bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Preclinical Activity of JNJ-7957, a Novel BCMA×CD3 Bispecific Antibody for the Treatment of Multiple Myeloma, Is Potentiated by Daratumumab
Authors: Frerichs Kristine A. , Broekmans Marloes E.C. , Marin Soto Jhon A. , van Kessel Berris , Heymans Martijn W. , Holthof Lisa C. , Verkleij Christie P.M. , Boominathan Rengasamy , Vaidya Bhavesh , Sendecki Jocelyn , Axel Amy , Gaudet Francois , Pillarisetti Kodandaram , Zweegman Sonja , Adams Homer C. , Mutis Tuna , van de Donk Niels W.C.J.
Published: April 2023

AbstractPurpose:
Multiple myeloma (MM) patients with disease refractory to all available drugs have a poor outcome, indicating the need for new agents with novel mechanisms of action.
Experimental Design:
We evaluated the anti-MM activity of the fully human BCMA×CD3 bispecific antibody JNJ-7957 in cell lines and bone marrow (BM) samples. The impact of several tumor- and host-related factors on sensitivity to JNJ-7957 therapy was also evaluated.
Results:
We show that JNJ-7957 has potent activity against 4 MM cell lines, against tumor cells in 48 of 49 BM samples obtained from MM patients, and in 5 of 6 BM samples obtained from primary plasma cell leukemia patients. JNJ-7957 activity was significantly enhanced in patients with prior daratumumab treatment, which was partially due to enhanced killing capacity of daratumumab-exposed effector cells. BCMA expression did not affect activity of JNJ-7957. High T-cell frequencies and high effector:target ratios were associated with improved JNJ-7957–mediated lysis of MM cells. The PD-1/PD-L1 axis had a modest negative impact on JNJ-7957 activity against tumor cells from daratumumab-naïve MM patients. Soluble BCMA impaired the ability of JNJ-7957 to kill MM cells, although higher concentrations were able to overcome this negative effect.
Conclusions:
JNJ-7957 effectively kills MM cells ex vivo, including those from heavily pretreated MM patients, whereby several components of the immunosuppressive BM microenvironment had only modest effects on its killing capacity. Our findings support the ongoing trial with JNJ-7957 as single agent and provide the preclinical rationale for evaluating JNJ-7957 in combination with daratumumab in MM.
Data from Harmonizing Cell-Free DNA Collection and Processing Practices through Evidence-Based Guidance
Authors: Greytak Sarah R. , Engel Kelly B. , Parpart-Li Sonya , Murtaza Muhammed , Bronkhorst Abel J. , Pertile Mark D. , Moore Helen M.
Published: April 2023

Abstract
Circulating cell-free DNA (cfDNA) is rapidly transitioning from discovery research to an important tool in clinical decision making. However, the lack of harmonization of preanalytic practices across institutions may compromise the reproducibility of cfDNA-derived data and hamper advancements in cfDNA testing in the clinic. Differences in cellular genomic contamination, cfDNA yield, integrity, and fragment length have been attributed to different collection tube types and anticoagulants, processing delays and temperatures, tube agitation, centrifugation protocols and speeds, plasma storage duration and temperature, the number of freeze-thaw events, and cfDNA extraction and quantification methods, all of which can also ultimately impact subsequent downstream analysis. Thus, there is a pressing need for widely applicable standards tailored for cfDNA analysis that include all preanalytic steps from blood draw to analysis. The NCI's Biorepositories and Biospecimen Research Branch has developed cfDNA-specific guidelines that are based upon published evidence and have been vetted by a panel of internationally recognized experts in the field. The guidelines include optimal procedures as well as acceptable alternatives to facilitate the generation of evidence-based protocols by individual laboratories and institutions. The aim of the document, which is entitled “Biospecimen Evidence-based Best Practices for Cell-free DNA: Biospecimen Collection and Processing,” is to improve the accuracy of cfDNA analysis in both basic research and the clinic by improving and harmonizing practices across institutions.
Data from Adaptive Immune Resistance to Intravesical BCG in Non–Muscle Invasive Bladder Cancer: Implications for Prospective BCG-Unresponsive Trials
Authors: Kates Max , Matoso Andres , Choi Woonyoung , Baras Alexander S. , Daniels Marcus J. , Lombardo Kara , Brant Aaron , Mikkilineni Nina , McConkey David J. , Kamat Ashish M. , Svatek Robert S. , Porten Sima P. , Meeks Joshua J. , Lerner Seth P. , Dinney Colin P. , Black Peter C. , McKiernan James M. , Anderson Chris , Drake Charles G. , Bivalacqua Trinity J.
Published: April 2023

AbstractPurpose:
To characterize immune cell expression among patients with non–muscle invasive bladder cancer (NMIBC) treated with Bacillus Calmette-Guerin (BCG).
Experimental Design:
Patients with NMIBC treated with intravesical BCG (2008–2015) were identified, and a tissue microarray was constructed using paired pre- and post-BCG bladder samples. Among patients undergoing BCG, cystoscopic evaluation began 3 months after initiating BCG treatment to determine therapeutic response. IHC was performed for CD8, CD4, FoxP3, PD-L1 (SP-142 and 22C3), and PD-1. A full slide review of PD-L1+ staining tumors was performed to characterize PD-L1 and CD8 colocalization. RNA-seq was performed on cored tumors from available specimens. We compared immune cell populations between BCG responders and nonresponders, and between pretreatment and postreatment tumor samples. Baseline PD-L1 staining in the BCG naïve population was then validated in a separate cohort.
Results:
The final cohort contained 63 pretreatment NMIBC cases, including 31 BCG responders and 32 BCG nonresponders. No differences in CD4, CD8, or FoxP3 expression were identified between responders and nonresponders. Baseline PD-L1 expression (22C3 and SP-142) was observed in 25% to 28% of nonresponders and 0% to 4% of responders (P < 0.01). PD-L1+ cells in BCG nonresponders colocalized with CD8+ T cells. In addition, BCG therapy did not increase PD-L1 gene expression (RNA-seq) or protein levels (IHC). The number of pretreatment CD4+ T cells was very low among PD-L1+ nonresponders (12%) and high among PD-L1− nonresponders (50%, P < 0.01). In a separate cohort of 57 patients with NMIBC undergoing BCG, baseline PD-L1 (22C3) staining was similar (26%).
Conclusions:
One mechanism of BCG failure may be adaptive immune resistance. Baseline tumor PD-L1 expression predicts an unfavorable response to BCG and if validated, could be used to guide therapeutic decisions.
Data from PI3K Inhibitors Curtail MYC-Dependent Mutant p53 Gain-of-Function in Head and Neck Squamous Cell Carcinoma
Authors: Ganci Federica , Pulito Claudio , Valsoni Sara , Sacconi Andrea , Turco Chiara , Vahabi Mahrou , Manciocco Valentina , Mazza Emilia Maria Cristina , Meens Jalna , Karamboulas Christina , Nichols Anthony C. , Covello Renato , Pellini Raul , Spriano Giuseppe , Sanguineti Giuseppe , Muti Paola , Bicciato Silvio , Ailles Laurie , Strano Sabrina , Fontemaggi Giulia , Blandino Giovanni
Published: April 2023

