bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Antibody-based Delivery of TNF to the Tumor Neovasculature Potentiates the Therapeutic Activity of a Peptide Anticancer Vaccine
Authors: Probst Philipp , Stringhini Marco , Ritz Danilo , Fugmann Tim , Neri Dario
Published: April 2023

AbstractPurpose:
There is a growing interest in the use of tumor antigens for therapeutic vaccination strategies. Unfortunately, in most cases, the use of peptide vaccines in patients does not mediate shrinkage of solid tumor masses.

Experimental Design: Here, we studied the opportunity to boost peptide vaccination with F8-TNF, an antibody fusion protein that selectively delivers TNF to the tumor extracellular matrix. AH1, a model antigen to investigate CD8+ T-cell immunity in BALB/c mice, was used as vaccine.
Results:
Peptide antigens alone exhibited only a modest tumor growth inhibition. However, anticancer activity could be substantially increased by combination with F8-TNF. Analysis of T cells in tumors and in draining lymph nodes revealed a dramatic expansion of AH1-specific CD8+ T cells, which were strongly positive for PD-1, LAG-3, and TIM-3. The synergistic anticancer activity, observed in the combined use of peptide vaccination and F8-TNF, was largely due to the ability of the fusion protein to induce a rapid hemorrhagic necrosis in the tumor mass, thus leaving few residual tumor cells. While the cell surface phenotype of tumor-infiltrating CD8+ T cells did not substantially change upon treatment, the proportion of AH1-specific T cells was strongly increased in the combination therapy group, reaching more than 50% of the CD8+ T cells within the tumor mass.
Conclusions:
Because both peptide vaccination strategies and tumor-homing TNF fusion proteins are currently being studied in clinical trials, our study provides a rationale for the combination of these 2 regimens for the treatment of patients with cancer.
Data from Leveraging Bioorthogonal Click Chemistry to Improve 225Ac-Radioimmunotherapy of Pancreatic Ductal Adenocarcinoma
Authors: Poty Sophie , Carter Lukas M. , Mandleywala Komal , Membreno Rosemery , Abdel-Atti Dalya , Ragupathi Ashwin , Scholz Wolfgang W. , Zeglis Brian M. , Lewis Jason S.
Published: April 2023

AbstractPurpose:
Interest in targeted alpha-therapy has surged due to α-particles' high cytotoxicity. However, the widespread clinical use of this approach could be limited by on-/off-target toxicities. Here, we investigated the inverse electron-demand Diels–Alder ligation between an 225Ac-labeled tetrazine radioligand and a trans-cyclooctene–bearing anti-CA19.9 antibody (5B1) for pretargeted α-radioimmunotherapy (PRIT) of pancreatic ductal adenocarcinoma (PDAC). This alternative strategy is expected to reduce nonspecific toxicities as compared with conventional radioimmunotherapy (RIT).

Experimental Design: A side-by-side comparison of 225Ac-PRIT and conventional RIT using a directly 225Ac-radiolabeled immunoconjugate evaluates the therapeutic efficacy and toxicity of both methodologies in PDAC murine models.
Results:
A comparative biodistribution study of the PRIT versus RIT methodology underscored the improved pharmacokinetic properties (e.g., prolonged tumor uptake and increased tumor-to-tissue ratios) of the PRIT approach. Cerenkov imaging coupled to PRIT confirmed the in vivo biodistribution of 225Ac-radioimmunoconjugate but—importantly—further allowed for the ex vivo monitoring of 225Ac's radioactive daughters' redistribution. Human dosimetry was extrapolated from the mouse biodistribution and confirms the clinical translatability of 225Ac-PRIT. Furthermore, longitudinal therapy studies performed in subcutaneous and orthotopic PDAC models confirm the therapeutic efficacy of 225Ac-PRIT with the observation of prolonged median survival compared with control cohorts. Finally, a comparison with conventional RIT highlighted the potential of 225Ac-PRIT to reduce hematotoxicity while maintaining therapeutic effectiveness.
Conclusions:
The ability of 225Ac-PRIT to deliver a radiotherapeutic payload while simultaneously reducing the off-target toxicity normally associated with RIT suggests that the clinical translation of this approach will have a profound impact on PDAC therapy.
Data from Exosome-Transmitted PSMA3 and PSMA3-AS1 Promote Proteasome Inhibitor Resistance in Multiple Myeloma
Authors: Xu Hongxia , Han Huiying , Song Sha , Yi Nengjun , Qian Chen'ao , Qiu Yingchun , Zhou Wenqi , Hong Yating , Zhuang Wenyue , Li Zhengyi , Li Bingzong , Zhuang Wenzhuo
Published: April 2023

AbstractPurpose:
How exosomal RNAs released within the bone marrow microenvironment affect proteasome inhibitors' (PI) sensitivity of multiple myeloma is currently unknown. This study aims to evaluate which exosomal RNAs are involved and by which molecular mechanisms they exert this function.

Experimental Design: Exosomes were characterized by dynamic light scattering, transmission electron microscopy, and Western blot analysis. Coculture experiments were performed to assess exosomal RNAs transferring from mesenchymal stem cells (MSC) to multiple myeloma cells. The role of PSMA3-AS1 in PI sensitivity was further evaluated in vivo. To determine the prognostic significance of circulating exosomal PSMA3 and PSMA3-AS1, a cohort of patients with newly diagnosed multiple myeloma was enrolled to study. Cox regression models and Kaplan–Meier curves were used to analyze progression-free survival (PFS) and overall survival (OS).
Results:
We identified that PSMA3 and PSMA3-AS1 in MSCs could be packaged into exosomes and transferred to myeloma cells, thus promoting PI resistance. PSMA3-AS1 could form an RNA duplex with pre-PSMA3, which transcriptionally promoted PSMA3 expression by increasing its stability. In xenograft models, intravenously administered siPSMA3-AS1 was found to be effective in increasing carfilzomib sensitivity. Moreover, plasma circulating exosomal PSMA3 and PSMA3-AS1 derived from patients with multiple myeloma were significantly associated with PFS and OS.
Conclusions:
This study suggested a unique role of exosomal PSMA3 and PSMA3-AS1 in transmitting PI resistance from MSCs to multiple myeloma cells, through a novel exosomal PSMA3-AS1/PSMA3 signaling pathway. Exosomal PSMA3 and PSMA3-AS1 might act as promising therapeutic targets for PI resistance and prognostic predictors for clinical response.
Data from Blocking Monocytic Myeloid-Derived Suppressor Cell Function via Anti-DC-HIL/GPNMB Antibody Restores the In Vitro Integrity of T Cells from Cancer Patients
Authors: Kobayashi Masato , Chung Jin-Sung , Beg Muhammad , Arriaga Yull , Verma Udit , Courtney Kevin , Mansour John , Haley Barbara , Khan Saad , Horiuchi Yutaka , Ramani Vijay , Harker David , Gopal Purva , Araghizadeh Farshid , Cruz Ponciano D. , Ariizumi Kiyoshi
Published: April 2023

