bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Phase I/II Multicenter Trial of a Novel Therapeutic Cancer Vaccine, HepaVac-101, for Hepatocellular Carcinoma
Authors: Löffler Markus W. , Gori Stefania , Izzo Francesco , Mayer-Mokler Andrea , Ascierto Paolo A. , Königsrainer Alfred , Ma Yuk Ting , Sangro Bruno , Francque Sven , Vonghia Luisa , Inno Alessandro , Avallone Antonio , Ludwig Jörg , Alcoba Diego Duarte , Flohr Christian , Aslan Katrin , Mendrzyk Regina , Schuster Heiko , Borrelli Marco , Valmori Danila , Chaumette Tanguy , Heidenreich Regina , Gouttefangeas Cécile , Forlani Greta , Tagliamonte Maria , Fusco Caterina , Penta Roberta , Iñarrairaegui Mercedes , Gnad-Vogt Ulrike , Reinhardt Carsten , Weinschenk Toni , Accolla Roberto S. , Singh-Jasuja Harpreet , Rammensee Hans-Georg , Buonaguro Luigi
Published: April 2023

AbstractPurpose:
Immunotherapy for hepatocellular carcinoma (HCC) shows considerable promise in improving clinical outcomes. HepaVac-101 represents a single-arm, first-in-human phase I/II multicenter cancer vaccine trial for HCC (NCT03203005). It combines multipeptide antigens (IMA970A) with the TLR7/8/RIG I agonist CV8102. IMA970A includes 5 HLA-A*24 and 7 HLA-A*02 as well as 4 HLA-DR restricted peptides selected after mass spectrometric identification in human HCC tissues or cell lines. CV8102 is an RNA-based immunostimulator inducing a balanced Th1/Th2 immune response.
Patients and Methods:
A total of 82 patients with very early- to intermediate-stage HCCs were enrolled and screened for suitable HLA haplotypes and 22 put on study treatment. This consisted in a single infusion of low-dose cyclophosphamide followed by nine intradermal coadministrations of IMA970A and CV8102. Only patients with no disease relapse after standard-of-care treatments were vaccinated. The primary endpoints of the HepaVac-101 clinical trial were safety, tolerability, and antigen-specific T-cell responses. Secondary or exploratory endpoints included additional immunologic parameters and survival endpoints.
Results:
The vaccination showed a good safety profile. Transient mild-to-moderate injection-site reactions were the most frequent IMA970A/CV8102-related side effects. Immune responses against ≥1 vaccinated HLA class I tumor-associated peptide (TAA) and ≥1 vaccinated HLA class II TAA were respectively induced in 37% and 53% of the vaccinees.
Conclusions:
Immunotherapy may provide a great improvement in treatment options for HCC. HepaVac-101 is a first-in-human clinical vaccine trial with multiple novel HLA class I– and class II–restricted TAAs against HCC. The results are initial evidence for the safety and immunogenicity of the vaccine. Further clinical evaluations are warranted.
Data from Updated Efficacy Outcomes of Anti-PD-1 Antibodies plus Multikinase Inhibitors for Patients with Advanced Gastric Cancer with or without Liver Metastases in Clinical Trials
Authors: Yukami Hiroki , Kawazoe Akihito , Lin Yi-Tzu , Koyama Shohei , Fukuoka Shota , Hara Hiroki , Takahashi Naoki , Kojima Takashi , Asayama Masako , Yoshii Takako , Bando Hideaki , Kotani Daisuke , Nakamura Yoshiaki , Kuboki Yasutoshi , Mishima Saori , Wakabayashi Masashi , Kuwata Takeshi , Goto Masahiro , Higuchi Kazuhide , Yoshino Takayuki , Doi Toshihiko , Nishikawa Hiroyoshi , Shitara Kohei
Published: April 2023

AbstractPurpose:
We previously reported preliminary activity of regorafenib plus nivolumab (REGONIVO) or lenvatinib plus pembrolizumab (LENPEM) in advanced gastric cancer (AGC). Meanwhile, several studies demonstrated liver metastases are less responsive to immunotherapy.
Patients and Methods:
Combined efficacy outcomes with a longer follow-up in a phase Ib trial of REGONIVO and a phase II trial of LENPEM were examined in AGC with or without liver metastases (REGONIVO plus LENPEM cohort). We also investigated the efficacy of anti-PD-1 monotherapies (anti-PD-1 monotherapy cohort). A comparison of the immune microenvironment between gastric primary tumors and liver metastases was also conducted by multiplex IHC.
Results:
In the REGONIVO plus LENPEM cohort, with a median follow-up of 14.0 months, objective response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS) were 46%, 7.8 months, and 15.6 months in patients with liver metastases, while 69%, 6.9 months, and 15.5 months in those without. In the anti-PD-1 monotherapy cohort, with a median follow-up of 27.6 months, ORR, mPFS, and mOS were 9%, 1.4 months, and 6.4 months in patients with liver metastases, while 22%, 2.3 months, and 9.0 months in those without. Multiplex IHC revealed liver metastases were associated with an abundance of immune-suppressive cells, such as tumor-associated macrophages and regulatory T cells, with fewer CD8+ T cells compared with gastric primary tumors.
Conclusions:
Anti-PD-1 antibodies plus regorafenib or lenvatinib for AGC showed promising antitumor activity with a longer follow-up, irrespective of liver metastases status, despite a more immune-suppressive tumor microenvironment in liver metastases.
Data from A Cathepsin-Targeted Quenched Activity–Based Probe Facilitates Enhanced Detection of Human Tumors during Resection
Authors: Kennedy Gregory T. , Holt David E. , Azari Feredun S. , Bernstein Elizabeth , Nadeem Bilal , Chang Ashley , Sullivan Neil T. , Segil Alix , Desphande Charuhas , Bensen Eric , Santini John T. , Kucharczuk John C. , Delikatny Edward J. , Bogyo Matthew , Egan A.J. Matthew , Bradley Charles W. , Eruslanov Evgeniy , Lickliter Jason D. , Wright Gavin , Singhal Sunil
Published: April 2023