AbstractPurpose:
Mutation of TP53 gene is a hallmark of head and neck squamous cell carcinoma (HNSCC) not yet exploited therapeutically. TP53 mutation frequently leads to the synthesis of mutant p53 proteins with gain-of-function activity, associated with radioresistance and high incidence of local recurrences in HNSCC.
Experimental Design:
Mutant p53–associated functions were investigated through gene set enrichment analysis in the Cancer Genome Atlas cohort of HNSCC and in a panel of 22 HNSCC cell lines. Mutant p53–dependent transcripts were analyzed in HNSCC cell line Cal27, carrying mutant p53H193L; FaDu, carrying p53R248L; and Detroit 562, carrying p53R175H. Drugs impinging on mutant p53-MYC–dependent signature were identified interrogating Connectivity Map (https://clue.io) derived from the Library of Integrated Network–based Cellular Signatures (LINCS) database (http://lincs.hms.harvard.edu/) and analyzed in HNSCC cell lines and patient-derived xenografts (PDX) models.
Results:
We identified a signature of transcripts directly controlled by gain-of-function mutant p53 protein and prognostic in HNSCC, which is highly enriched of MYC targets. Specifically, both in PDX and cell lines of HNSCC treated with the PI3Kα-selective inhibitor BYL719 (alpelisib) the downregulation of mutant p53/MYC-dependent signature correlates with response to this compound. Mechanistically, mutant p53 favors the binding of MYC to its target promoters and enhances MYC protein stability. Treatment with BYL719 disrupts the interaction of MYC, mutant p53, and YAP proteins with MYC target promoters. Of note, depletion of MYC, mutant p53, or YAP potentiates the effectiveness of BYL719 treatment.
Conclusions:
Collectively, the blocking of this transcriptional network is an important determinant for the response to BYL719 in HNSCC.
Data from Mogamulizumab in Combination with Durvalumab or Tremelimumab in Patients with Advanced Solid Tumors: A Phase I Study
Authors: Zamarin Dmitriy , Hamid Omid , Nayak-Kapoor Asha , Sahebjam Solmaz , Sznol Mario , Collaku Agron , Fox Floyd E. , Marshall Margaret A. , Hong David S.
Published: April 2023

AbstractPurpose:
The study goal was to determine safety, antitumor activity, and pharmacodynamic profile of mogamulizumab, an anti–C-C chemokine receptor 4 (anti-CCR4) mAb targeting effector regulatory T cells (eTreg), in combination with mAb checkpoint inhibitors durvalumab or tremelimumab.
Patients and Methods:
This was a multicenter, phase I, dose escalation study, followed by disease-specific cohort expansion (NCT02301130). Mogamulizumab dose escalation proceeded with concurrent dose escalation of durvalumab or tremelimumab in patients with advanced solid tumors. Cohort expansion occurred with mogamulizumab 1 mg/kg plus durvalumab 10 mg/kg or tremelimumab 10 mg/kg in patients with advanced pancreatic cancer.
Results:
Forty patients were enrolled during dose escalation, followed by 24 patients during dose expansion. No dose-limiting toxicities occurred during dose escalation. No new or unexpected toxicities were seen. Tolerability, the primary endpoint, was acceptable utilizing mogamulizumab 1 mg/kg plus durvalumab or tremelimumab 10 mg/kg in the combined dose escalation and dose expansion cohorts (each n = 19). At these doses, the objective response rate was 5.3% (95% confidence interval, 0.1%–26.0%; one partial response) with each combination treatment. At all doses, mogamulizumab treatment led to almost complete depletion of peripheral eTregs, as well as reduction of intratumoral Tregs in the majority of patients. There was no clear correlation of clinical response with peripheral or intratumoral reduction in CCR4+ eTregs or with baseline degree of CCR4+ expression.
Conclusions:
Mogamulizumab in combination with durvalumab or tremelimumab did not result in potent antitumor efficacy in patients with advanced solid tumors. Tolerability of mogamulizumab 1 mg/kg combined with durvalumab or tremelimumab 10 mg/kg was acceptable.
Data from CA-125 ELIMination Rate Constant K (KELIM) Is a Marker of Chemosensitivity in Patients with Ovarian Cancer: Results from the Phase II CHIVA Trial
Authors: You Benoit , Robelin Patrick , Tod Michel , Louvet Christophe , Lotz Jean-Pierre , Abadie-Lacourtoisie Sophie , Fabbro Michel , Desauw Christophe , Bonichon-Lamichhane Nathalie , Kurtz Jean-Emmanuel , Follana Philippe , Leheurteur Marianne , Piano Francesco Del , Ferron Gwénael , De Rauglaudre Gaëtan , Ray-Coquard Isabelle , Combe Pierre , Chevalier-Place Annick , Joly Florence , Leary Alexandra , Pujade-Lauraine Eric , Freyer Gilles , Colomban Olivier
Published: April 2023

