bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from A Phase II Study of Abemaciclib in Patients with Brain Metastases Secondary to Hormone Receptor–Positive Breast Cancer
Authors: Tolaney Sara M. , Sahebjam Solmaz , Le Rhun Emilie , Bachelot Thomas , Kabos Peter , Awada Ahmad , Yardley Denise , Chan Arlene , Conte Pierfranco , Diéras Véronique , Lin Nancy U. , Bear Melissa , Chapman Sonya C. , Yang Zhengyu , Chen Yanyun , Anders Carey K.
Published: April 2023

AbstractPurpose:
The primary objective was to evaluate intracranial objective response rate (iORR) in patients receiving abemaciclib with brain or leptomeningeal metastases (LM) secondary to hormone receptor–positive (HR+) metastatic breast cancer (MBC). Secondary objectives evaluated extracranial response, abemaciclib pharmacokinetics, brain metastases tissue exposure, and safety.
Patients and Methods:
This nonrandomized, phase II study (NCT02308020) enrolled patients in tumor subtype–specific cohorts A–D: A (HR+, HER2− MBC), B (HR+, HER2+ MBC), C (HR+ MBC LM), and D (brain metastases surgical resection). Abemaciclib 200 mg was administered twice daily as monotherapy or with endocrine therapy, or 150 mg twice daily with trastuzumab. Cohorts A and B used a Simon two-stage design.
Results:
In cohort A (n = 58), 3 patients were confirmed responders resulting in an iORR of 5.2% [95% confidence interval (CI), 0.0–10.9], and the intracranial clinical benefit rate (iCBR) was 24% (95% CI, 13.1–35.2). Median overall survival (OS) was 12.5 months (95% CI, 9.3–16.4). A volumetric decrease in target intracranial lesions was experienced by 38% of patients. In cohort B (n = 27), there were no confirmed intracranial responses. An iCBR of 11% (95% CI, 0.0–23.0) was observed. Median OS was 10.1 months (95% CI, 4.2–14.3). A volumetric decrease in target intracranial lesions was experienced by 22% of patients. In cohort C (n = 10), one confirmed complete parenchymal response was observed. In cohort D (n = 9), unbound brain metastases concentrations of total active abemaciclib analytes were 96- [cyclin-dependent kinase 4 (CDK4)] and 19-fold (CDK6) above in vitro IC50. Safety was consistent with prior studies.
Conclusions:
This study did not meet its primary endpoint. Abemaciclib was associated with an iCBR of 24% in patients with heavily pretreated HR+, HER2− MBC. Abemaciclib achieved therapeutic concentrations in brain metastases tissue, far exceeding those necessary for CDK4 and CDK6 inhibition. Further studies are warranted, including assessing novel abemaciclib-based combinations.
Data from How to Train Your T Cells: Overcoming Immune Dysfunction in Multiple Myeloma
Authors: Cohen Adam D. , Raje Noopur , Fowler Jessica A. , Mezzi Khalid , Scott Emma C. , Dhodapkar Madhav V.
Published: April 2023

Abstract
The progression of multiple myeloma, a hematologic malignancy characterized by unregulated plasma cell growth, is associated with increasing innate and adaptive immune system dysfunction, notably in the T-cell repertoire. Although treatment advances in multiple myeloma have led to deeper and more durable clinical responses, the disease remains incurable for most patients. Therapeutic strategies aimed at overcoming the immunosuppressive tumor microenvironment and activating the host immune system have recently shown promise in multiple myeloma, particularly in the relapsed and/or refractory disease setting. As the efficacy of T-cell–dependent immuno-oncology therapy is likely affected by the health of the endogenous T-cell repertoire, these therapies may also provide benefit in alternate treatment settings (e.g., precursor disease; after stem cell transplantation). This review describes T-cell–associated changes during the evolution of multiple myeloma and provides an overview of T-cell–dependent immuno-oncology approaches under investigation. Vaccine and checkpoint inhibitor interventions are being explored across the multiple myeloma disease continuum; treatment modalities that redirect patient T cells to elicit an anti–multiple myeloma response, namely, chimeric antigen receptor (CAR) T cells and bispecific antibodies [including BiTE (bispecific T-cell engager) molecules], have been primarily evaluated to date in the relapsed and/or refractory disease setting. CAR T cells and bispecific antibodies/antibody constructs directed against B-cell maturation antigen have generated excitement, with clinical data demonstrating deep responses. An increased understanding of the complex interplay between the immune system and multiple myeloma throughout the disease course will aid in maximizing the potential for T-cell–dependent immuno-oncology strategies in multiple myeloma.
Data from Surfactant Expression Defines an Inflamed Subtype of Lung Adenocarcinoma Brain Metastases that Correlates with Prolonged Survival
Authors: Pocha Kolja , Mock Andreas , Rapp Carmen , Dettling Steffen , Warta Rolf , Geisenberger Christoph , Jungk Christine , Martins Leila R. , Grabe Niels , Reuss David , Debus Juergen , von Deimling Andreas , Abdollahi Amir , Unterberg Andreas , Herold-Mende Christel C.
Published: April 2023