AbstractPurpose:
Blocking the function of myeloid-derived suppressor cells (MDSC) is an attractive approach for cancer immunotherapy. Having shown DC-HIL/GPNMB to be the T-cell-inhibitory receptor mediating the suppressor function of MDSCs, we evaluated the potential of anti-DC-HIL mAb as an MDSC-targeting cancer treatment.
Experimental Design:
Patients with metastatic cancer (n = 198) were analyzed by flow cytometry for DC-HIL or PDL1 expression on blood CD14+HLA-DRno/lo MDSCs. Their suppressor function was assessed by in vitro coculture with autologous T cells, and the ability of anti-DC-HIL or anti-PDL1 mAb to reverse such function was determined. Tumor expression of these receptors was examined histologically, and the antitumor activity of the mAb was evaluated by attenuated growth of colon cancers in mice.
Results:
Patients with metastatic cancer had high blood levels of DC-HIL+ MDSCs compared with healthy controls. Anti-DC-HIL mAb reversed the in vitro function in ∼80% of cancer patients tested, particularly for colon cancer. Despite very low expression on blood MDSCs, anti-PDL1 mAb was as effective as anti-DC-HIL mAb in reversing MDSC function, a paradoxical phenomenon we found to be due to upregulated expression of PDL1 by T-cell-derived IFNγ in cocultures. DC-HIL is not expressed by colorectal cancer cells but by CD14+ cells infiltrating the tumor. Finally, anti-DC-HIL mAb attenuated growth of preestablished colon tumors by reducing MDSCs and increasing IFNγ-secreting T cells in the tumor microenvironment, with similar outcomes to anti-PDL1 mAb.
Conclusions:
Blocking DC-HIL function is a potentially useful treatment for at least colorectal cancer with high blood levels of DC-HIL+ MDSCs.

See related commentary by Colombo, p. 453
Data from Intratumoral Comparison of Nanoparticle Entrapped Docetaxel (CPC634) with Conventional Docetaxel in Patients with Solid Tumors
Authors: Atrafi Florence , van Eerden Ruben A.G. , van Hylckama Vlieg Marte A.M , Oomen-de Hoop Esther , de Bruijn Peter , Lolkema Martijn P. , Moelker Adriaan , Rijcken Cristianne J. , Hanssen Rob , Sparreboom Alex , Eskens Ferry A.L.M. , Mathijssen Ron H.J. , Koolen Stijn L.W.
Published: April 2023

AbstractPurpose:
CPC634 is a novel nanoparticle entrapping docetaxel, developed to enhance the intratumoral chemotherapy exposure. This randomized cross-over study compared the intratumoral and plasma pharmacokinetics of CPC634 with conventional docetaxel.
Patients and Methods:
Adult patients with solid tumors were randomized to receive CPC634 (75 mg/m2) in cycle 1, and conventional docetaxel (75 mg/m2) in cycle 2 or vice versa. The study was powered to identify a 25% increase of intratumoral total docetaxel exposure after CPC634 infusion compared with conventional docetaxel. Four patients were allocated per tumor sampling time point, that is, 24, 48, 72, and 96 hours, 7 and 14 days after infusion during both cycles. Total docetaxel and released docetaxel from the nanoparticle were determined in tumor tissue derived from a metastatic lesion and in plasma. Pharmacokinetic data were analyzed using linear mixed modeling.
Results:
In total, 24 evaluable patients were included. In the tumor, CPC634 exhibited a 461% higher total docetaxel (P < 0.001) and a comparable released docetaxel concentration (P = 0.43). Plasma AUCinf was 27% higher (P = 0.001) and Cmax was 91% lower (P < 0.001) for CPC634 released docetaxel. The median observed neutrophil count nadir after conventional docetaxel treatment was lower (0.50 × 109/L) compared with CPC634 (4.30 × 109/L; P < 0.001).
Conclusions:
Here, we demonstrated that CPC634 enhanced the intratumoral total docetaxel exposure compared with conventional docetaxel. The lower incidence of neutropenia during CPC634 treatment is presumably related to lower plasma Cmax of released docetaxel. The unique pharmacokinetic profile of CPC634 nanoparticles has the potential to improve docetaxel treatment. A phase II efficacy trial of CPC634 is currently ongoing.
Data from High-Throughput Functional Evaluation of Variants of Unknown Significance in ERBB2
Authors: Nagano Masaaki , Kohsaka Shinji , Ueno Toshihide , Kojima Shinya , Saka Kanju , Iwase Hirotaro , Kawazu Masahito , Mano Hiroyuki
Published: April 2023

Abstract
Purpose: The advent of next-generation sequencing technologies has enabled the identification of several activating mutations of Erb-B2 receptor tyrosine kinase 2 (ERBB2) among various cancers. However, the significance of infrequent mutations has not been fully investigated. Herein, we comprehensively assessed the functional significance of the ERBB2 mutations in a high-throughput manner.

Experimental Design: We evaluated the transforming activities and drug sensitivities of 55 nonsynonymous ERBB2 mutations using the mixed-all-nominated-in-one (MANO) method.