AbstractPurpose:
In patients with ovarian cancer receiving neoadjuvant chemotherapy, the first-line treatment success will depend on both the tumor-primary chemosensitivity and the completeness of interval debulking surgery (IDS). The modeled CA-125 ELIMination rate constant K (KELIM), calculated with the CA-125 longitudinal kinetics during the first 100 chemotherapy days, is a validated early marker of tumor chemosensitivity. The objective was to investigate the role of the chemosensitivity relative to the success of first-line medical–surgical treatment.
Experimental Design:
The CA-125 concentrations were prospectively measured in the randomized phase II trial CHIVA (NCT01583322, carboplatin–paclitaxel regimen ± nintedanib, and IDS, n = 188 patients). The KELIM predictive value regarding the tumor response rate, likelihood of complete IDS, risk of subsequent platinum-resistant relapse (PtRR), progression-free survival (PFS), and overall survival (OS) was assessed using univariate and multivariate tests.
Results:
The data from 134 patients were analyzed. KELIM was an independent and major predictor of subsequent PtRR risk, and of survivals. The final logistic regression model, including KELIM [OR = 0.13; 95% confidence interval (CI), 0.03–0.49] and complete IDS (no vs. yes, OR = 0.30; 95% CI, 0.11–0.76) highlights the preponderant role of chemosensitivity on the success of the first-line treatment. In patients with highly chemosensitive diseases, the patient prognosis was driven more by the chemotherapy-induced antitumor effects than by the surgery.
Conclusions:
The tumor-primary chemosensitivity, assessed by the modeled CA-125 KELIM calculated during neoadjuvant chemotherapy (http://www.biomarker-kinetics.org/CA-125-neo), may be a major parameter to consider for decision-making regarding IDS attempt, and selecting patients for treatments meant to reverse the primary chemoresistance.

See related commentary by May and Oza, p. 4432
Data from Synthetic High-density Lipoprotein Nanodiscs for Personalized Immunotherapy Against Gliomas
Authors: Scheetz Lindsay , Kadiyala Padma , Sun Xiaoqi , Son Sejin , Hassani Najafabadi Alireza , Aikins Marisa , Lowenstein Pedro R. , Schwendeman Anna , Castro Maria G. , Moon James J.
Published: April 2023

AbstractPurpose:
Gliomas are brain tumors with dismal prognoses. The standard-of-care treatments for gliomas include surgical resection, radiation, and temozolomide administration; however, they have been ineffective in providing significant increases in median survival. Antigen-specific cancer vaccines and immune checkpoint blockade may provide promising immunotherapeutic approaches for gliomas.
Experimental Design:
We have developed immunotherapy delivery vehicles based on synthetic high-density lipoprotein (sHDL) loaded with CpG, a Toll-like receptor-9 agonist, and tumor-specific neoantigens to target gliomas and elicit immune-mediated tumor regression.
Results:
We demonstrate that vaccination with neoantigen peptide-sHDL/CpG cocktail in combination with anti–PD-L1 immune checkpoint blocker elicits robust neoantigen-specific T-cell responses against GL261 cells and eliminated established orthotopic GL261 glioma in 33% of mice. Mice remained tumor free upon tumor cell rechallenge in the contralateral hemisphere, indicating the development of immunologic memory. Moreover, in a genetically engineered murine model of orthotopic mutant IDH1 (mIDH1) glioma, sHDL vaccination with mIDH1 neoantigen eliminated glioma in 30% of animals and significantly extended the animal survival, demonstrating the versatility of our approach in multiple glioma models.
Conclusions:
Overall, our strategy provides a general roadmap for combination immunotherapy against gliomas and other cancer types.
Data from Intratumoral IL12 mRNA Therapy Promotes TH1 Transformation of the Tumor Microenvironment
Authors: Hewitt Susannah L. , Bailey Dyane , Zielinski John , Apte Ameya , Musenge Faith , Karp Russell , Burke Shannon , Garcon Fabien , Mishra Ankita , Gurumurthy Sushma , Watkins Amanda , Arnold Kristen , Moynihan James , Clancy-Thompson Eleanor , Mulgrew Kathy , Adjei Grace , Deschler Katharina , Potz Darren , Moody Gordon , Leinster David A. , Novick Steve , Sulikowski Michal , Bagnall Chris , Martin Philip , Lapointe Jean-Martin , Si Han , Morehouse Chris , Sedic Maja , Wilkinson Robert W. , Herbst Ronald , Frederick Joshua P. , Luheshi Nadia
Published: April 2023

AbstractPurpose:
While immune checkpoint inhibitors such as anti–PD-L1 are rapidly becoming the standard of care in the treatment of many cancers, only a subset of treated patients have long-term responses. IL12 promotes antitumor immunity in mouse models; however, systemic recombinant IL12 had significant toxicity and limited efficacy in early clinical trials.
Experimental Design:
We therefore designed a novel intratumoral IL12 mRNA therapy to promote local IL12 tumor production while mitigating systemic effects.
Results:
A single intratumoral dose of mouse (m)IL12 mRNA induced IFNγ and CD8+ T-cell–dependent tumor regression in multiple syngeneic mouse models, and animals with a complete response demonstrated immunity to rechallenge. Antitumor activity of mIL12 mRNA did not require NK and NKT cells. mIL12 mRNA antitumor activity correlated with TH1 tumor microenvironment (TME) transformation. In a PD-L1 blockade monotherapy-resistant model, antitumor immunity induced by mIL12 mRNA was enhanced by anti–PD-L1. mIL12 mRNA also drove regression of uninjected distal lesions, and anti–PD-L1 potentiated this response. Importantly, intratumoral delivery of mRNA encoding membrane-tethered mIL12 also drove rejection of uninjected lesions with very limited circulating IL12p70, supporting the hypothesis that local IL12 could induce a systemic antitumor immune response against distal lesions. Furthermore, in ex vivo patient tumor slice cultures, human IL12 mRNA (MEDI1191) induced dose-dependent IL12 production, downstream IFNγ expression and TH1 gene expression.
Conclusions:
These data demonstrate the potential for intratumorally delivered IL12 mRNA to promote TH1 TME transformation and robust antitumor immunity.

