherapy dramatically increases T-cell priming in draining lymphoid tissues, leading to reduction/eradication of the primary tumor or distant metastasis in a CD8 + T cell-dependent fashion . We hypothesized that B cells play a key role in controlling the T-cell responses to radioiodine (131I) therapy in patients with DTC and DTC associated with T2DM (DTC + T2DM). Our study aimed to evaluate the effects of 131I on TNFR2 and B cells in DTC and DTC + T2DM patients.
Material and Methods: Peripheral blood was collected from 42 female patients with DTC (mean age 44.6 ± 10.7 years) and 16 with DTC + T2DM (mean age 50.1 ± 9.8 years) before and 4 days after the I-131 administration (3.7 GBq). The distribution of circulating lymphocyte subpopulations was measured by flow cytometry and the serum levels of TNFR2 by ELISA. A dose calibrator was used to measure blood activity with a microcurie accuracy.
Results: Radioactivity of the blood samples was higher in DTC + T2DM patients than in those without T2DM (P < 0.001). Increased radioactivity of blood collected 4 days after the same dose of 131I /patient intake indicates a low 131I uptake in the DTC + T2DM group. In the presence of T2DM, 131I led to an increase in the serum TNFR2 concentration (P = 0.01), CD19 + B-lymphocytes (P = 0.03), and a reduction in CD8 + T-cells count number (P = 0.02). In contrast, in DTC patients, 131I therapy resulted in enhanced anti-tumor immunity mediated by CD8 + T-cells (P = 0.04) by inhibiting TNFR2.
Conclusions: The therapeutic efficacy of targeted radionuclide therapy with high-dose depends on the presence of CD8 + T cells both before and after 131I intake. Our results suggest that proliferation of CD8 + T cells after 131I is reduced in the presence of TNFR2 and CD-19 + B cells in DTC + T2DM.
Funding Acknowledgement: This work was supported by a grant from the Romanian Ministry of Education and Research, CCCDI—UEFISCDI, project number PN-III-P2-2.1-PED-2019–3313, within PNCDI III.