AbstractPurpose:
To provide a better understanding of the interplay between the immune system and brain metastases to advance therapeutic options for this life-threatening disease.
Experimental Design:
Tumor-infiltrating lymphocytes (TIL) were quantified by semiautomated whole-slide analysis in brain metastases from 81 lung adenocarcinomas. Multi-color staining enabled phenotyping of TILs (CD3, CD8, and FOXP3) on a single-cell resolution. Molecular determinants of the extent of TILs in brain metastases were analyzed by transcriptomics in a subset of 63 patients. Findings in lung adenocarcinoma brain metastases were related to published multi-omic primary lung adenocarcinoma The Cancer Genome Atlas data (n = 230) and single-cell RNA-sequencing (scRNA-seq) data (n = 52,698).
Results:
TIL numbers within tumor islands was an independent prognostic marker in patients with lung adenocarcinoma brain metastases. Comparative transcriptomics revealed that expression of three surfactant metabolism-related genes (SFTPA1, SFTPB, and NAPSA) was closely associated with TIL numbers. Their expression was not only prognostic in brain metastasis but also in primary lung adenocarcinoma. Correlation with scRNA-seq data revealed that brain metastases with high expression of surfactant genes might originate from tumor cells resembling alveolar type 2 cells. Methylome-based estimation of immune cell fractions in primary lung adenocarcinoma confirmed a positive association between lymphocyte infiltration and surfactant expression. Tumors with a high surfactant expression displayed a transcriptomic profile of an inflammatory microenvironment.
Conclusions:
The expression of surfactant metabolism-related genes (SFTPA1, SFTPB, and NAPSA) defines an inflamed subtype of lung adenocarcinoma brain metastases characterized by high abundance of TILs in close vicinity to tumor cells, a prolonged survival, and a tumor microenvironment which might be more accessible to immunotherapeutic approaches.
Data from EVOLVE: A Multicenter Open-Label Single-Arm Clinical and Translational Phase II Trial of Cediranib Plus Olaparib for Ovarian Cancer after PARP Inhibition Progression
Authors: Lheureux Stephanie , Oaknin Ana , Garg Swati , Bruce Jeffrey P. , Madariaga Ainhoa , Dhani Neesha C. , Bowering Valerie , White Justin , Accardi Sarah , Tan Qian , Braunstein Marsela , Karakasis Katherine , Cirlan Iulia , Pedersen Stephanie , Li Tiantiam , Fariñas-Madrid Lorena , Lee Yeh Chen , Liu Zhihui (Amy) , Pugh Trevor J. , Oza Amit M.
Published: April 2023