See related commentary by Cirella et al., p. 6080
Data from Multiplexed Evaluation of Microdosed Antineoplastic Agents In Situ in the Tumor Microenvironment of Patients with Soft Tissue Sarcoma
Authors: Gundle Kenneth R. , Deutsch Gary B. , Goodman Howard J. , Pollack Seth M. , Thompson Matthew J. , Davis Jessica L. , Lee Mee-Young , Ramirez Daniel C. , Kerwin William , Bertout Jessica A. , Grenley Marc O. , Sottero Kimberly H.W. , Beirne Emily , Frazier Jason , Dey Joyoti , Ellison Micah , Klinghoffer Richard A. , Maki Robert G.
Published: April 2023

AbstractPurpose:
A persistent issue in cancer drug development is the discordance between robust antitumor drug activity observed in laboratory models and the limited benefit frequently observed when patients are treated with the same agents in clinical trials. Difficulties in accurately modeling the complexities of human tumors may underlie this problem. To address this issue, we developed Comparative In Vivo Oncology (CIVO), which enables in situ investigation of multiple microdosed drugs simultaneously in a patient's tumor. This study was designed to test CIVO's safety and feasibility in patients with soft tissue sarcoma (STS).
Patients and Methods:
We conducted a single arm, prospective, 13-patient pilot study. Patients scheduled for incisional biopsy or tumor resection were CIVO-injected 1 to 3 days prior to surgery. Saline or microdoses of anticancer agents were percutaneously injected into the tumor in a columnar fashion through each of eight needles. Following excision, drug responses were evaluated in the injected tissue.
Results:
The primary objective was met, establishing CIVO's feasibility and safety. Device-related adverse events were limited to transient grade 1 nonserious events. In addition, biomarker evaluation of localized tumor response to CIVO microinjected drugs by IHC or with NanoString GeoMx Digital Spatial Profiler demonstrated consistency with known mechanisms of action of each drug, impact on the tumor microenvironment, and historic clinical activity.
Conclusions:
These results are an advance toward use of CIVO as a translational research tool for early evaluation of investigational agents and drug combinations in a novel approach to phase 0 trials.

See related commentary by Sleijfer and Lolkema, p. 3897
Data from T-Cell Infiltration and Adaptive Treg Resistance in Response to Androgen Deprivation With or Without Vaccination in Localized Prostate Cancer
Authors: Obradovic Aleksandar Z. , Dallos Matthew C. , Zahurak Marianna L. , Partin Alan W. , Schaeffer Edward M. , Ross Ashley E. , Allaf Mohamad E. , Nirschl Thomas R. , Liu David , Chapman Carolyn G. , O'Neal Tanya , Cao Haiyi , Durham Jennifer N. , Guner Gunes , Baena-Del Valle Javier A. , Ertunc Onur , De Marzo Angelo M. , Antonarakis Emmanuel S. , Drake Charles G.
Published: April 2023

AbstractPurpose:
Previous studies suggest that androgen deprivation therapy (ADT) promotes antitumor immunity in prostate cancer. Whether a vaccine-based approach can augment this effect remains unknown.
Patients and Methods:
We conducted a neoadjuvant, randomized study to quantify the immunologic effects of a GM-CSF–secreting allogeneic cellular vaccine in combination with low-dose cyclophosphamide (Cy/GVAX) followed by degarelix versus degarelix alone in patients with high-risk localized prostate adenocarcinoma who were planned for radical prostatectomy.
Results:
Both Cy/GVAX plus degarelix and degarelix alone led to significant increases in intratumoral CD8+ T-cell infiltration and PD-L1 expression as compared with a cohort of untreated, matched controls. However, the CD8+ T-cell infiltrate was accompanied by a proportional increase in regulatory T cells (Treg), suggesting that adaptive Treg resistance may dampen the immunogenicity of ADT. Although Cy/GVAX followed by degarelix was associated with a modest improvement in time-to-PSA progression and time-to-next treatment, as well as an increase in PD-L1, there was no difference in the CD8+ T-cell infiltrate as compared with degarelix alone. Gene expression profiling demonstrated that CHIT1, a macrophage marker, was differentially upregulated with Cy/GVAX plus degarelix compared with degarelix alone.
Conclusions:
Our results highlight that ADT with or without Cy/GVAX induces a complex immune response within the prostate tumor microenvironment. These data have important implications for combining ADT with immunotherapy. In particular, our finding that ADT increases both CD8+ T cells and Tregs supports the development of regimens combining ADT with Treg-depleting agents in the treatment of prostate cancer.
Data from Phase I Study of P-cadherin–targeted Radioimmunotherapy with 90Y-FF-21101 Monoclonal Antibody in Solid Tumors
Authors: Subbiah Vivek , Erwin William , Mawlawi Osama , McCoy Asa , Wages David , Wheeler Catherine , Gonzalez-Lepera Carlos , Liu Holly , Macapinlac Homer , Meric-Bernstam Funda , Hong David S. , Pant Shubham , Le Dao , Santos Elmer , Gonzalez Jose , Roszik Jason , Suzuki Takeaki , Subach Ruth Ann , Madden Timothy , Johansen Mary , Nomura Fumiko , Satoh Hirokazu , Matsuura Tadashi , Kajita Masamichi , Nakamura Eri , Funase Yuichi , Matsushima Satoshi , Ravizzini Gregory
Published: April 2023