AbstractPurpose:
Fluorescence-guided surgery using tumor-targeted contrast agents has been developed to improve the completeness of oncologic resections. Quenched activity–based probes that fluoresce after covalently binding to tumor-specific enzymes have been proposed to improve specificity, but none have been tested in humans. Here, we report the successful clinical translation of a cathepsin activity–based probe (VGT-309) for fluorescence-guided surgery.
Experimental Design:
We optimized the specificity, dosing, and timing of VGT-309 in preclinical models of lung cancer. To evaluate clinical feasibility, we conducted a canine study of VGT-309 during pulmonary tumor resection. We then conducted a randomized, double-blind, dose-escalation study in healthy human volunteers receiving VGT-309 to evaluate safety. Finally, we tested VGT-309 in humans undergoing lung cancer surgery.
Results:
In preclinical models, we found highly specific tumor cell labeling that was blocked by a broad spectrum cathepsin inhibitor. When evaluating VGT-309 for guidance during resection of canine tumors, we found that the probe selectively labeled tumors and demonstrated high tumor-to-background ratio (TBR; range: 2.15–3.71). In the Phase I human study, we found that VGT-309 was safe at all doses studied. In the ongoing Phase II trial, we report two cases in which VGT-309 localized visually occult, non-palpable tumors (TBRs = 2.83 and 7.18) in real time to illustrate its successful clinical translation and potential to improve surgical management.
Conclusions:
This first-in-human study demonstrates the safety and feasibility of VGT-309 to label human pulmonary tumors during resection. These results may be generalizable to other cancers due to cathepsin overexpression in many solid tumors.
Data from Pembrolizumab Monotherapy for Previously Untreated Advanced Hepatocellular Carcinoma: Data from the Open-Label, Phase II KEYNOTE-224 Trial
Authors: Verset Gontran , Borbath Ivan , Karwal Mark , Verslype Chris , Van Vlierberghe Hans , Kardosh Adel , Zagonel Vittorina , Stal Per , Sarker Debashis , Palmer Daniel H. , Vogel Arndt , Edeline Julien , Cattan Stephane , Kudo Masatoshi , Cheng Ann-Lii , Ogasawara Sadahisa , Daniele Bruno , Chan Stephen L. , Knox Jennifer J. , Qin Shukui , Siegel Abby B. , Chisamore Michael , Hatogai Ken , Wang Anran , Finn Richard S. , Zhu Andrew X.
Published: April 2023

AbstractPurpose:
KEYNOTE-224 cohort 1 demonstrated that pembrolizumab was efficacious and tolerable in patients with advanced hepatocellular carcinoma (HCC) previously treated with sorafenib. We report results from KEYNOTE-224 (NCT02702414) cohort 2, which enrolled patients with advanced HCC and no prior systemic therapy.
Patients and Methods:
KEYNOTE-224 was an open-label, multicountry phase II trial. Eligible patients in cohort 2 had advanced HCC not amenable or refractory to locoregional therapy and not previously treated with systemic therapy. Patients received pembrolizumab 200 mg intravenously every 3 weeks for ≤2 years. Primary endpoint was objective response rate (ORR) by central imaging review per RECIST v1.1. Secondary endpoints included duration of response (DOR), disease control rate (DCR), time to progression (TTP), progression-free survival (PFS), overall survival (OS), and safety/tolerability.
Results:
Between September 4, 2018, and February 20, 2019, 51 patients were allocated in cohort 2. The median time from the first dose to data cutoff (January 19, 2021) was 27 months (range, 23–29). ORR was 16% [95% confidence interval (CI), 7–29] and was similar across key subgroups. Median DOR was 16 months (range, 3–24+), and DCR was 57%. The median PFS was 4 months (95% CI, 2–8), and median TTP was 4 months (95% CI, 3–9). Median OS was 17 months (95% CI, 8–23). Grade ≥3 treatment-related adverse events occurred in 16% of patients.
Conclusions:
In patients with advanced HCC with no prior systemic therapy, pembrolizumab provided durable antitumor activity, promising OS, and had a safety profile consistent with previous observations. These findings support further evaluation of pembrolizumab-based regimens for HCC.
Data from Modulation of the Estrogen/erbB2 Receptors Cross-talk by CDK4/6 Inhibition Triggers Sustained Senescence in Estrogen Receptor– and ErbB2-positive Breast Cancer
Authors: Viganò Lucia , Locatelli Alberta , Ulisse Adele , Galbardi Barbara , Dugo Matteo , Tosi Diego , Tacchetti Carlo , Daniele Tiziana , Győrffy Balázs , Sica Lorenzo , Macchini Marina , Zambetti Milvia , Zambelli Stefania , Bianchini Giampaolo , Gianni Luca
Published: April 2023