AbstractPurpose:
PARP inhibitors (PARPi) are standard-of-care therapy for high-grade serous ovarian cancer (HGSOC). We investigated combining cediranib (antiangiogenic) with olaparib (PARPi) at emergence of PARPi resistance.
Patients and Methods:
The proof-of-concept EVOLVE study (NCT02681237) assessed cediranib–olaparib combination therapy after progression on a PARPi. Women with HGSOC and radiographic evidence of disease progression were enrolled into one of three cohorts: platinum sensitive after PARPi; platinum resistant after PARPi; or progression on standard chemotherapy after progression on PARPi (exploratory cohort). Patients received olaparib tablets 300 mg twice daily with cediranib 20 mg once daily until progression or unacceptable toxicity. The coprimary endpoints were objective response rate (RECIST v1.1) and progression-free survival (PFS) at 16 weeks. Archival tissue (PARPi-naïve) and baseline biopsy (post-PARPi) samples were mandatory. Genomic mechanisms of resistance were assessed by whole-exome and RNA sequencing.
Results:
Among 34 heavily pretreated patients, objective responses were observed in 0 of 11 (0%) platinum-sensitive patients, 2 of 10 (20%) platinum-resistant patients, and 1 of 13 (8%) in the exploratory cohort. Sixteen-week PFS rates were 55%, 50%, and 39%, respectively. The most common grade 3 toxicities were diarrhea (12%) and anemia (9%). Acquired genomic alterations at PARPi progression were reversion mutations in BRCA1, BRCA2, or RAD51B (19%); CCNE1 amplification (16%); ABCB1 upregulation (15%); and SLFN11 downregulation (7%). Patients with reversion mutations in homologous recombination genes and/or ABCB1 upregulation had poor outcomes.
Conclusions:
This is currently the largest post-PARPi study identifying genomic mechanisms of resistance to PARPis. In this setting, the activity of cediranib–olaparib varied according to the PARPi resistance mechanism.
Data from Female Immunity Protects from Cutaneous Squamous Cell Carcinoma
Authors: Budden Timothy , Gaudy-Marqueste Caroline , Craig Sarah , Hu Yuan , Earnshaw Charles H. , Gurung Shilpa , Ra Amelle , Akhras Victoria , Shenjere Patrick , Green Ruth , Jamieson Lynne , Lear John , Motta Luisa , Caulín Carlos , Oudit Deemesh , Furney Simon J. , Virós Amaya
Published: April 2023

AbstractPurpose:
Cancer susceptibility and mortality are higher in males, and the mutational and transcriptomic landscape of cancer differs by sex. The current assumption is that men are at higher risk of epithelial cancers as they expose more to carcinogens and accumulate more damage than women. We present data showing women present with less aggressive primary cutaneous squamous cell carcinoma (cSCC) and early strong immune activation.
Experimental Design:
We explored clinical and molecular sexual disparity in immunocompetent and immunosuppressed patients with primary cSCC (N = 738, N = 160), advanced-stage cSCC (N = 63, N = 20) and FVB/N mice exposed to equal doses of DMBA, as well as in human keratinocytes by whole-exome, bulk, and single-cell RNA sequencing.
Results:
We show cSCC is more aggressive in men, and immunocompetent women develop mild cSCC, later in life. To test whether sex drives disparity, we exposed male and female mice to equal doses of carcinogen, and found males present with more aggressive, metastatic cSCC than females. Critically, females activate cancer immune-related expression pathways and CD4 and CD8 T-cell infiltration independently of mutations, a response that is absent in prednisolone-treated animals. In contrast, males increase the rate of mitosis and proliferation in response to carcinogen. Women's skin and keratinocytes also activate immune-cancer fighting pathways and immune cells at UV radiation–damaged sites. Critically, a compromised immune system leads to high-risk, aggressive cSCC specifically in women.
Conclusions:
This work shows the immune response is sex biased in cSCC and highlights female immunity offers greater protection than male immunity.
Data from MET Alterations Are a Recurring and Actionable Resistance Mechanism in ALK-Positive Lung Cancer
Authors: Dagogo-Jack Ibiayi , Yoda Satoshi , Lennerz Jochen K. , Langenbucher Adam , Lin Jessica J. , Rooney Marguerite M. , Prutisto-Chang Kylie , Oh Audris , Adams Nathaniel A. , Yeap Beow Y. , Chin Emily , Do Andrew , Marble Hetal D. , Stevens Sara E. , Digumarthy Subba R. , Saxena Ashish , Nagy Rebecca J. , Benes Cyril H. , Azzoli Christopher G. , Lawrence Michael S. , Gainor Justin F. , Shaw Alice T. , Hata Aaron N.
Published: April 2023