Results: G776V, G778_S779insG, and L841V were newly revealed to be activating mutations. Although afatinib, neratinib, and osimertinib were shown to be effective against most of the ERBB2 mutations, only osimertinib demonstrated good efficacy against L755P and L755S mutations, the most common mutations in breast cancer. In contrast, afatinib and neratinib were predicted to be more effective than other inhibitors for the A775_776insYVMA mutation, the most frequent ERBB2 mutation in lung cancer. We surveyed the prevalence of concurrent ERBB2 mutation with gene amplification and found that approximately 30% of ERBB2-amplified urothelial carcinomas simultaneously carried ERBB2 mutations, altering their sensitivity to trastuzumab, an mAb against ERBB2. Furthermore, the MANO method was applied to evaluate the functional significance of 17 compound mutations within ERBB2 reported in the COSMIC database, revealing that compound mutations involving L755S were sensitive to osimertinib but insensitive to afatinib and neratinib.

Conclusions: Several ERBB2 mutations showed varying sensitivities to ERBB2-targeted inhibitors. Our comprehensive assessment of ERBB2 mutations offers a fundamental database to help customize therapy for ERBB2-driven cancers.

We identified several ERBB2 mutations as activating mutations related to tumorigenesis. In addition, our comprehensive evaluation revealed that several ERBB2 mutations showed varying sensitivities to ERBB2-targeted inhibitors, and thus, the functional significance of each variant should be interpreted precisely to design the best treatment for each patient. Clin Cancer Res; 24(20); 5112–22. ©2018 AACR.
Data from The Impact of Early-Phase Trial Design in the Drug Development Process
Authors: Conaway Mark R. , Petroni Gina R.
Published: April 2023

AbstractPurpose:
Many of the therapeutic agents that are being used currently were developed using the 3+3 decision rule for dose finding. Over the past 30 years, several dose-finding designs have been proposed and evaluated, including the “continual reassessment method” (CRM) and the “Bayesian optimal interval design” (BOIN). This research investigates the role of the choice of an early-phase design on the likelihood that drugs entering the drug development pipeline will have 2 successful phase III trials.

Experimental Design: Using simulation, each agent in a population of hypothetical agents was tracked through the drug development process, from initial dose finding to 2 confirmatory phase III trials. Varying the designs of the phase I, II, and III trials allows for an assessment of the effect of the choice of designs on the proportion of agents with successful phase III trials.
Results:
The results indicate that using the CRM or BOIN, rather than the 3+3, substantially enhances the proportion of effective agents that have successful phase III trials, with the CRM having a greater effect than BOIN. A larger phase II trial magnifies the effect of the phase I design.
Conclusions:
The results underscore the importance of the choice of the early-phase designs. Use of the 3+3 results in fewer agents with successful phase III trials compared with the CRM or BOIN. The difference is more pronounced among highly effective agents. In addition, the results show the importance of a sufficiently powered phase II trial.
Data from Local Intracerebral Immunomodulation Using Interleukin-Expressing Mesenchymal Stem Cells in Glioblastoma
Authors: Mohme Malte , Maire Cecile L. , Geumann Ulf , Schliffke Simon , Dührsen Lasse , Fita Krystian , Akyüz Nuray , Binder Mascha , Westphal Manfred , Guenther Christine , Lamszus Katrin , Hermann Felix G. , Schmidt Nils Ole
Published: April 2023

AbstractPurpose:
Mesenchymal stem cells (MSCs) show an inherent brain tumor tropism that can be exploited for targeted delivery of therapeutic genes to invasive glioma. We assessed whether a motile MSC-based local immunomodulation is able to overcome the immunosuppressive glioblastoma microenvironment and to induce an antitumor immune response.
Experimental Design:
We genetically modified MSCs to coexpress high levels of IL12 and IL7 (MSCIL7/12, Apceth-301). Therapeutic efficacy was assessed in two immunocompetent orthotopic C57BL/6 glioma models using GL261 and CT2A. Immunomodulatory effects were assessed by multicolor flow cytometry to profile immune activation and exhaustion of tumor-infiltrating immune cells. Diversity of the tumor-specific immune response as analyzed using T-cell receptor sequencing.
Results:
Intratumoral administration of MSCIL7/12 induced significant tumor growth inhibition and remission of established intracranial tumors, as demonstrated by MR imaging. Notably, up to 50% of treated mice survived long-term. Rechallenging of survivors confirmed long-lasting tumor immunity. Local treatment with MSCIL7/12 was well tolerated and led to a significant inversion of the CD4+/CD8+ T-cell ratio with an intricate, predominantly CD8+ effector T-cell–mediated antitumor response. T-cell receptor sequencing demonstrated an increased diversity of TILs in MSCIL7/12-treated mice, indicating a broader tumor-specific immune response with subsequent oligoclonal specification during generation of long-term immunity.
Conclusions:
Local MSC-based immunomodulation is able to efficiently alter the immunosuppressive microenvironment in glioblastoma. The long-lasting therapeutic effects warrant a rapid clinical translation of this concept and have led to planning of a phase I/II study of apceth-301 in recurrent glioblastoma.
Data from Anaplastic Lymphoma Kinase Mutation (ALK F1174C) in Small Cell Carcinoma of the Prostate and Molecular Response to Alectinib
Authors: Carneiro Benedito A. , Pamarthy Sahithi , Shah Ami N. , Sagar Vinay , Unno Kenji , Han HuiYing , Yang Ximing J. , Costa Rubens B. , Nagy Rebecca J. , Lanman Richard B. , Kuzel Timothy M. , Ross Jeffrey S. , Gay Laurie , Elvin Julia A. , Ali Siraj M. , Cristofanilli Massimo , Chae Young K. , Giles Francis J. , Abdulkadir Sarki A.
Published: April 2023

Abstract
Purpose: Small cell carcinoma of the prostate (SCCP) is an aggressive disease that can arise de novo or by transdifferentiation from prostate adenocarcinoma. Alterations in anaplastic lymphoma kinase (ALK) gene are involved in neuroblastoma, lung cancer, and other malignancies, but its role in SCCP has not been documented. We describe a patient with refractory de novo SCCP with ALK F1174C–activating mutation who obtained clinical benefit from treatment with ALK inhibitor.