AbstractPurpose:
The interplay between estrogen receptor (ER) and erbB tyrosine-kinase receptors (RTK) impacts growth and progression of ER-positive (ER+)/HER2-positive (HER2+) breast cancer and generates mitogenic signals converging onto the Cyclin-D1/CDK4/6 complex. We probed this cross-talk combining endocrine-therapy (fulvestrant), dual HER2-blockade (trastuzumab and pertuzumab), and CDK4/6-inhibition (palbociclib; PFHPert).
Experimental Design:
Cytotoxic drug effects, interactions, and pharmacodynamics were studied after 72 hours of treatment and over 6 more days of culture after drug wash-out in three ER+/HER2+, two HER2low, and two ER-negative (ER−)/HER2+ breast cancer cell lines. We assessed gene-expression dynamic and association with Ki67 downregulation in 28 patients with ER+/HER2+ breast cancer treated with neoadjuvant PFHPert in NA-PHER2 trial (NCT02530424).
Results:
In vitro, palbociclib and/or fulvestrant induced a functional activation of RTKs signalling. PFHPert had additive or synergistic antiproliferative activity, interfered with resistance mechanisms linked to the RTKs/Akt/MTORC1 axis and induced sustained senescence. Unexpected synergism was found in HER2low cells. In patients, Ki67 downregulation at week 2 and surgery were significantly associated to upregulation of senescence-related genes (P = 7.7E-4 and P = 1.8E-4, respectively). Activation of MTORC1 pathway was associated with high Ki67 at surgery (P = 0.019).
Conclusions:
Resistance associated with the combination of drugs targeting ER and HER2 can be bypassed by cotargeting Rb, enhancing transition from quiescence to sustained senescence. MTORC1 pathway activation is a potential mechanism of escape and RTKs functional activation may be an alternative pathway for survival also in ER+/HER2low tumor. PFHPert combination is an effective chemotherapy-free regimen for ER+/HER2+ breast cancer, and the mechanistic elucidation of sensitivity/resistance patterns may provide insights for further treatment refinement.
Data from A Randomized Trial of Fulvestrant, Everolimus, and Anastrozole for the Front-line Treatment of Patients with Advanced Hormone Receptor–positive Breast Cancer, SWOG S1222
Authors: Moore Halle C.F. , Barlow William E. , Somlo George , Gralow Julie R. , Schott Anne F. , Hayes Daniel F. , Kuhn Peter , Hicks James B. , Welter Lisa , Dy Philip A. , Yeon Christina H. , Conlin Alison K. , Balcueva Ernie , Lew Danika L. , Tripathy Debasish , Pusztai Lajos , Hortobagyi Gabriel N.
Published: April 2023

AbstractPurpose:
Metastatic hormone receptor (HR)-positive, HER2-negative breast cancer is an important cause of cancer mortality. Endocrine treatment with or without additional targeted therapies has been the mainstay of treatment. This trial was designed to evaluate the combination of fulvestrant plus everolimus versus fulvestrant, everolimus, and anastrozole compared with fulvestrant alone in the first-line treatment of advanced HR-positive, HER2-negative breast cancer.
Patients and Methods:
This randomized placebo-controlled trial included postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had received no prior systemic therapy for metastatic disease. Participants were randomized to one of three treatment arms and the primary outcome was progression-free survival (PFS), comparing combinations of fulvestrant and everolimus with or without anastrozole with fulvestrant alone. Circulating tumor cells (CTC), as measured with two different methods, and circulating tumor DNA (ctDNA) were evaluated serially prior to treatment and the beginning of the second cycle of therapy.
Results:
Due in part to changes in clinical practice, the study was closed after accruing only 37 participants. There was no evidence that everolimus-containing combination treatment improved PFS or overall survival relative to fulvestrant alone. When modeled continuously, an association was observed of baseline CTC and ctDNA with poorer survival.
Conclusions:
Although power of the study was limited, the findings were unable to support the routine use of everolimus combination endocrine therapy in the first-line treatment of advanced hormone-sensitive breast cancer. Prognostic impact of baseline ctDNA and copy-number variations in CTC was demonstrated.
Data from Preclinical Development of [211At]meta- astatobenzylguanidine ([211At]MABG) as an Alpha Particle Radiopharmaceutical Therapy for Neuroblastoma
Authors: Batra Vandana , Samanta Minu , Makvandi Mehran , Groff David , Martorano Paul , Elias Jimmy , Ranieri Pietro , Tsang Matthew , Hou Catherine , Li Yimei , Pawel Bruce , Martinez Daniel , Vaidyanathan Ganesan , Carlin Sean , Pryma Daniel A. , Maris John M.
Published: April 2023

AbstractPurpose:
[131I]meta-iodobenzylguanidine ([131I]MIBG) is a targeted radiotherapeutic administered systemically to deliver beta particle radiation in neuroblastoma. However, relapses in the bone marrow are common. [211At]meta-astatobenzylguanidine ([211At] MABG) is an alpha particle emitter with higher biological effectiveness and short path length which effectively sterilizes microscopic residual disease. Here we investigated the safety and antitumor activity [211At]MABG in preclinical models of neuroblastoma.
Experimental Design:
We defined the maximum tolerated dose (MTD), biodistribution, and toxicity of [211At]MABG in immunodeficient mice in comparison with [131I]MIBG. We compared the antitumor efficacy of [211At]MABG with [131I]MIBG in three murine xenograft models. Finally, we explored the efficacy of [211At]MABG after tail vein xenografting designed to model disseminated neuroblastoma.
Results:
The MTD of [211At]MABG was 66.7 MBq/kg (1.8 mCi/kg) in CB17SC scid−/− mice and 51.8 MBq/kg (1.4 mCi/kg) in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice. Biodistribution of [211At]MABG was similar to [131I]MIBG. Long-term toxicity studies on mice administered with doses up to 41.5 MBq/kg (1.12 mCi/kg) showed the radiotherapeutic to be well tolerated. Both 66.7 MBq/kg (1.8 mCi/kg) single dose and fractionated dosing 16.6 MBq/kg/fraction (0.45 mCi/kg) × 4 over 11 days induced marked tumor regression in two of the three models studied. Survival was significantly prolonged for mice treated with 12.9 MBq/kg/fraction (0.35 mCi/kg) × 4 doses over 11 days [211At]MABG in the disseminated disease (IMR-05NET/GFP/LUC) model (P = 0.003) suggesting eradication of microscopic disease.
Conclusions:
[211At]MABG has significant survival advantage in disseminated models of neuroblastoma. An alpha particle emitting radiopharmaceutical may be effective against microscopic disseminated disease, warranting clinical development.
Data from A Phase Ib/II Randomized Study of RO4929097, a Gamma-Secretase or Notch Inhibitor with or without Vismodegib, a Hedgehog Inhibitor, in Advanced Sarcoma
Authors: Gounder Mrinal M. , Rosenbaum Evan , Wu Nian , Dickson Mark A. , Sheikh Tahir N. , D'Angelo Sandra P. , Chi Ping , Keohan Mary Lou , Erinjeri Joseph P. , Antonescu Cristina R. , Agaram Narasimhan , Hameed Meera R. , Martindale Moriah , Lefkowitz Robert A. , Crago Aimee M. , Singer Sam , Tap William D. , Takebe Naoko , Qin Li-Xuan , Schwartz Gary K.
Published: April 2023