AbstractPurpose:
Most ALK-positive lung cancers will develop ALK-independent resistance after treatment with next-generation ALK inhibitors. MET amplification has been described in patients progressing on ALK inhibitors, but frequency of this event has not been comprehensively assessed.
Experimental Design:
We performed FISH and/or next-generation sequencing on 207 posttreatment tissue (n = 101) or plasma (n = 106) specimens from patients with ALK-positive lung cancer to detect MET genetic alterations. We evaluated ALK inhibitor sensitivity in cell lines with MET alterations and assessed antitumor activity of ALK/MET blockade in ALK-positive cell lines and 2 patients with MET-driven resistance.
Results:
MET amplification was detected in 15% of tumor biopsies from patients relapsing on next-generation ALK inhibitors, including 12% and 22% of biopsies from patients progressing on second-generation inhibitors or lorlatinib, respectively. Patients treated with a second-generation ALK inhibitor in the first-line setting were more likely to develop MET amplification than those who had received next-generation ALK inhibitors after crizotinib (P = 0.019). Two tumor specimens harbored an identical ST7-MET rearrangement, one of which had concurrent MET amplification. Expressing ST7-MET in the sensitive H3122 ALK-positive cell line induced resistance to ALK inhibitors that was reversed with dual ALK/MET inhibition. MET inhibition resensitized a patient-derived cell line harboring both ST7-MET and MET amplification to ALK inhibitors. Two patients with ALK-positive lung cancer and acquired MET alterations achieved rapid responses to ALK/MET combination therapy.
Conclusions:
Treatment with next-generation ALK inhibitors, particularly in the first-line setting, may lead to MET-driven resistance. Patients with acquired MET alterations may derive clinical benefit from therapies that target both ALK and MET.
Data from YAP/TAZ Transcriptional Coactivators Create Therapeutic Vulnerability to Verteporfin in EGFR-mutant Glioblastoma
Authors: Vigneswaran Krishanthan , Boyd Nathaniel H. , Oh Se-Yeong , Lallani Shoeb , Boucher Andrew , Neill Stewart G. , Olson Jeffrey J. , Read Renee D.
Published: April 2023

AbstractPurpose:
Glioblastomas (GBMs), neoplasms derived from glia and neuroglial progenitor cells, are the most common and lethal malignant primary brain tumors diagnosed in adults, with a median survival of 14 months. GBM tumorigenicity is often driven by genetic aberrations in receptor tyrosine kinases, such as amplification and mutation of EGFR.
Experimental Design:
Using a Drosophila glioma model and human patient–derived GBM stem cells and xenograft models, we genetically and pharmacologically tested whether the YAP and TAZ transcription coactivators, effectors of the Hippo pathway that promote gene expression via TEA domain (TEAD) cofactors, are key drivers of GBM tumorigenicity downstream of oncogenic EGFR signaling.
Results:
YAP and TAZ are highly expressed in EGFR-amplified/mutant human GBMs, and their knockdown in EGFR-amplified/mutant GBM cells inhibited proliferation and elicited apoptosis. Our results indicate that YAP/TAZ-TEAD directly regulates transcription of SOX2, C-MYC, and EGFR itself to create a feedforward loop to drive survival and proliferation of human GBM cells. Moreover, the benzoporphyrin derivative verteporfin, a disruptor of YAP/TAZ-TEAD–mediated transcription, preferentially induced apoptosis of cultured patient-derived EGFR-amplified/mutant GBM cells, suppressed expression of YAP/TAZ transcriptional targets, including EGFR, and conferred significant survival benefit in an orthotopic xenograft GBM model. Our efforts led us to design and initiate a phase 0 clinical trial of Visudyne, an FDA-approved liposomal formulation of verteporfin, where we used intraoperative fluorescence to observe verteporfin uptake into tumor cells in GBM tumors in human patients.
Conclusions:
Together, our data suggest that verteporfin is a promising therapeutic agent for EGFR-amplified and -mutant GBM.
Data from Targeting DNA Repair to Drive Immune Responses: It's Time to Reconsider the Strategy for Clinical Translation
Authors: Takahashi Nobuyuki , Surolia Ira , Thomas Anish
Published: April 2023

Abstract
PARP inhibition induces robust local and systemic antitumor immune responses and curative responses when combined with immune checkpoint blockade in many preclinical studies. However, the combination has not markedly improved antitumor effect compared with individual agents in clinical trials to date. We propose that the data from these trials indicate a lack of synergistic interaction of PARP inhibition and immune checkpoint blockade, with implications for reexamining our current strategies for clinical translation. As current mouse models do not recapitulate the genomic heterogeneity or tumor microenvironment of human cancers, better models are urgently needed. Tumor-extrinsic factors modulate immune checkpoint blockade response and they may be better assessed in early-phase clinical trials with frequent tissue and blood sampling. Further work is also needed to uncover the dose and schedule dependency of DNA repair modulation on the immune system. In homologous recombination repair–deficient tumors, randomized trials should be prioritized to address whether the benefit is superior to that of PARP inhibitor monotherapy. In tumors that are not homologous recombination repair deficient, research biopsies should be integrated to early-phase clinical trials to discover biomarkers that can predict clinical benefit. These considerations are relevant to the variety of adjunctive therapeutics being combined with immune checkpoint blockade to improve probability, duration, and potency of antitumor activity.
Data from Analysis of Pre- and Posttreatment Tissues from the SWOG S0800 Trial Reveals an Effect of Neoadjuvant Chemotherapy on the Breast Cancer Genome
Authors: Powles Ryan L. , Wali Vikram B. , Li Xiaotong , Barlow William E. , Nahleh Zeina , Thompson Alastair M. , Godwin Andrew K. , Hatzis Christos , Pusztai Lajos
Published: April 2023