Experimental Design: Next-generation sequencing (NGS) was used to analyze primary and circulating tumor DNA (ctDNA). Prostate cancer databases were queried for alterations in ALK gene, mRNA, and its impact in clinical outcomes. In vitro prostate cell line/organoid models were generated by lentiviral-mediated expression of ALK and ALK F1174C and assessed for response to ALK inhibitors crizotinib and alectinib.

Results: NGS analysis of the primary tumor and ctDNA of a 39-year-old patient with refractory SSCP identified ALK F1174C mutation. Treatment with second-generation ALK inhibitor alectinib resulted in radiographic stable disease for over 6 months, symptomatic improvement, and significant molecular response as reflected by declining ctDNA allele fraction. Analysis of prostate cancer datasets showed that ALK amplification was associated with poor outcome. In prostate cancer cells and organoids, ALK F1174C expression enhanced growth and induced expression of the neuroendocrine marker neuron-specific enolase. Alectinib was more effective than crizotinib in inhibiting ALK F1174C–expressing cell growth.

Conclusions: These findings implicate ALK-activating mutations in SCCP pathogenesis and suggest the therapeutic potential of targeting ALK molecular alterations in some patients with SCCP. Clin Cancer Res; 24(12); 2732–9. ©2018 AACR.
Data from Final Report of a Phase I Trial of Olaparib with Cetuximab and Radiation for Heavy Smoker Patients with Locally Advanced Head and Neck Cancer
Authors: Karam Sana D. , Reddy Krishna , Blatchford Patrick J. , Waxweiler Tim , DeLouize Alicia M. , Oweida Ayman , Somerset Hilary , Marshall Carrie , Young Christian , Davies Kurtis D. , Kane Madeleine , Tan Aik Choo , Wang Xiao Jing , Jimeno Antonio , Aisner Dara L. , Bowles Daniel W. , Raben David
Published: April 2023

Abstract
Purpose: Our goal was to evaluate the safety and toxicity of combining a PARP inhibitor, olaparib, with cetuximab and fractionated intensity-modulated radiotherapy for patients with locally advanced head and neck cancer and heavy smoking histories.

Patients and Methods: Patients with ≥10 packs/year history of smoking were treated with olaparib at doses ranging from 25–200 mg orally twice daily beginning approximately 10 days prior to initiation of and with concurrent radiation (69.3 Gy in 33 fractions) using a time-to-event continual reassessment method model. Cetuximab was administered starting approximately 5 days prior to radiation per standard of care.

Results: A total of 16 patients were entered onto the study, with 15 evaluable for acute toxicity. The most common treatment-related grade 3–4 side effects were radiation dermatitis and mucositis (38% and 69%, respectively). The MTD was determined to be 50 mg orally twice daily, but the recommended phase II dose was deemed to be 25 mg orally twice daily. At a median follow-up of 26 months, the actuarial median overall survival was 37 months, but was not reached for other endpoints. Two-year overall survival, progression-free survival, local control, and distant control rates were 72%, 63%, 72%, and 79%, respectively. Patients who continued to smoke during therapy experienced higher recurrence rates. MYC and KMT2A were identified as potential correlatives of response on gene amplification and mutational analysis.

Conclusions: Olaparib at 25 mg orally twice daily with concurrent cetuximab and radiation was well tolerated with reduced dermatitis within the radiation field. Response rates were promising for this high-risk population. Clin Cancer Res; 24(20); 4949–59. ©2018 AACR.
Data from Lobular Carcinomas In Situ Display Intralesion Genetic Heterogeneity and Clonal Evolution in the Progression to Invasive Lobular Carcinoma
Authors: Lee Ju Youn , Schizas Michail , Geyer Felipe C. , Selenica Pier , Piscuoglio Salvatore , Sakr Rita A. , Ng Charlotte K.Y. , Carniello Jose V. Scarpa , Towers Russell , Giri Dilip D. , de Andrade Victor P. , Papanastasiou Anastasios D. , Viale Agnes , Harris Reuben S. , Solit David B. , Weigelt Britta , Reis-Filho Jorge S. , King Tari A.
Published: April 2023

AbstractPurpose:
Lobular carcinoma in situ (LCIS) is a preinvasive lesion of the breast. We sought to define its genomic landscape, whether intralesion genetic heterogeneity is present in LCIS, and the clonal relatedness between LCIS and invasive breast cancers.

Experimental Design: We reanalyzed whole-exome sequencing (WES) data and performed a targeted amplicon sequencing validation of mutations identified in 43 LCIS and 27 synchronous more clinically advanced lesions from 24 patients [9 ductal carcinomas in situ (DCIS), 13 invasive lobular carcinomas (ILC), and 5 invasive ductal carcinomas (IDC)]. Somatic genetic alterations, mutational signatures, clonal composition, and phylogenetic trees were defined using validated computational methods.
Results:
WES of 43 LCIS lesions revealed a genomic profile similar to that previously reported for ILCs, with CDH1 mutations present in 81% of the lesions. Forty-two percent (18/43) of LCIS were found to be clonally related to synchronous DCIS and/or ILCs, with clonal evolutionary patterns indicative of clonal selection and/or parallel/branched progression. Intralesion genetic heterogeneity was higher among LCIS clonally related to DCIS/ILC than in those nonclonally related to DCIS/ILC. A shift from aging to APOBEC-related mutational processes was observed in the progression from LCIS to DCIS and/or ILC in a subset of cases.
Conclusions:
Our findings support the contention that LCIS has a repertoire of somatic genetic alterations similar to that of ILCs, and likely constitutes a nonobligate precursor of breast cancer. Intralesion genetic heterogeneity is observed in LCIS and should be considered in studies aiming to develop biomarkers of progression from LCIS to more advanced lesions.
Data from Rebalancing Protein Homeostasis Enhances Tumor Antigen Presentation
Authors: Jaeger Alex M. , Stopfer Lauren , Lee Sunmin , Gaglia Giorgio , Sandel Demi , Santagata Sandro , Lin Nancy U. , Trepel Jane B. , White Forest , Jacks Tyler , Lindquist Susan , Whitesell Luke
Published: April 2023

AbstractPurpose:
Despite the accumulation of extensive genomic alterations, many cancers fail to be recognized as “foreign” and escape destruction by the host immune system. Immunotherapies designed to address this problem by directly stimulating immune effector cells have led to some remarkable clinical outcomes, but unfortunately, most cancers fail to respond, prompting the need to identify additional immunomodulatory treatment options.