AbstractPurpose:
Because the Hedgehog and Notch pathways are often overexpressed in mesenchymal malignancies, we evaluated the efficacy of concurrent inhibition of Notch and Hedgehog signaling using the gamma-secretase inhibitor (GSI) RO4929097 and the smoothened antagonist vismodegib in unresectable or metastatic sarcoma.
Patients and Methods:
In this investigator-initiated trial, phase Ib used standard 3+3 dose escalation in which patients first received vismodegib once daily for 21 days, followed by the combination of RO4929097 concurrently with vismodegib in 21-day cycles. In phase II, patients were randomized to RO4929097 alone or in combination with vismodegib.
Results:
Nine patients were treated in phase Ib with no dose-limiting toxicities. RO4929097 at 15 mg daily in combination with 150 mg daily of vismodegib was declared the recommended phase II dose. Most adverse events were grade ≤ 2. In phase II (closed early due to discontinuation of RO4929097 evaluation), 34 patients were randomized to RO4929097 alone and 33 to RO4929097 plus vismodegib. RO4929097 did not interfere with the steady-state concentration of vismodegib, while vismodegib reduced the plasma concentration of RO492909. No patients had an objective response. Neither progression-free nor overall survival differed significantly between treatment arms. Paired tumor biopsies from a subset of patients demonstrated inhibition of cleaved Notch.
Conclusions:
The combination of RO4929097 plus vismodegib was generally well tolerated. Although accrual to this study was not completed, vismodegib did not meaningfully enhance the clinical efficacy of RO4929097 in an unplanned analysis. GSIs and GSIs plus vismodegib can inhibit intratumoral Notch and downstream phosphorylated Akt signaling.
Data from Overcoming Taxane Resistance: Preclinical and Phase 1 Studies of Relacorilant, a Selective Glucocorticoid Receptor Modulator, with Nab-Paclitaxel in Solid Tumors
Authors: Munster Pamela N. , Greenstein Andrew E. , Fleming Gini F. , Borazanci Erkut , Sharma Manish R. , Custodio Joseph M. , Tudor Iulia Cristina , Pashova Hristina I. , Shepherd Stacie Peacock , Grauer Andreas , Sachdev Jasgit C.
Published: April 2023

AbstractPurpose:
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 (GR) modulator relacorilant with taxanes can enhance antitumor activity.
Patients and Methods:
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 < 0.001). Compared with paclitaxel alone, relacorilant + paclitaxel reduced tumor growth and slowed time to progression in xenograft models (both P < 0.0001). 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 (≥16 weeks) with relacorilant + nab-paclitaxel and 28.6% (12/42) experienced longer duration of benefit than on prior taxane (up to 6.4×). The most common dose-limiting toxicity of the combination was neutropenia, which was manageable with prophylactic G-CSF. Clinical benefit with relacorilant + nab-paclitaxel was also associated with GR-regulated transcript-level changes in a panel of GR-controlled genes.
Conclusions:
The observed preclinical, clinical, and GR-specific pharmacodynamic responses 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.
Data from Integrated DNA and RNA Sequencing Reveals Drivers of Endocrine Resistance in Estrogen Receptor–Positive Breast Cancer
Authors: Xia Youli , He Xiaping , Renshaw Lorna , Martinez-Perez Carlos , Kay Charlene , Gray Mark , Meehan James , Parker Joel S. , Perou Charles M. , Carey Lisa A. , Dixon J. Michael , Turnbull Arran
Published: April 2023

AbstractPurpose:
Endocrine therapy resistance (ETR) remains the greatest challenge in treating patients with hormone receptor–positive breast cancer. We set out to identify molecular mechanisms underlying ETR through in-depth genomic analysis of breast tumors.
Experimental Design:
We collected pre-treatment and sequential on-treatment tumor samples from 35 patients with estrogen receptor–positive breast cancer treated with neoadjuvant then adjuvant endocrine therapy; 3 had intrinsic resistance, 19 acquired resistance, and 13 remained sensitive. Response was determined by changes in tumor volume neoadjuvantly and by monitoring for adjuvant recurrence. Twelve patients received two or more lines of endocrine therapy, with subsequent treatment lines being initiated at the time of development of resistance to the previous endocrine therapy. DNA whole-exome sequencing and RNA sequencing were performed on all samples, totalling 169 unique specimens. DNA mutations, copy-number alterations, and gene expression data were analyzed through unsupervised and supervised analyses to identify molecular features related to ETR.
Results:
Mutations enriched in ETR included ESR1 and GATA3. The known ESR1 D538G variant conferring ETR was identified, as was a rarer E380Q variant that confers endocrine hypersensitivity. Resistant tumors which acquired resistance had distinct gene expression profiles compared with paired sensitive tumors, showing elevated pathways including ER, HER2, GATA3, AKT, RAS, and p63 signaling. Integrated analysis in individual patients highlighted the diversity of ETR mechanisms.
Conclusions:
The mechanisms underlying ETR are multiple and characterized by diverse changes in both somatic genetic and transcriptomic profiles; to overcome resistance will require an individualized approach utilizing genomic and genetic biomarkers and drugs tailored to each patient.
Data from Clinical Impact of Immune Cells and Their Spatial Interactions in Diffuse Large B-Cell Lymphoma Microenvironment
Authors: Autio Matias , Leivonen Suvi-Katri , Brück Oscar , Karjalainen-Lindsberg Marja-Liisa , Pellinen Teijo , Leppä Sirpa
Published: April 2023