AbstractPurpose:
We performed whole-exome sequencing (WES) of pre- and posttreatment cancer tissues to assess the somatic mutation landscape of tumors before and after neoadjuvant taxane and anthracycline chemotherapy with or without bevacizumab.
Experimental Design:
Twenty-nine pretreatment biopsies from the SWOG S0800 trial were subjected to WES to identify mutational patterns associated with response to neoadjuvant chemotherapy. Nine matching samples with residual cancer after therapy were also analyzed to assess changes in mutational patterns in response to therapy.
Results:
In pretreatment samples, a higher proportion of mutation signature 3, a BRCA-mediated DNA repair deficiency mutational signature, was associated with higher rate of pathologic complete response (pCR; median signature weight 24%, range 0%–38% in pCR vs. median weight 0%, range 0%–19% in residual disease, Wilcoxon rank sum, Bonferroni P = 0.007). We found no biological pathway level mutations associated with pCR or enriched in posttreatment samples. We observed statistically significant enrichment of high functional impact mutations in the “E2F targets” and “G2–M checkpoint” pathways in residual cancer samples implicating these pathways in resistance to therapy and a significant depletion of mutations in the “myogenesis pathway” suggesting the cells harboring these variants were effectively eradicated by therapy.
Conclusions:
These results suggest that genomic disturbances in BRCA-related DNA repair mechanisms, reflected by a dominant mutational signature 3, confer increased chemotherapy sensitivity. Cancers that survive neoadjuvant chemotherapy frequently have alterations in cell-cycle–regulating genes but different genes of the same pathways are affected in different patients.
Data from Selinexor in Combination with R-CHOP for Frontline Treatment of Non-Hodgkin Lymphoma: Results of a Phase I Study
Authors: Seymour Erlene K. , Khan Husain Yar , Li Yiwei , Chaker Mahmoud , Muqbil Irfana , Aboukameel Amro , Ramchandren Radhakrishanan , Houde Christiane , Sterbis Golbon , Yang Jay , Bhutani Divaya , Pregja Silvana , Reichel Kathy , Huddlestun Amy , Neveux Colleen , Corona Kelly , Landesman Yosef , Shah Jatin , Kauffman Michael , Shacham Sharon , Mohammad Ramzi M. , Azmi Asfar S. , Zonder Jeffrey A.
Published: April 2023

AbstractPurpose:
The nuclear exporter protein exportin-1 (XPO1) is overexpressed in non-Hodgkin lymphoma (NHL) and correlates with poor prognosis. We evaluated enhancing R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) activity in NHL by targeted inhibition of XPO1 using the selective inhibitor of nuclear export (SINE) compounds.
Patients and Methods:
We evaluated the antitumor activity of SINE compounds in combination with CHO chemotherapy in vitro and in vivo. Newly diagnosed NHL patients in a phase I dose-escalation study received R-CHOP for 6 cycles with weekly selinexor (60, 80, and 100 mg), then selinexor maintenance therapy for one year. RT-PCR, Western blotting, and RNA sequencing were performed on patient blood samples.
Results:
SINE compounds synergized with CHO in vitro in NHL cell lines and in vivo in our murine xenograft model. In our phase I study, selinexor was dosed at 60 mg (n = 6) and 80 mg (n = 6). The most common adverse events (AE) among 12 patients were fatigue (67%) and nausea (100%). Grade 3–4 AEs were infrequent. Ten evaluable patients had an overall response rate of 100% and complete remission rate of 90% with sustained remissions (median follow-up: 476 days). Maximally tolerated dose was not reached; however, the recommended phase II dose was 60 mg selinexor weekly after evaluating tolerability and discontinuation rates for each dose cohort. Analysis of patient blood samples revealed downregulation of XPO1 and several prosurvival markers.
Conclusions:
SINE compounds enhance the activity of CHO in vitro and in vivo. Selinexor in combination with R-CHOP was generally well tolerated and showed encouraging efficacy in NHL (NCT03147885).
Data from Combination of PARP Inhibitor Olaparib, and PD-L1 Inhibitor Durvalumab, in Recurrent Ovarian Cancer: a Proof-of-Concept Phase II Study
Authors: Lampert Erika J. , Zimmer Alexandra , Padget Michelle , Cimino-Mathews Ashley , Nair Jayakumar R. , Liu Yingmiao , Swisher Elizabeth M. , Hodge James W. , Nixon Andrew B. , Nichols Erin , Bagheri Mohammad H. , Levy Elliott , Radke Marc R. , Lipkowitz Stanley , Annunziata Christina M. , Taube Janis M. , Steinberg Seth M. , Lee Jung-Min
Published: April 2023