Experimental Design: We elucidated the effect of a novel treatment paradigm using sustained, low-dose HSP90 inhibition in vitro and in syngeneic mouse models using genetic and pharmacologic tools. Profiling of treatment-associated tumor cell antigens was performed using immunoprecipitation followed by peptide mass spectrometry.
Results:
We show that sustained, low-level inhibition of HSP90 both amplifies and diversifies the antigenic repertoire presented by tumor cells on MHC-I molecules through an IFNγ-independent mechanism. In stark contrast, we find that acute, high-dose exposure to HSP90 inhibitors, the only approach studied in the clinic to date, is broadly immunosuppressive in cell culture and in patients with cancer. In mice, chronic non-heat shock–inducing HSP90 inhibition slowed progression of colon cancer implants, but only in syngeneic animals with intact immune function. Addition of a single dose of nonspecific immune adjuvant to the regimen dramatically increased efficacy, curing a subset of mice receiving combination therapy.
Conclusions:
These highly translatable observations support reconsideration of the most effective strategy for targeting HSP90 to treat cancers and suggest a practical approach to repurposing current orally bioavailable HSP90 inhibitors as a new immunotherapeutic strategy.

See related commentary by Srivastava and Callahan, p. 6277
Data from Pathologic Complete Response after Neoadjuvant Chemotherapy and Impact on Breast Cancer Recurrence and Survival: A Comprehensive Meta-analysis
Authors: Spring Laura M. , Fell Geoffrey , Arfe Andrea , Sharma Chandni , Greenup Rachel , Reynolds Kerry L. , Smith Barbara L. , Alexander Brian , Moy Beverly , Isakoff Steven J. , Parmigiani Giovanni , Trippa Lorenzo , Bardia Aditya
Published: April 2023

AbstractPurpose:
While various studies have highlighted the prognostic significance of pathologic complete response (pCR) after neoadjuvant chemotherapy (NAT), the impact of additional adjuvant therapy after pCR is not known.
Experimental Design:
PubMed was searched for studies with NAT for breast cancer and individual patient-level data was extracted for analysis using plot digitizer software. HRs, with 95% probability intervals (PI), measuring the association between pCR and overall survival (OS) or event-free survival (EFS), were estimated using Bayesian piece-wise exponential proportional hazards hierarchical models including pCR as predictor.
Results:
Overall, 52 of 3,209 publications met inclusion criteria, totaling 27,895 patients. Patients with a pCR after NAT had significantly better EFS (HR = 0.31; 95% PI, 0.24–0.39), particularly for triple-negative (HR = 0.18; 95% PI, 0.10–0.31) and HER2+ (HR = 0.32; 95% PI, 0.21–0.47) disease. Similarly, pCR after NAT was also associated with improved survival (HR = 0.22; 95% PI, 0.15–0.30). The association of pCR with improved EFS was similar among patients who received subsequent adjuvant chemotherapy (HR = 0.36; 95% PI, 0.19–0.67) and those without adjuvant chemotherapy (HR = 0.36; 95% PI, 0.27–0.54), with no significant difference between the two groups (P = 0.60).
Conclusions:
Achieving pCR following NAT is associated with significantly better EFS and OS, particularly for triple-negative and HER2+ breast cancer. The similar outcomes with or without adjuvant chemotherapy in patients who attain pCR likely reflects tumor biology and systemic clearance of micrometastatic disease, highlighting the potential of escalation/deescalation strategies in the adjuvant setting based on neoadjuvant response.

See related commentary by Esserman, p. 2771
Data from PD-L1 Protein Expression on Both Tumor Cells and Macrophages are Associated with Response to Neoadjuvant Durvalumab with Chemotherapy in Triple-negative Breast Cancer
Authors: Ahmed Fahad Shabbir , Gaule Patricia , McGuire John , Patel Katir , Blenman Kim , Pusztai Lajos , Rimm David L.
Published: April 2023

AbstractPurpose:
In both the IMpassion 130 trial in the metastatic setting and in Keynote 522 in the neoadjuvant setting, patients with triple-negative breast cancer (TNBC) showed benefit from PD-1 axis immunotherapy. Here, we assess PD-L1 expression on both tumor and immune cells using quantitative immunofluorescence to assess association with benefit from neoadjuvant durvalumab concurrent with chemotherapy in TNBC.
Experimental Design:
Pretreatment core needle biopsies (n = 69) were obtained from patients who participated in a phase I/II clinical trial (NCT02489448). The final analysis included 45 patients [pathologic complete response (pCR) = 18, non-pCR = 27] due to technical issues and insufficient tissue. Slides were stained using a previously validated Ultivue DNA-based Ultimapper kit (CD8, CD68, PD-L1, Cytokeratin/Sox10, and Hoechst counterstain). The PD-L1 expression was analyzed by molecular compartmentalization without segmentation using AQUA software (version 3.2.2.1) in three tissue compartments including tumor (cytokeratin-positive cells), CD68+ cells, and overall stroma.
Results:
In patients with pCR, PD-L1 expression was significantly higher in tumor cells, in CD68+ cells and in the stroma compared with patients non-pCR. There was no difference in the amount of CD68+ cells in the tumor or stromal compartments between cases with pCR and non-pCR.
Conclusions:
Expression of PD-L1 in tumor cells, immune cells in stroma, and colocalized with CD68+ cells is associated with higher rates of pCR to durvalumab and chemotherapy in TNBC.
Data from Talimogene Laherparepvec and Pembrolizumab in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (MASTERKEY-232): A Multicenter, Phase 1b Study
Authors: Harrington Kevin J. , Kong Anthony , Mach Nicolas , Chesney Jason A. , Fernandez Beatriz Castelo , Rischin Danny , Cohen Ezra E.W. , Radcliffe Hoi-Shen , Gumuscu Burak , Cheng Jonathan , Snyder Wendy , Siu Lillian L.
Published: April 2023