AbstractPurpose:
Tumor-infiltrating immune cells have prognostic significance and are attractive therapeutic targets. Yet, the clinical significance of their spatial organization and phenotype in diffuse large B-cell lymphoma (DLBCL) is unclear.
Experimental Design:
We characterized T cells, macrophages, and their spatial interactions by multiplex IHC (mIHC) in 178 patients with DLBCL and correlated the data with patient demographics and survival. We validated the findings on gene expression data from two external DLBCL cohorts comprising 633 patients.
Results:
Macrophage and T-cell contents divided the samples into T cell–inflamed (60%) and noninflamed (40%) subgroups. The T cell–inflamed lymphoma microenvironment (LME) was also rich in other immune cells, defining immune hot phenotype, which did not as such correlate with outcome. However, when we divided the patients according to T-cell and macrophage contents, LME characterized by high T-cell/low macrophage content or a corresponding gene signature was associated with superior survival [5-year overall survival (OS): 92.3% vs. 74.4%, P = 0.036; 5-year progression-free survival (PFS): 92.6% vs. 69.8%, P = 0.012]. High proportion of PD-L1- and TIM3-expressing CD163− macrophages in the T cell–inflamed LME defined a group of patients with poor outcome [OS: HR = 3.22, 95% confidence interval (CI), 1.63–6.37, Padj = 0.011; PFS: HR = 2.76, 95% CI, 1.44–5.28, Padj = 0.016]. Furthermore, PD-L1 and PD-1 were enriched on macrophages interacting with T cells.
Conclusions:
Our data demonstrate that the interplay between macrophages and T cells in the DLBCL LME is immune checkpoint dependent and clinically meaningful.
Data from Liquid Biopsy Detects Early Molecular Response and Predicts Benefit to First-Line Chemotherapy plus Cetuximab in Metastatic Colorectal Cancer: PLATFORM-B Study
Authors: Vidal Joana , Fernández-Rodríguez Maria Concepción , Casadevall David , García-Alfonso Pilar , Páez David , Guix Marta , Alonso Vicente , Cano Maria Teresa , Santos Cristina , Durán Gema , Elez Elena , Manzano José Luís , Garcia-Carbonero Rocío , Ferreiro Reyes , Losa Ferran , Pineda Estela , Sastre Javier , Rivera Fernando , Bellosillo Beatriz , Tabernero Josep , Aranda Enrique , Salazar Ramon , Montagut Clara
Published: April 2023

AbstractPurpose:
Chemotherapy plus anti-EGFR is standard first-line therapy in RAS wild-type (wt) metastatic colorectal cancer (mCRC), but biomarkers of early response are clinically needed. We aimed to define the utility of ctDNA to assess early response in patients with mCRC receiving first-line anti-EGFR therapy.
Experimental Design:
Prospective multicentric study of tissue patients with RAS wt mCRC treated with first-line chemotherapy plus cetuximab undergoing sequential liquid biopsies. Baseline and early (C3) ctDNA were analyzed by NGS. Trunk mutations were assessed as surrogate marker of total tumor burden. RAS/BRAF/MEK/EGFR-ECD were considered mutations of resistance. ctDNA results were correlated with clinical outcome.
Results:
One hundred patients were included. ctDNA was detected in 72% of patients at baseline and 34% at C3. Decrease in ctDNA trunk mutations correlated with progression-free survival (PFS; HR, 0.23; P = 0.001). RAS/BRAF were the only resistant mutations detected at C3. An increase in the relative fraction of RAS/BRAF at C3 was followed by an expansion of the RAS clone until PD, and was associated with shorter PFS (HR, 10.5; P < 0.001). The best predictor of response was the combined analysis of trunk and resistant mutations at C3. Accordingly, patients with “early molecular response” (decrease in trunk and decrease in resistant mutations) had better response (77.5% vs. 25%, P = 0.008) and longer PFS (HR, 0.18; P < 0.001) compared with patients with “early molecular progression” (increase in trunk and/or increase in resistant mutations).
Conclusions:
ctDNA detects early molecular response and predicts benefit to chemotherapy plus cetuximab. A comprehensive NGS-based approach is recommended to integrate information on total disease burden and resistant mutations.

See related commentary by Eluri et al., p. 302
Data from Triple-Negative PAM50 Non-Basal Breast Cancer Subtype Predicts Benefit from Extended Adjuvant Capecitabine
Authors: Asleh Karama , Lluch Ana , Goytain Angela , Barrios Carlos , Wang Xue Q. , Torrecillas Laura , Gao Dongxia , Ruiz-Borrego Manuel , Leung Samuel , Bines José , Guerrero-Zotano Ángel , García-Sáenz Jose Ángel , Cejalvo Juan Miguel , Herranz Jesus , Torres Roberto , Haba-Rodriguez Juan de la , Ayala Francisco , Gómez Henry , Rojo Federico , Nielsen Torsten O. , Martin Miguel
Published: April 2023

AbstractPurpose:
Predictive biomarkers for capecitabine benefit in triple-negative breast cancer (TNBC) have been recently proposed using samples from phase III clinical trials, including non-basal phenotype and biomarkers related to angiogenesis, stroma, and capecitabine activation genes. We aimed to validate these findings on the larger phase III GEICAM/CIBOMA clinical trial.
Experimental Design:
Tumor tissues from patients with TNBC randomized to standard (neo)adjuvant chemotherapy followed by capecitabine versus observation were analyzed using a 164-gene NanoString custom nCounter codeset measuring mRNA expression. A prespecified statistical plan sought to verify the predictive capacity of PAM50 non-basal molecular subtype and tested the hypotheses that breast tumors with increased expression of (meta)genes for cytotoxic cells, mast cells, endothelial cells, PDL2, and 38 individual genes benefit from adjuvant capecitabine for distant recurrence-free survival (DRFS; primary endpoint) and overall survival.
Results:
Of the 876 women enrolled in the GEICAM/CIBOMA trial, 658 (75%) were evaluable for analysis (337 with capecitabine and 321 without). Of these cases, 553 (84%) were profiled as PAM50 basal-like whereas 105 (16%) were PAM50 non-basal. Non-basal subtype was the most significant predictor for capecitabine benefit [HRcapecitabine, 0.19; 95% confidence interval (CI), 0.07–0.54; P < 0.001] when compared with PAM50 basal-like (HRcapecitabine, 0.9; 95% CI, 0.63–1.28; P = 0.55; Pinteraction<0.001, adjusted P value = 0.01). Analysis of biological processes related to PAM50 non-basal subtype revealed its enrichment for mast cells, extracellular matrix, angiogenesis, and features of mesenchymal stem-like TNBC subtype.
Conclusions:
In this prespecified correlative analysis of the GEICAM/CIBOMA trial, PAM50 non-basal status identified patients with early-stage TNBC most likely to benefit from capecitabine.
Data from Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience
Authors: Marmouset Vincent , Decroocq Justine , Garciaz Sylvain , Etienne Gabriel , Belhabri Amine , Bertoli Sarah , Gastaud Lauris , Simand Célestine , Chantepie Sylvain , Uzunov Madalina , Genthon Alexis , Berthon Céline , Chiche Edmond , Dumas Pierre-Yves , Vargaftig Jacques , Salmeron Géraldine , Lemasle Emilie , Tavernier Emmanuelle , Delage Jérémy , Loirat Marion , Morineau Nadine , Blanc-Durand Félix , Pautier Patricia , Vergé Véronique , Auger Nathalie , Thomas Myrtille , Stefani Laetitia , Lepelley Marion , Boyer Thomas , Thepot Sylvain , Gourin Marie-Pierre , Bourquard Pascal , Duchmann Matthieu , Morice Pierre-Marie , Michallet Mauricette , Adès Lionel , Fenaux Pierre , Récher Christian , Dombret Hervé , Pagès Arnaud , Marzac Christophe , Leary Alexandra , Micol Jean-Baptiste
Published: April 2023