AbstractPurpose:
90Y-FF-21101 is an Yttrium-90–conjugated, chimeric mAb that is highly specific for binding to human placental (P)-cadherin, a cell-to-cell adhesion molecule overexpressed and associated with cancer invasion and metastatic dissemination in many cancer types. We report the clinical activity of 90Y-FF-21101 in a first-in-human phase I study in patients with advanced solid tumors.
Patients and Methods:
The safety and efficacy of 90Y-FF-21101 were evaluated in a phase I 3+3 dose-escalation study in patients with advanced solid tumors (n = 15) over a dose range of 5–25 mCi/m2. Dosimetry using 111In-FF-21101 was performed 1 week prior to assess radiation doses to critical organs. Patients who demonstrated clinical benefit received repeated 90Y-FF-21101 administration every 4 months.
Results:
111In-FF-21101 uptake was observed primarily in the spleen, kidneys, testes, lungs, and liver, with tumor uptake observed in the majority of patients. Organ dose estimates for all patients were below applicable limits. P-cadherin expression H-scores ranged from 0 to 242 with 40% of samples exhibiting scores ≥100. FF-21101 protein pharmacokinetics were linear with increasing antibody dose, and the mean half-life was 69.7 (±12.1) hours. Radioactivity clearance paralleled antibody clearance. A complete clinical response was observed in a patient with clear cell ovarian carcinoma, correlating with a high tumor P-cadherin expression. Stable disease was observed in a variety of other tumor types, without dose-limiting toxicity.
Conclusions:
The favorable safety profile and initial antitumor activity observed for 90Y-FF-21101 warrant further evaluation of this radioimmunotherapeutic (RIT) approach and provide initial clinical data supporting P-cadherin as a potential target for cancer treatment.
Data from Long-term Outcomes of Oral Vinorelbine in Advanced, Progressive Desmoid Fibromatosis and Influence of CTNNB1 Mutational Status
Authors: Mir Olivier , Honoré Charles , Chamseddine Ali N. , Dômont Julien , Dumont Sarah N. , Cavalcanti Andrea , Faron Matthieu , Rimareix Françoise , Haddag-Miliani Leila , Le Péchoux Cécile , Levy Antonin , Court Charles , Briand Sylvain , Fadel Elie , Mercier Olaf , Bayle Arnaud , Brunet Anaïs , Ngo Carine , Rouleau Etienne , Adam Julien , Le Cesne Axel
Published: April 2023

AbstractPurpose:
Desmoid-type fibromatosis (DF) are locally aggressive neoplasms, with a need for effective systemic treatment in case of progression to avoid the short- and long-term complications of local treatments.
Experimental Design:
We retrospectively analyzed the outcomes of adult patients with DF treated with oral vinorelbine (90 mg once weekly) at Gustave Roussy Cancer Institute (Villejuif, Paris, France). Only patients with documented progressive disease according to RECIST v1.1 for more than 3 months (±2 weeks) before treatment initiation were included.
Results:
From 2009 to 2019, 90 out of 438 patients with DF were eligible for this analysis. Vinorelbine was given alone in 56 patients (62%), or concomitantly with endocrine therapy in 34 patients, for a median duration of 6.7 months. A partial response was observed in 29% and stable disease in another 57%. With a median follow-up of 52.4 months, the median time to treatment failure (TTF) was not reached. Progression-free rates at 6 and 12 months were 88.7% and 77.5%, respectively. Concomitant endocrine therapy was associated with longer TTF in women [HR, 2.16; 95% confidence interval (CI), 1.06–4.37; P = 0.03). Among 64 patients with documented CTNNB1 mutational status, p.S45F or p.S45P mutations were associated with longer TTF compared with p.T41A or wild-type tumors (HR, 2.78; 95% CI, 1.23–6.27; P = 0.04). Toxicity profile was favorable, without grade 3–4 toxicity, except for one grade 3 neutropenia.
Conclusions:
Oral vinorelbine is an effective, affordable, and well-tolerated regimen in patients with advanced, progressive DF. Prolonged activity was observed in patients with tumors harboring CTNNB1 p.S45F or p.S45P mutations.
Data from Evidencing a Pancreatic Ductal Adenocarcinoma Subpopulation Sensitive to the Proteasome Inhibitor Carfilzomib
Authors: Fraunhoffer Nicolas A. , Abuelafia Analía Meilerman , Bigonnet Martin , Gayet Odile , Roques Julie , Telle Emmanuel , Santofimia-Castaño Patricia , Borrello María Teresa , Chuluyan Eduardo , Dusetti Nelson , Iovanna Juan
Published: April 2023

AbstractPurpose:
Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a survival rate less than 5%. Multiple chemotherapeutic drugs have been tested to improve patient prognosis; however, the clinical efficacy of these treatments is low. One of the most controversial family of drugs are the proteasome inhibitors, which have displayed promising effects in preclinical studies, but low clinical performance. Here, we unravel a specific transcriptomic signature that discriminates a subgroup of patients sensitive to the proteasome inhibitor carfilzomib.
Experimental Design:
First, we identified a subpopulation of PDAC-derived primary cells cultures (PDPCC) sensitive to the proteasome inhibitor carfilzomib. Then, we selected a transcriptomic signature that predicts carfilzomib chemosensitivity using independent component analysis on the transcriptome of PDPCC. Finally, we validated the signature in an independent cohort of PDAC biopsy-derived pancreatic organoids.
Results:
Sensitive phenotype was characterized by a high expression of genes related with a cornified/squamous pathway and a downregulation of epithelial–mesenchymal transition genes. Interestingly, carfilzomib-sensitive transcriptomic profile did not show any association with the proteasome activity but strongly correlates with ATF4 and CHOP expression, which are key markers of the unfolded protein response and critical to trigger the cell death program. Concordantly, sensitive phenotype showed a high level of the de novo RNA and protein synthesis compared with the resistant one and, most important, cell death induced by carfilzomib is dependent of the translational activity.
Conclusions:
We demonstrate the existence of a carfilzomib-sensitive PDAC subgroup with a specific transcriptomic phenotype that could explain the biological reason for this responsiveness.
Data from Targeting PD-1 or PD-L1 in Metastatic Kidney Cancer: Combination Therapy in the First-Line Setting
Authors: Aggen David H. , Drake Charles G. , Rini Brian I.
Published: April 2023

Abstract
Recent FDA approvals of regimens targeting programmed death 1 (PD-1) in combination with anti-CTLA-4 or with VEGF tyrosine kinase inhibitors are reshaping front-line therapy for metastatic kidney cancer. In parallel, therapeutics specific for programmed death ligand 1 (PD-L1), one of the two major ligands for PD-1, are under continued investigation. Surprisingly, not all PD-1 and PD-L1 agents lead to similar clinical outcomes, potentially due to biological differences in the cellular expression and regulation of these targets. Here, we review current clinical data on combination immune checkpoint inhibitor therapy in metastatic kidney cancer and discuss the relevant biology of PD-1 and PD-L1. The design of future rational combination therapy trials in metastatic renal cell carcinoma will rely upon an understanding of this biology, along with an evolving understanding of immune cell populations and their functional states in the tumor microenvironment.
Data from Phosphorylated Acetyl-CoA Carboxylase Is Associated with Clinical Benefit with Regorafenib in Relapsed Glioblastoma: REGOMA Trial Biomarker Analysis
Authors: Indraccolo Stefano , De Salvo Gian Luca , Verza Martina , Caccese Mario , Esposito Giovanni , Piga Ilaria , Del Bianco Paola , Pizzi Marco , Gardiman Marina Paola , Eoli Marica , Rudà Roberta , Brandes Alba Ariela , Ibrahim Toni , Rizzato Simona , Lolli Ivan , Zagonel Vittorina , Lombardi Giuseppe
Published: April 2023