AbstractPurpose:
The prognosis for patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) is poor, and only a minority of patients benefit from checkpoint immunotherapy. Talimogene laherparepvec (T-VEC), an oncolytic immunotherapy approved for advanced melanoma, in combination with pembrolizumab may yield enhanced antitumor activity over either agent alone.
Patients and Methods:
This was a phase Ib/III, multicenter trial testing intratumoral T-VEC combined with intravenous pembrolizumab in R/M HNSCC refractory to platinum-based chemotherapy. For phase Ib, primary endpoint was incidence of dose-limiting toxicity (DLT). Key secondary endpoints included objective response rate and progression-free survival per irRECIST, overall survival, and safety.
Results:
Thirty-six patients were enrolled into the phase Ib study. The data cut-off date was August 28, 2018. Median follow-up was 5.8 months (range, 0.3–24.2). One DLT of T-VEC–related fatal arterial hemorrhage was reported. Twenty (55.6%) and 21 (58.3%) patients experienced adverse events (AE) related to T-VEC and pembrolizumab, respectively. Besides the DLT, there were no treatment-related fatal AEs. A confirmed partial response was observed in 5 (13.9%) patients. Ten (27.8%) patients were unevaluable for response due to early death. Median PFS and OS were 3.0 months [95% confidence interval (Cl), 2.0–5.8] and 5.8 months (95% Cl, 2.9–11.4), respectively.
Conclusions:
The combination of T-VEC and pembrolizumab demonstrated a tolerable safety profile in R/M HNSCC. The efficacy with the combination was similar to that with pembrolizumab monotherapy in historical HNSCC studies. Phase III part of this study was not further pursued (ClinicalTrials.gov Identifier: NCT02626000).
Data from Randomized Phase II Trial of Carboplatin–Paclitaxel Compared with Carboplatin–Paclitaxel–Trastuzumab in Advanced (Stage III–IV) or Recurrent Uterine Serous Carcinomas that Overexpress Her2/Neu (NCT01367002): Updated Overall Survival Analysis
Authors: Fader Amanda N. , Roque Dana M. , Siegel Eric , Buza Natalia , Hui Pei , Abdelghany Osama , Chambers Setsuko , Secord Angeles Alvarez , Havrilesky Laura , O'Malley David M. , Backes Floor J. , Nevadunsky Nicole , Edraki Babak , Pikaart Dirk , Lowery William , ElSahwi Karim , Celano Paul , Bellone Stefania , Azodi Masoud , Litkouhi Babak , Ratner Elena , Silasi Dan-Arin , Schwartz Peter E. , Santin Alessandro D.
Published: April 2023

AbstractPurpose:
Uterine-serous-carcinoma (USC) is an aggressive variant of endometrial cancer. On the basis of preliminary results of a multicenter, randomized phase II trial, trastuzumab (T), a humanized-mAb targeting Her2/Neu, in combination with carboplatin/paclitaxel (C/P), is recognized as an alternative in treating advanced/recurrent HER2/Neu-positive USC. We report the updated survival analysis of NCT01367002.
Patients and Methods:
Eligible patients had stage III to IV or recurrent disease. Participants were randomized 1:1 to receive C/P for six cycles ± T followed by maintenance T until progression or toxicity. Progression-free survival (PFS) was the primary endpoint; overall survival (OS) and toxicity were secondary endpoints.
Results:
Sixty-one patients were randomized. After a median-follow-up of 25.9 months, 43 progressions and 38 deaths occurred among 58 evaluable patients. Updated median-PFS continued to favor the T-arm, with medians of 8.0 months versus 12.9 months in the control and T-arms (HR = 0.46; 90% CI, 0.28–0.76; P = 0.005). Median-PFS was 9.3 months versus 17.7 months among 41 patients with stage III to IV disease undergoing primary treatment (HR = 0.44; 90% CI, 0.23–0.83; P = 0.015), and 7.0 months versus 9.2 months among 17 patients with recurrent disease (HR = 0.12; 90% CI, 0.03–0.48; P = 0.004). OS was higher in the T compared with the control arm, with medians of 29.6 months versus 24.4 months (HR = 0.58; 90% CI, 0.34–0.99; P = 0.046). The benefit was most notable in those with stage III to IV disease, with survival median not reached in the T-arm versus 24.4 months in the control arm (HR = 0.49; 90% CI, 0.25–0.97; P = 0.041). Toxicity was not different between arms.
Conclusions:
Addition of T to C/P increased PFS and OS in women with advanced/recurrent HER2/Neu-positive USC, with the greatest benefit seen for the treatment of stage III to IV disease.
Data from Preclinical Efficacy of a PSMA-Targeted Thorium-227 Conjugate (PSMA-TTC), a Targeted Alpha Therapy for Prostate Cancer
Authors: Hammer Stefanie , Hagemann Urs B. , Zitzmann-Kolbe Sabine , Larsen Aasmund , Ellingsen Christine , Geraudie Solene , Grant Derek , Indrevoll Baard , Smeets Roger , von Ahsen Oliver , Kristian Alexander , Lejeune Pascale , Hennekes Hartwig , Karlsson Jenny , Bjerke Roger M. , Ryan Olav B. , Cuthbertson Alan S. , Mumberg Dominik
Published: April 2023