AbstractPurpose:
To provide insights into the diagnosis and management of therapy-related myeloid neoplasms (t-MN) following PARP inhibitors (PARPi).
Experimental Design:
In a French cancer center, we identified and described the profiles of 13 t-MN diagnosed among 37 patients with ovarian cancer referred to hematology consultation for cytopenia under PARPi. Next, we described these 13 t-MN post-PARPi among 37 t-MN post ovarian cancer according to PARPi exposure. Finally, we described 69 t-MN post-PARPi in a national cohort.
Results:
From 2016 to 2021, cumulative incidence of t-MN was 3.5% (13/373) among patients with ovarian cancer treated with PARPi. At time of hematologic consultation, patients with t-MN had a longer PARPi exposure (9 vs. 3 months, P = 0.01), lower platelet count (74 vs. 173 G/L, P = 0.0005), and more cytopenias (2 vs. 1, P = 0.0005). Compared with t-MN not exposed to PARPi, patients with t-MN-PARPi had more BRCA1/2 germline mutation (61.5% vs. 0%, P = 0.03) but similar overall survival (OS). In the national cohort, most t-MN post-PARPi had a complex karyotype (61%) associated with a high rate of TP53 mutation (71%). Median OS was 9.6 months (interquartile range, 4–14.6). In multivariate analysis, a longer time between end of PARPi and t-MN (HR, 1.046; P = 0.02), olaparib compared with other PARPi (HR, 5.82; P = 0.003) and acute myeloid leukemia (HR, 2.485; P = 0.01) were associated with shorter OS.
Conclusions:
In a large series, we described a high incidence of t-MN post-PARPi associated with unfavorable cytogenetic and molecular abnormalities leading to poor OS. Early detection is crucial, particularly in cases of delayed cytopenia.
Data from A Therapeutic Antigen-Presenting Cell-Targeting DNA Vaccine VB10.16 in HPV16-Positive High-Grade Cervical Intraepithelial Neoplasia: Results from a Phase I/IIa Trial
Authors: Hillemanns Peter , Denecke Agnieszka , Woelber Linn , Böhmer Gerd , Jentschke Matthias , Schjetne Karoline W. , Bruins Slot Karsten M.H. , Fredriksen Agnete B.
Published: April 2023

AbstractPurpose:
To evaluate the safety, immunogenicity and efficacy of a therapeutic DNA vaccine VB10.16, using a unique modular vaccine technology that is based on linking antigens to CCL3L1 targeting module, in women with HPV16-positive high-grade cervical intraepithelial neoplasia (CIN).
Patients and Methods:
We conducted a first-in-human, open-label, phase I/IIa clinical trial of VB10.16 in subjects with confirmed HPV16-positive CIN 2/3. The primary endpoint was the proportion of participants with adverse events, including dose-limiting toxicities. Secondary outcome measures included measuring the E6/E7-specific cellular immune response. In the Expansion cohort HPV16 clearance, regression of CIN lesion size and grading were assessed during a 12-month follow-up period.
Results:
A total of 34 women were enrolled: 16 in two dose cohorts and 18 in the expansion cohort. No serious adverse events or dose-limiting toxicities were observed, and none of the subjects discontinued treatment with VB10.16 due to an adverse event. Mild to moderate injection site reactions were the most commonly reported adverse event (79%). HPV16-specific T-cell responses were observed after vaccination in the majority of the subjects. In the expansion cohort, HPV16 clearance was seen in 8 of 17 evaluable subjects (47%). Reductions in lesion size were seen in 16 subjects (94%) and 10 subjects (59%) had regression to CIN 0/1. Correlation between strong IFNγ T-cell responses and lesion size reduction was statistically significant (P < 0.001)
Conclusions:
The novel therapeutic DNA vaccine VB10.16 was well tolerated and showed promising evidence of efficacy and strong HPV16-specific T-cell responses in subjects with high-grade CIN.
Data from Preclinical and Clinical Efficacy of Trastuzumab Deruxtecan in Breast Cancer Brain Metastases
Authors: Kabraji Sheheryar , Ni Jing , Sammons Sarah , Li Tianyu , Van Swearingen Amanda E.D. , Wang Yanzhi , Pereslete Alyssa , Hsu Liangge , DiPiro Pamela J. , Lascola Chris , Moore Heather , Hughes Melissa , Raghavendra Akshara S. , Gule-Monroe Maria , Murthy Rashmi K. , Winer Eric P. , Anders Carey K. , Zhao Jean J. , Lin Nancy U.
Published: April 2023