AbstractPurpose:
Preclinical studies show that antiangiogenic therapy exacerbates tumor glycolysis and activates liver kinase B1/AMP kinase (AMPK), a pathway involved in the regulation of tumor metabolism. We investigated whether certain metabolism-related in situ biomarkers could predict benefit to regorafenib in the phase II randomized REGOMA trial.
Patients and Methods:
IHC and digital pathology analysis were used to investigate the expression in glioblastoma (GBM) sections of monocarboxylate transporter 1 and 4 (MCT1 and MCT4), associated with OXPHOS and glycolysis, respectively, phosphorylated AMPK (pAMPK), and phosphorylated acetyl-CoA carboxylase (pACC), a canonical target of AMPK activity. The status of each biomarker was associated with clinical endpoints, including overall survival (OS) and progression-free survival (PFS) in patients with relapsed GBM treated either with regorafenib or lomustine.
Results:
Between November 2015 and February 2017, 119 patients were enrolled (n = 59 regorafenib and n = 60 lomustine) and stratified for surgery at recurrence, and baseline characteristics were balanced. Biomarker analysis was performed in 84 patients (71%), including 42 patients of the regorafenib arm and 42 patients of the lomustine arm. Among all markers analyzed, only pACC showed predictive value in terms of OS. In fact, median OS was 9.3 months [95% confidence interval (CI), 5.6–13.2] for regorafenib and 5.5 months (95% CI, 4.2–6.6) for lomustine for pACC-positive patients, HR, 0.37 (95% CI, 0.20–0.70); log rank P = 0.0013; test for interaction = 0.0453. No statistically significant difference was demonstrated for PFS according to pACC status.
Conclusions:
We found that AMPK pathway activation is associated with clinical benefit from treatment with regorafenib in relapsed GBM.
Data from Acute Statin Treatment Improves Antibody Accumulation in EGFR- and PSMA-Expressing Tumors
Authors: Pereira Patrícia M.R. , Mandleywala Komal , Ragupathi Ashwin , Lewis Jason S.
Published: April 2023

AbstractPurpose:
Statins are cholesterol-depleting drugs used to treat patients with hypercholesterolemia. Preclinically, statins disrupt trafficking of receptors present at the cell membrane. Membrane receptors, defined as tumor biomarkers and therapeutic targets, are often internalized by an endocytic pathway. Indeed, receptor endocytosis and recycling are dynamic mechanisms that often affect receptor density at the cell surface. In therapies using monoclonal antibodies (mAb), a downregulation in receptor density at the cell surface decreases antibody binding to the extracellular domain of the membrane receptor. Here, we determined the potential of lovastatin, simvastatin, and rosuvastatin in preclinically modulating epidermal growth factor receptor (EGFR) and prostate-specific membrane antigen (PSMA) receptor density at the tumor cell surface.
Experimental Design:
Small-animal PET was used to study the binding of 89Zr-labeled antibodies in ectopic xenografts. Ex vivo analyses were performed to determine changes in endocytic proteins, EGFR, and PSMA surface levels.
Results:
Acute statin treatment using lovastatin, simvastatin, or rosuvastatin enhanced tumors' avidity for the mAbs panitumumab, cetuximab, and huJ591. Statins temporarily modulated caveolin-1, cavin-1, endophilin, clathrin, and dynamin proteins in EGFR- and PSMA-overexpressing xenografts.
Conclusions:
These data show the potential of statins as pharmacologic modulators of endocytic proteins for improved tumors' accumulation of mAbs. The translational significance of these findings lies in the potential of statins to temporarily modulate the heterogeneous presence of receptors at the cell membrane, a characteristic often associated with poor response in tumors to therapeutic antibodies.
Data from Discovery of Berberine that Targetedly Induces Autophagic Degradation of both BCR-ABL and BCR-ABL T315I through Recruiting LRSAM1 for Overcoming Imatinib Resistance
Authors: Yin Zhao , Huang Guiping , Gu Chunming , Liu Yanjun , Yang Juhua , Fei Jia
Published: April 2023

AbstractPurpose:
Imatinib, the breakpoint cluster region protein (BCR)/Abelson murine leukemia viral oncogene homolog (ABL) inhibitor, is widely used to treat chronic myeloid leukemia (CML). However, imatinib resistance develops in many patients. Therefore, new drugs with improved therapeutic effects are urgently needed. Berberine (BBR) is a potent BCR-ABL inhibitor for imatinib-sensitive and -resistant CML.
Experimental Design:
Protein structure analysis and virtual screening were used to identify BBR targets in CML. Molecular docking analysis, surface plasmon resonance imaging, nuclear magnetic resonance assays, and thermoshift assays were performed to confirm the BBR target. The change in BCR-ABL protein expression after BBR treatment was assessed by Western blotting. The effects of BBR were assessed in vitro in cell lines, in vivo in mice, and in human CML bone marrow cells as a potential strategy to overcome imatinib resistance.
Results:
We discovered that BBR bound to the protein tyrosine kinase domain of BCR-ABL. BBR inhibited the activity of BCR-ABL and BCR-ABL with the T315I mutation, and it also degraded these proteins via the autophagic lysosome pathway by recruiting E3 ubiquitin-protein ligase LRSAM1. BBR inhibited the cell viability and colony formation of CML cells and prolonged survival in CML mouse models with imatinib sensitivity and resistance.
Conclusions:
The results show that BBR directly binds to and degrades BCR-ABL and BCR-ABL T315I via the autophagic lysosome pathway by recruiting LRSAM1. The use of BBR is a new strategy to improve the treatment of patients with CML with imatinib sensitivity or resistance.