AbstractPurpose:
Prostate-specific membrane antigen (PSMA) is an attractive target for radionuclide therapy of metastatic castration-resistant prostate cancer (mCRPC). PSMA-targeted alpha therapy (TAT) has shown early signs of activity in patients with prostate cancer refractory to beta radiation. We describe a novel, antibody-based TAT, the PSMA-targeted thorium-227 conjugate PSMA-TTC (BAY 2315497) consisting of the alpha-particle emitter thorium-227 complexed by a 3,2-HOPO chelator covalently linked to a fully human PSMA-targeting antibody.
Experimental Design:
PSMA-TTC was characterized for affinity, mode of action, and cytotoxic activity in vitro. Biodistribution, pharmacokinetics, and antitumor efficacy were investigated in vivo using cell line and patient-derived xenograft (PDX) models of prostate cancer.
Results:
PSMA-TTC was selectively internalized into PSMA-positive cells and potently induced DNA damage, cell-cycle arrest, and apoptosis in vitro. Decrease in cell viability was observed dependent on the cellular PSMA expression levels. In vivo, PSMA-TTC showed strong antitumor efficacy with T/C values of 0.01 to 0.31 after a single injection at 300 to 500 kBq/kg in subcutaneous cell line and PDX models, including models resistant to standard-of-care drugs such as enzalutamide. Furthermore, inhibition of both cancer and cancer-induced abnormal bone growth was observed in a model mimicking prostate cancer metastasized to bone. Specific tumor uptake and efficacy were demonstrated using various PSMA-TTC doses and dosing schedules. Induction of DNA double-strand breaks was identified as a key mode of action for PSMA-TTC both in vitro and in vivo.
Conclusions:
The strong preclinical antitumor activity of PSMA-TTC supports its clinical evaluation, and a phase I trial is ongoing in mCRPC patients (NCT03724747).
Data from Safety and Efficacy of Vorinostat Plus Sirolimus or Everolimus in Patients with Relapsed Refractory Hodgkin Lymphoma
Authors: Janku Filip , Park Haeseong , Call S. Greg , Madwani Kiran , Oki Yasuhiro , Subbiah Vivek , Hong David S. , Naing Aung , Velez-Bravo Vivianne M. , Barnes Tamara G. , Hagemeister Fredrick B. , Falchook Gerald S. , Karp Daniel D. , Wheler Jennifer J. , Piha-Paul Sarina A. , Garrido-Laguna Ignacio , Shpall Elizabeth J. , Fayad Luis E. , Neelapu Sattva S. , Meric-Bernstam Funda , Kurzrock Razelle , Fanale Michelle A.
Published: April 2023

AbstractPurpose:
Preclinical and early clinical data suggested that combining histone deacetylase (HDAC) and mTOR inhibitors can synergistically inhibit Hodgkin lymphoma.
Patients and Methods:
During the dose-escalation study (ClinicalTrials.gov number: NCT01087554) with the HDAC inhibitor vorinostat and the mTOR inhibitor sirolimus (V+S), a patient with Hodgkin lymphoma refractory to nine prior therapies demonstrated a partial response (PR) lasting for 18.5 months, which promoted additional enrollment of patients with Hodgkin lymphoma as well as exploration of an alternative combination of vorinostat and mTOR inhibitor everolimus (V+E).
Results:
A total of 40 patients with refractory Hodgkin lymphoma received V+S (n = 22) or V+E (n = 18). Patients received a median of five prior therapies, including brentuximab (n = 39), autologous stem cell transplantation (n = 26), and allogeneic stem cell transplantation (n = 12). The most frequent grade ≥3 treatment-related adverse event was thrombocytopenia in 55% and 67% of patients treated with V+S and V+E, respectively. Complete response was reported in 6 (27%) patients treated with V+S and 2 (11%) patients treated with V+E, and PR was reported in 6 patients (27%) treated with V+S and 4 (22%) patients treated with V+E (objective response rate of 55% and 33%, respectively). In summary, combined HDAC and mTOR inhibition had encouraging activity in heavily pretreated patients with relapsed/refractory Hodgkin lymphoma and warrants further investigation.
Conclusions:
Combined HDAC and mTOR inhibition has salutary activity in patients with relapsed refractory Hodgkin lymphoma and warrants further investigation.
Data from The Nanocind Signature Is an Independent Prognosticator of Recurrence and Death in Uterine Leiomyosarcomas
Authors: Croce Sabrina , Lesluyes Tom , Valle Carine , M'Hamdi Loubna , Thébault Noémie , Pérot Gaëlle , Stoeckle Eberhard , Noël Jean-Christophe , Fontanges Quitterie , Devouassoux-Shisheboran Mojgan , Querleu Denis , Guyon Frédéric , Floquet Anne , Chakiba Camille , Mayeur Laetitia , Rebier Flora , MacGrogan Gaëtan Marie , Soubeyran Isabelle , Le Guellec Sophie , Chibon Frédéric
Published: April 2023

AbstractPurpose:
Uterine leiomyosarcoma, which accounts for 7% of all soft-tissue sarcomas and 1%–3% of all uterine malignancies, is an aggressive tumor responsible for a significant proportion of uterine cancer–related deaths. While Federation Internationale des Gynaecologistes et Obstetristes (FIGO) stage is the most important prognostic factor, metastatic and relapse rates at stage I exceed 50% so it is currently impossible to predict the clinical outcome of stage I leiomyosarcomas. In 2010, our team published a transcriptomic signature composed of 67 genes related to chromosome biogenesis, mitosis control, and chromosome segregation. It has demonstrated its prognostic value in many cancer types and was recently successfully applied to formalin-fixed, paraffin-embedded sarcomas by NanoCind on NanoString technology, making another step forward toward its use in routine practice.
Experimental Design:
Sixty uterine leiomyosarcomas at any stage, including 40 localized in the uterus (stage I), were analyzed with the NanoCind (CINSARC with NanoString) signature. Its prognostic value was evaluated for overall survival and relapse-free survival and compared in multivariate analysis with other prognostic markers like FIGO staging and genomic index.
Results:
The NanoCind signature was able to split the heterogeneous group of uterine leiomyosarcomas of any stage including stage I into two distinct groups with different relapse-free survival and overall survival. These results were validated on an independent cohort of uterine leiomyosarcomas in The Cancer Genome Atlas consortium.
Conclusions:
The NanoCind signature is a powerful prognosticator that outperforms FIGO staging and the genomic index. The CINSARC signature is platform independent and “ready to use” and should now be used for randomization in future therapeutic trials.
Data from TRK Fusions Are Enriched in Cancers with Uncommon Histologies and the Absence of Canonical Driver Mutations
Authors: Rosen Ezra Y. , Goldman Debra A. , Hechtman Jaclyn F. , Benayed Ryma , Schram Alison M. , Cocco Emiliano , Shifman Sophie , Gong Yixiao , Kundra Ritika , Solomon James P. , Bardelli Alberto , Scaltriti Maurizio , Drilon Alexander , Iasonos Alexia , Taylor Barry S. , Hyman David M.
Published: April 2023