AbstractPurpose:
Brain metastases can occur in up to 50% of patients with metastatic HER2-positive breast cancer. Because patients with active brain metastases were excluded from previous pivotal clinical trials, the central nervous system (CNS) activity of the antibody–drug conjugate trastuzumab deruxtecan (T-DXd) is not well characterized.
Experimental Design:
We studied how T-DXd affects growth and overall survival in orthotopic patient-derived xenografts (PDX) of HER2-positive and HER2-low breast cancer brain metastases (BCBM). Separately, we evaluated the effects of T-DXd in a retrospective cohort study of 17 patients with stable or active brain metastases.
Results:
T-DXd inhibited tumor growth and prolonged survival in orthotopic PDX models of HER2-positive (IHC 3+) and HER2-low (IHC 2+/FISH ratio < 2) BCBMs. T-DXd reduced tumor size and prolonged survival in a T-DM1–resistant HER2-positive BCBM PDX model. In a retrospective multi-institutional cohort study of 17 patients with predominantly HER2-positive BCBMs, the CNS objective response rate (ORR) was 73% (11/15) while extracranial response rate was 45% (5/11). In the subset of patients with untreated or progressive BCBM at baseline, the CNS ORR was 70% (7/10). The median time on treatment with T-DXd was 8.9 (1.3–16.2) months, with 42% (7/17) remaining on treatment at data cutoff.
Conclusions:
T-DXd demonstrates evidence of CNS activity in HER2-positive and HER2-low PDX models of BCBM and preliminary evidence of clinical efficacy in a multi-institution case series of patients with BCBM. Prospective clinical trials to further evaluate CNS activity of T-DXd in patients with active brain metastases are warranted.

See related commentary by Soffietti and Pellerino, p. 8
Data from Predicting Molecular Subtype and Survival of Rhabdomyosarcoma Patients Using Deep Learning of H&E Images: A Report from the Children's Oncology Group
Authors: Milewski David , Jung Hyun , Brown G. Thomas , Liu Yanling , Somerville Ben , Lisle Curtis , Ladanyi Marc , Rudzinski Erin R. , Choo-Wosoba Hyoyoung , Barkauskas Donald A. , Lo Tammy , Hall David , Linardic Corinne M. , Wei Jun S. , Chou Hsien-Chao , Skapek Stephen X. , Venkatramani Rajkumar , Bode Peter K. , Steinberg Seth M. , Zaki George , Kuznetsov Igor B. , Hawkins Douglas S. , Shern Jack F. , Collins Jack , Khan Javed
Published: April 2023

AbstractPurpose:
Rhabdomyosarcoma (RMS) is an aggressive soft-tissue sarcoma, which primarily occurs in children and young adults. We previously reported specific genomic alterations in RMS, which strongly correlated with survival; however, predicting these mutations or high-risk disease at diagnosis remains a significant challenge. In this study, we utilized convolutional neural networks (CNN) to learn histologic features associated with driver mutations and outcome using hematoxylin and eosin (H&E) images of RMS.
Experimental Design:
Digital whole slide H&E images were collected from clinically annotated diagnostic tumor samples from 321 patients with RMS enrolled in Children's Oncology Group (COG) trials (1998–2017). Patches were extracted and fed into deep learning CNNs to learn features associated with mutations and relative event-free survival risk. The performance of the trained models was evaluated against independent test sample data (n = 136) or holdout test data.
Results:
The trained CNN could accurately classify alveolar RMS, a high-risk subtype associated with PAX3/7-FOXO1 fusion genes, with an ROC of 0.85 on an independent test dataset. CNN models trained on mutationally-annotated samples identified tumors with RAS pathway with a ROC of 0.67, and high-risk mutations in MYOD1 or TP53 with a ROC of 0.97 and 0.63, respectively. Remarkably, CNN models were superior in predicting event-free and overall survival compared with current molecular-clinical risk stratification.
Conclusions:
This study demonstrates that high-risk features, including those associated with certain mutations, can be readily identified at diagnosis using deep learning. CNNs are a powerful tool for diagnostic and prognostic prediction of rhabdomyosarcoma, which will be tested in prospective COG clinical trials.
Data from Circulating Tumor and Immune Cells for Minimally Invasive Risk Stratification of Smoldering Multiple Myeloma
Authors: Termini Rosalinda , Žihala David , Terpos Evangelos , Perez-Montaña Albert , Jelínek Tomáš , Raab Marc , Weinhold Niels , Mai Elias K. , Grab Anna Luise , Corre Jill , Vergez Francois , Sacco Antonio , Chiarini Marco , Giustini Viviana , Tucci Alessandra , Rodriguez Sara , Moreno Cristina , Perez Cristina , Maia Catarina , Martín-Sánchez Esperanza , Guerrero Camilla , Botta Cirino , Garces Juan-Jose , Lopez Aitziber , Tamariz-Amador Luis-Esteban , Prosper Felipe , Bargay Joan , Cabezudo Maria-Elena , Ocio Enrique M. , Hájek Roman , Martinez-Lopez Joaquin , Solano Fernando , Iglesias Rebeca , Paiva Artur , Geraldes Catarina , Vitoria Helena , Gomez Clara , De Arriba Felipe , Ludwig Heinz , Garcia-Guiñon Antoni , Casanova Maria , Alegre Adrian , Cabañas Valentin , Sirvent Maialen , Oriol Albert , de la Rubia Javier , Hernández-Rivas José-Ángel , Palomera Luis , Sarasa Maria , Rios Pablo , Puig Noemi , Mateos Maria-Victoria , Flores-Montero Juan , Orfao Alberto , Goldschmidt Hartmut , Avet-Loiseau Hervé , Roccaro Aldo M. , San-Miguel Jesus F. , Paiva Bruno
Published: April 2023