See related commentary by Elf, p. 3899
Data from Association of Anti-TNF with Decreased Survival in Steroid Refractory Ipilimumab and Anti-PD1–Treated Patients in the Dutch Melanoma Treatment Registry
Authors: Verheijden Rik J. , May Anne M. , Blank Christian U. , Aarts Maureen J.B. , van den Berkmortel Franchette W.P.J. , van den Eertwegh Alfonsus J.M. , de Groot Jan Willem B. , Boers-Sonderen Marye J. , van der Hoeven Jacobus J.M. , Hospers Geke A. , Piersma Djura , van Rijn Rozemarijn S. , ten Tije Albert J. , van der Veldt Astrid A.M. , Vreugdenhil Gerard , van Zeijl Michiel C.T. , Wouters Michel W.J.M. , Haanen John B.A.G. , Kapiteijn Ellen , Suijkerbuijk Karijn P.M.
Published: April 2023

AbstractPurpose:
Unleashing the immune system by PD-1 and/or CTLA-4 blockade can cause severe immune-related toxicity necessitating immunosuppressive treatment. Whether immunosuppression for toxicity impacts survival is largely unknown.
Experimental Design:
Using data from the prospective nationwide Dutch Melanoma Treatment Registry (DMTR), we analyzed the association between severe toxicity and overall survival (OS) in 1,250 patients with advanced melanoma who were treated with immune checkpoint inhibitors (ICI) in first line between 2012 and 2017. Furthermore, we analyzed whether toxicity management affected survival in these patients.
Results:
A total of 1,250 patients were included, of whom 589 received anti-PD1 monotherapy, 576 ipilimumab, and 85 combination therapy. A total of 312 patients (25%) developed severe (grade ≥3) toxicity. Patients experiencing severe ICI toxicity had a significantly prolonged survival with a median OS of 23 months compared with 15 months for patients without severe toxicity [hazard ratio (HRadj) = 0.77; 95% confidence interval (CI), 0.63–0.93]. Among patients experiencing severe toxicity, survival was significantly decreased in patients who received anti-TNF ± steroids for steroid-refractory toxicity compared with patients who were managed with steroids only (HRadj = 1.61; 95% CI, 1.03–2.51), with a median OS of 17 and 27 months, respectively.
Conclusions:
Patients experiencing severe ICI toxicity have a prolonged OS. However, this survival advantage is abrogated when anti-TNF is administered for steroid-refractory toxicity. Further prospective studies are needed to assess the effect of different immunosuppressive regimens on checkpoint inhibitor efficacy.

See related commentary by Weber and Postow, p. 2085
Data from FGFR2c Mesenchymal Isoform Expression Is Associated with Poor Prognosis and Further Refines Risk Stratification within Endometrial Cancer Molecular Subtypes
Authors: Sengal Asmerom T. , Patch Ann-Marie , Snell Cameron E. , Smith Deborah S. , Leung Samuel C.Y. , Talhouk Aline , Williams Elizabeth D. , McAlpine Jessica N. , Pollock Pamela M.
Published: April 2023

AbstractPurpose:
The two most common molecular subtypes of endometrial cancers, mismatch repair deficient (MMRd) and p53 wild-type (p53wt) comprise the majority of endometrial cancers and have intermediate prognoses where additional risk stratification biomarkers are needed. Isoform switching of FGFR2 from FGFR2b to FGFR2c (normally expressed in mesenchymal cells), has been reported in other solid carcinomas. The objective of this study was to investigate the role of FGFR2c in risk stratification of endometrial cancer.
Experimental Design:
We have developed and optimized a BaseScope RNA ISH assay to detect FGFR2c. FGFR2c expression was determined in a preliminary screening cohort of 78 endometrial cancers and a clinically and molecularly annotated Vancouver cohort (n = 465). Cox regression model analyses were performed to assess the prognostic value of FGFR2c.
Results:
Univariate and multivariate analyses revealed FGFR2c expression was significantly associated with shorter disease-specific survival (DSS) and progression-free survival (PFS) in endometrioid endometrial cancer (EEC, n = 302). Notably, FGFR2c expression was significantly associated with shorter PFS and DSS in patients with grade 3 EECs (P < 0.003 and P < 0.002) and the European Society Medical Oncology (ESMO) high-risk group (P < 0.0001 and P < 0.002), respectively. Moreover, within the MMRd subtype, FGFR2c expression was significantly associated with shorter PFS (P < 0.048) and DSS (P < 0.001).
Conclusions:
FGFR2c expression appears an independent prognostic biomarker in patients with EEC and further discerns the outcomes within grade 3 tumors, ESMO high-risk groups, as well as within the MMRd and p53wt subtypes. FGFR2c inclusion into future molecular subtyping can further refine risk stratification of EEC.
Data from Radiotheranostic Agent 64Cu-cyclam-RAFT-c(-RGDfK-)4 for Management of Peritoneal Metastasis in Ovarian Cancer
Authors: Jin Zhao-Hui , Tsuji Atsushi B. , Degardin Mélissa , Sugyo Aya , Obara Satoshi , Wakizaka Hidekatsu , Nagatsu Kotaro , Hu Kuan , Zhang Ming-Rong , Dumy Pascal , Boturyn Didier , Higashi Tatsuya
Published: April 2023