AbstractPurpose:
TRK inhibitors achieve marked tumor-agnostic efficacy in TRK fusion–positive cancers and consequently are now an established standard of care. Little is known, however, about the demographics, outcomes, response to alternative standard therapies, or genomic characteristics of TRK fusion–positive cancers.
Experimental Design:
Utilizing a center-wide screening program involving more than 26,000 prospectively sequenced patients, genomic and clinical data from all cases with TRK fusions were extracted. An integrated analysis was performed of genomic, therapeutic, and phenomic outcomes.
Results:
We identified 76 cases with confirmed TRK fusions (0.28% overall prevalence) involving 48 unique rearrangements and 17 cancer types. The presence of a TRK fusion was associated with depletion of concurrent oncogenic drivers (P < 0.001) and lower tumor mutation burden (P < 0.001), with the exception of colorectal cancer where TRK fusions cooccur with microsatellite instability (MSI-H). Longitudinal profiling in a subset of patients indicated that TRK fusions were present in all sampled timepoints in 82% (14/17) of cases. Progression-free survival on first-line therapy, excluding TRK inhibitors, administered for advanced disease was 9.6 months [95% confidence interval (CI), 4.8–13.2]. The best overall response rate achieved with chemotherapy containing–regimens across all lines of therapy was 63% (95% CI, 41–81). Among 12 patients treated with checkpoint inhibitors, a patient with MSI-H colorectal cancer had the only observed response.
Conclusions:
TRK fusion–positive cancers can respond to alternative standards of care, although efficacy of immunotherapy in the absence of other predictive biomarkers (MSI-H) appears limited. TRK fusions are present in tumors with simple genomes lacking in concurrent drivers that may partially explain the tumor-agnostic efficacy of TRK inhibitors.
Data from A Phase I/II Study of Veliparib (ABT-888) in Combination with 5-Fluorouracil and Oxaliplatin in Patients with Metastatic Pancreatic Cancer
Authors: Pishvaian Michael J. , Wang Hongkun , He Aiwu Ruth , Hwang Jimmy J. , Smaglo Brandon G. , Kim Sunnie S. , Weinberg Benjamin A. , Weiner Louis M. , Marshall John L. , Brody Jonathan R.
Published: April 2023

AbstractPurpose:
Up to 17% of patients with pancreatic ductal adenocarcinoma (PDAC) harbor pathogenic (germline or somatic) mutations in a homologous recombination, DNA damage response and repair (HR-DDR) gene, such as BRCA1/2, or PALB2. Platinum-based chemotherapy, or treatment with PARP inhibitors are of particular benefit in these patients. However, there may be even greater benefit when platinums and PARP inhibitors are combined.
Patients and Methods:
We performed a single-arm, open-label, phase I/II study of the PARP inhibitor, veliparib, with 5-fluorouracil (no 5FU bolus) and oxaliplatin (FOLFOX) for patients with metastatic PDAC. Thirty-one patients were enrolled in a phase I dose escalation of veliparib (40 mg to 250 mg twice a day, days 1–7 of each 14-day cycle), to identify the recommended phase II dose (RP2D) of veliparib for the combination. Another 33 patients were enrolled in two parallel phase II trials to assess the objective response rate (ORR) in untreated or in previously treated patients. If available, germline or somatic testing was collected to identify pathogenic HR-DDR mutations.
Results:
The combination of veliparib and FOLFOX was tolerable at a RP2D of veliparib of 200 mg twice a day. The primary endpoint for both phase II cohorts was met, and the ORR overall was 26%. There was greater activity in platinum-naïve patients, and those who harbored a pathogenic HR-DDR mutation. Specifically, the ORR of HR-DDR mutated, platinum-naïve patients was 57%.
Conclusions:
The combination of veliparib and FOLFOX was safe for patients with metastatic PDAC and showed promising activity particularly in patients with platinum-naïve disease that harbors a pathogenic HR-DDR mutation.
Data from AsiDNA Is a Radiosensitizer with no Added Toxicity in Medulloblastoma Pediatric Models
Authors: Ferreira Sofia , Foray Chloe , Gatto Alberto , Larcher Magalie , Heinrich Sophie , Lupu Mihaela , Mispelter Joel , Boussin François D. , Pouponnot Célio , Dutreix Marie
Published: April 2023

AbstractPurpose:
Medulloblastoma is an important cause of mortality and morbidity in pediatric oncology. Here, we investigated whether the DNA repair inhibitor, AsiDNA, could help address a significant unmet clinical need in medulloblastoma care, by improving radiotherapy efficacy without increasing radiation-associated toxicity.
Experimental Design:
To evaluate the brain permeability of AsiDNA upon systemic delivery, we intraperitoneally injected a fluorescence form of AsiDNA in models harboring brain tumors and in models still in development. Studies evaluated toxicity associated with combination of AsiDNA with radiation in the treatment of young developing animals at subacute levels, related to growth and development, and at chronic levels, related to brain organization and cognitive skills. Efficacy of the combination of AsiDNA with radiation was tested in two different preclinical xenografted models of high-risk medulloblastoma and in a panel of medulloblastoma cell lines from different molecular subgroups and TP53 status. Role of TP53 on the AsiDNA-mediated radiosensitization was analyzed by RNA-sequencing, DNA repair recruitment, and cell death assays.
Results:
Capable of penetrating young brain tissues, AsiDNA showed no added toxicity to radiation. Combination of AsiDNA with radiotherapy improved the survival of animal models more efficiently than increasing radiation doses. Medulloblastoma radiosensitization by AsiDNA was not restricted to a specific molecular group or status of TP53. Molecular mechanisms of AsiDNA, previously observed in adult malignancies, were conserved in pediatric models and resembled dose increase when combined with irradiation.
Conclusions:
Our results suggest that AsiDNA is an attractive candidate to improve radiotherapy in medulloblastoma, with no indication of additional toxicity in developing brain tissues.