AbstractPurpose:
Early intervention in smoldering multiple myeloma (SMM) requires optimal risk stratification to avoid under- and overtreatment. We hypothesized that replacing bone marrow (BM) plasma cells (PC) for circulating tumor cells (CTC), and adding immune biomarkers in peripheral blood (PB) for the identification of patients at risk of progression due to lost immune surveillance, could improve the International Myeloma Working Group 20/2/20 model.
Experimental Design:
We report the outcomes of 150 patients with SMM enrolled in the iMMunocell study, in which serial assessment of tumor and immune cells in PB was performed every 6 months for a period of 3 years since enrollment.
Results:
Patients with >0.015% versus ≤0.015% CTCs at baseline had a median time-to-progression of 17 months versus not reached (HR, 4.9; P < 0.001). Presence of >20% BM PCs had no prognostic value in a multivariate analysis that included serum free light-chain ratio >20, >2 g/dL M-protein, and >0.015% CTCs. The 20/2/20 and 20/2/0.015 models yielded similar risk stratification (C-index of 0.76 and 0.78). The combination of the 20/2/0.015 model with an immune risk score based on the percentages of SLAN+ and SLAN− nonclassical monocytes, CD69+HLADR+ cytotoxic NK cells, and CD4+CXCR3+ stem central memory T cells, allowed patient’ stratification into low, intermediate-low, intermediate-high, and high-risk disease with 0%, 20%, 39%, and 73% rates of progression at 2 years.
Conclusions:
This study showed that CTCs outperform BM PCs for assessing tumor burden. Additional analysis in larger series are needed to define a consensus cutoff of CTCs for minimally invasive stratification of SMM.
Data from Phase II Trial of Pembrolizumab and Anti-CD3 x Anti-HER2 Bispecific Antibody-Armed Activated T Cells in Metastatic Castration-Resistant Prostate Cancer
Authors: Vaishampayan Ulka N. , Thakur Archana , Chen Wei , Deol Abhinav , Patel Meera , Dobson Kimberlee , Dickow Brenda , Schalk Dana , Schienschang Amy , Whitaker Sarah , Polend Amanda , Fontana Joseph A. , Heath Elisabeth I. , Lum Lawrence G.
Published: April 2023

AbstractPurpose:
A phase II study was conducted to evaluate the safety and efficacy of the combination of HER2 bispecific antibody (HER2Bi)-armed activated T cells (HER2 BAT) and programmed death 1 inhibitor, pembrolizumab.
Patients and Methods:
Patients with metastatic castration-resistant prostate cancer (mCRPC) with 0 to 1 performance status and normal liver, kidney, and marrow function, pre- or post-docetaxel chemotherapy were eligible. Primary endpoint was 6-month progression-free survival (PFS). Peripheral blood mononuclear cells were obtained by a single apheresis, shipped to University of Virginia, activated with OKT3 and expanded for 14 days in IL2, harvested, and armed with HER2Bi and cryopreserved. HER2 BATs were infused twice weekly for 4 weeks and pembrolizumab was administered every 21 days for a maximum duration of 6 months starting 1 to 3 weeks prior to HER2 BATs infusion.
Results:
Fourteen patients were enrolled with a median age of 69 (range 57–82 years) and median PSA of 143.4 (range 8.2–4210 ng/dL). Two patients had peritoneal metastases, 1 had lymph node (LN) only metastases and 11 had bone metastases of which 7 had bone and LN metastases. All were pretreated with androgen receptor axis targeted agents and 7 (50%) had prior docetaxel chemotherapy. The toxicities were grade1–2 infusion reactions with fever, chills, headaches, nausea and/or myalgias. Primary endpoint of 6 month PFS was achieved in 5 of 14 patients (38.5%; 95% confidence interval, 19.5%–76.5%). Median PFS was 5 months and median survival was 31.6 months.
Conclusions:
The safety and promising efficacy makes this combination worthy of future investigation in mCRPC.
Data from EWS::FLI1 and HOXD13 Control Tumor Cell Plasticity in Ewing Sarcoma
Authors: Apfelbaum April A. , Wu Feinan , Hawkins Allegra G. , Magnuson Brian , Jiménez Jennifer A. , Taylor Sean D. , Wrenn Emma D. , Waltner Olivia , Pfaltzgraff Elise R. , Song Jane Y. , Hall Cody , Wellik Deneen M. , Ljungman Mats , Furlan Scott N. , Ryan Russell J.H. , Sarthy Jay F. , Lawlor Elizabeth R.
Published: April 2023

AbstractPurpose:
Propagation of Ewing sarcoma requires precise regulation of EWS::FLI1 transcriptional activity. Determining the mechanisms of fusion regulation will advance our understanding of tumor progression. Here we investigated whether HOXD13, a developmental transcription factor that promotes Ewing sarcoma metastatic phenotypes, influences EWS::FLI1 transcriptional activity.
Experimental Design:
Existing tumor and cell line datasets were used to define EWS::FLI1 binding sites and transcriptional targets. Chromatin immunoprecipitation and CRISPR interference were employed to identify enhancers. CUT&RUN and RNA sequencing defined binding sites and transcriptional targets of HOXD13. Transcriptional states were investigated using bulk and single-cell transcriptomic data from cell lines, patient-derived xenografts, and patient tumors. Mesenchymal phenotypes were assessed by gene set enrichment, flow cytometry, and migration assays.
Results:
We found that EWS::FLI1 creates a de novo GGAA microsatellite enhancer in a developmentally conserved regulatory region of the HOXD locus. Knockdown of HOXD13 led to widespread changes in expression of developmental gene programs and EWS::FLI1 targets. HOXD13 binding was enriched at established EWS::FLI1 binding sites where it influenced expression of EWS::FLI1-activated genes. More strikingly, HOXD13 bound and activated EWS::FLI1-repressed genes, leading to adoption of mesenchymal and migratory cell states that are normally suppressed by the fusion. Single-cell analysis confirmed that direct transcriptional antagonism between HOXD13-mediated gene activation and EWS::FLI1-dependent gene repression defines the state of Ewing sarcoma cells along a mesenchymal axis.
Conclusions:
Ewing sarcoma tumors are comprised of tumor cells that exist along a mesenchymal transcriptional continuum. The identity of cells along this continuum is, in large part, determined by the competing activities of EWS::FLI1 and HOXD13.

See related commentary by Weiss and Bailey, p. 4360