AbstractPurpose:
Ovarian cancer peritoneal metastases (OCPMs) are a pathophysiologically heterogeneous group of tumors that are rarely curable. αVβ3 integrin (αVβ3) is overexpressed on tumoral neovessels and frequently on ovarian cancer cells. Here, using two clinically relevant αVβ3-positive OCPM mouse models, we studied the theranostic potential of an αVβ3-specific radiopeptide, 64Cu-cyclam-RAFT-c(-RGDfK-)4 (64Cu-RaftRGD), and its intra- and intertumoral distribution in relation to the tumor microenvironment.
Experimental Design:
αVβ3-expressing peritoneal and subcutaneous models of ovarian carcinoma (IGR-OV1 and NIH:OVCAR-3) were established in nude mice. 64Cu-RaftRGD was administered either intravenously or intraperitoneally. We performed intratumoral distribution (ITD) studies, PET/CT imaging and quantification, biodistribution assay and radiation dosimetry, and therapeutic efficacy and toxicity studies.
Results:
Intraperitoneal administration was an efficient route for targeting 64Cu-RaftRGD to OCPMs with excellent tumor penetration. Using the fluorescence surrogate, Cy5.5-RaftRGD, in our unique high-resolution multifluorescence analysis, we found that the ITD of 64Cu-RaftRGD was spatially distinct from, but complementary to, that of hypoxia. 64Cu-RaftRGD–based PET enabled clear visualization of multiple OCPM deposits and ascites and biodistribution analysis demonstrated an inverse correlation between tumor uptake and tumor size (1.2–17.2 mm). 64Cu-RaftRGD at a radiotherapeutic dose (148 MBq/0.357 nmol) showed antitumor activities by inhibiting tumor cell proliferation and inducing apoptosis, with negligible toxicity.
Conclusions:
Collectively, these results demonstrate the all-in-one potential of 64Cu-RaftRGD for imaging guided radiotherapy of OCPM by targeting both tumoral neovessels and cancerous cells. On the basis of the ITD finding, we propose that pairing αVβ3- and hypoxia-targeted radiotherapies could improve therapeutic efficacy by overcoming the heterogeneity of ITD encountered with single-agent treatments.
Data from Oncogenic Genomic Alterations, Clinical Phenotypes, and Outcomes in Metastatic Castration-Sensitive Prostate Cancer
Authors: Stopsack Konrad H. , Nandakumar Subhiksha , Wibmer Andreas G. , Haywood Samuel , Weg Emily S. , Barnett Ethan S. , Kim Chloe J. , Carbone Emily A. , Vasselman Samantha E. , Nguyen Bastien , Hullings Melanie A. , Scher Howard I. , Morris Michael J. , Solit David B. , Schultz Nikolaus , Kantoff Philip W. , Abida Wassim
Published: April 2023

AbstractPurpose:
The genomic underpinning of clinical phenotypes and outcomes in metastatic castration-sensitive prostate cancer is unclear.
Experimental Design:
In patients with metastatic castration-sensitive prostate cancer at a tertiary referral center, clinical-grade targeted tumor sequencing was performed to quantify tumor DNA copy number alterations and alterations in predefined oncogenic signaling pathways. Disease volume was classified as high volume (≥4 bone metastases or visceral metastases) versus low volume.
Results:
Among 424 patients (88% white), 213 (50%) had high-volume disease and 211 (50%) had low-volume disease, 275 (65%) had de novo metastatic disease, and 149 (35%) had metastatic recurrence of nonmetastatic disease. Rates of castration resistance [adjusted hazard ratio, 1.84; 95% confidence interval (CI), 1.40–2.41] and death (adjusted hazard ratio, 3.71; 95% CI, 2.28–6.02) were higher in high-volume disease. Tumors from high-volume disease had more copy number alterations. The NOTCH, cell cycle, and epigenetic modifier pathways were the highest-ranking pathways enriched in high-volume disease. De novo metastatic disease differed from metastatic recurrences in the prevalence of CDK12 alterations but had similar prognosis. Rates of castration resistance differed 1.5-fold to 5-fold according to alterations in AR, SPOP (inverse), and TP53, and the cell cycle, WNT (inverse), and MYC pathways, adjusting for disease volume and other genomic pathways. Overall survival rates differed 2-fold to 4-fold according to AR, SPOP (inverse), WNT (inverse), and cell-cycle alterations. PI3K pathway alterations were not associated with prognosis once adjusted for other factors.
Conclusions:
This study identified genomic features associated with prognosis in metastatic castration-sensitive disease that may aid in molecular classification and treatment selection.
Data from Phase I Trial of Expanded, Activated Autologous NK-cell Infusions with Trastuzumab in Patients with HER2-positive Cancers
Authors: Lee Soo-Chin , Shimasaki Noriko , Lim Joline S.J. , Wong Andrea , Yadav Kritika , Yong Wei Peng , Tan Lip Kun , Koh Liang Piu , Poon Michelle L.M. , Tan Sing Huang , Ow Samuel G.W. , Bharwani Lavina , Yap Yoon Sim , Foo Mabel Z.Q. , Coustan-Smith Elaine , Sundar Raghav , Tan Hon Lyn , Chong Wan Qin , Kumarakulasinghe Nesaretnam Barr , Lieow Jedidah L.M. , Koe Priscillia J.X. , Goh Boon Cher , Campana Dario
Published: April 2023

AbstractPurpose:
Natural killer (NK) cells exert antibody-dependent cell cytotoxicity (ADCC). We infused expanded, activated autologous NK cells to potentiate trastuzumab-mediated ADCC in patients with HER2-positive malignancies.
Patients and Methods:
In a phase I trial, patients with treatment-refractory HER2-positive solid tumors received trastuzumab, with or without bevacizumab, and autologous NK cells expanded by 10-day coculture with K562-mb15-41BBL cells. Primary objectives included safety and recommended phase II dose determination; secondary objectives included monitoring NK-cell activity and RECIST antitumor efficacy.
Results:
In 60 cultures with cells from 31 subjects, median NK-cell expansion from peripheral blood was 340-fold (range, 91–603). NK cells expressed high levels of CD16, the mediator of ADCC, and exerted powerful killing of trastuzumab-targeted cells. In the 22 subjects enrolled in phase I dose escalation, trastuzumab plus NK cells were well tolerated; MTD was not reached. Phase IB (n = 9) included multiple cycles of NK cells (1 × 107/kg) and addition of bevacizumab. Although no objective response was observed, 6 of 19 subjects who received at least 1 × 107/kg NK cells at cycle 1 had stable disease for ≥6 months (median, 8.8 months; range 6.0–12.0). One patient, the only one with the high-affinity F158V CD16 variant, had a partial response. Peripheral blood NK cells progressively downregulated CD16 postinfusion; paired tumor biopsies showed increased NK cells, lymphocytic infiltrates, and apoptosis posttreatment.
Conclusions:
NK-cell therapy in combination with trastuzumab was well tolerated, with target engagement and preliminary antitumor activity, supporting continued assessment of this approach in phase II trials.