AbstractPurpose:
Preclinical studies suggest PARP inhibition (PARPi) induces immunostimulatory micromilieu in ovarian cancer thus complementing activity of immune checkpoint blockade. We conducted a phase II trial of PARPi olaparib and anti–PD-L1 durvalumab and collected paired fresh core biopsies and blood samples to test this hypothesis.
Patients and Methods:
In a single-center, proof-of-concept phase II study, we enrolled women aged ≥18 with recurrent ovarian cancer. All patients were immune checkpoint inhibitor–naïve and had measurable disease per RECISTv1.1, ECOG performance status 0–2, and adequate organ and marrow function. Patients received olaparib 300 mg twice daily and durvalumab 1,500 mg intravenously every 4 weeks until disease progression, unacceptable toxicity, or withdrawal of consent. Primary endpoint was overall response rate (ORR). Secondary objectives were safety and progression-free survival (PFS). Translational objectives included biomarker evaluation for relationships with clinical response and immunomodulatory effects by treatment.
Results:
Thirty-five patients with ovarian cancer [median, four prior therapies (IQR, 2–5.5), predominantly platinum-resistant (86%), BRCA wild-type (77%)] received at least one full cycle of treatment. ORR was 14% [5/35; 95% confidence interval (CI), 4.8%–30.3%]. Disease control rate (PR+SD) was 71% (25/35; 95% CI, 53.7%–85.4%). Treatment enhanced IFNγ and CXCL9/CXCL10 expression, systemic IFNγ/TNFα production, and tumor-infiltrating lymphocytes, indicating an immunostimulatory environment. Increased IFNγ production was associated with improved PFS [HR, 0.37 (95% CI, 0.16–0.87), P = 0.023], while elevated VEGFR3 levels were associated with worse PFS (HR, 3.22 (95% CI, 1.23–8.40), P = 0.017].
Conclusions:
The PARPi and anti–PD-L1 combination showed modest clinical activity in recurrent ovarian cancer. Our correlative study results suggest immunomodulatory effects by olaparib/durvalumab in patients and indicate that VEGF/VEGFR pathway blockade would be necessary for improved efficacy of the combination.
Data from Circulating T-cell Immunosenescence in Patients with Advanced Non–small Cell Lung Cancer Treated with Single-agent PD-1/PD-L1 Inhibitors or Platinum-based Chemotherapy
Authors: Ferrara Roberto , Naigeon Marie , Auclin Edouard , Duchemann Boris , Cassard Lydie , Jouniaux Jean-Mehdi , Boselli Lisa , Grivel Jonathan , Desnoyer Aude , Mezquita Laura , Texier Matthieu , Caramella Caroline , Hendriks Lizza , Planchard David , Remon Jordi , Sangaletti Sabina , Proto Claudia , Garassino Marina C. , Soria Jean-Charles , Marabelle Aurelien , Voisin Anne-Laure , Farhane Siham , Besse Benjamin , Chaput Nathalie
Published: April 2023

AbstractPurpose:
CD28, CD57, and KLRG1 have been previously identified as markers of T-cell immunosenescence. The impact of immunosenescence on anti-PD(L)-1 (ICI) or platinum-based chemotherapy (PCT) in patients with advanced non–small cell lung cancer (aNSCLC) is unknown.
Experimental Design:
The percentage of CD28−, CD57+, KLRG1+ among CD8+ T cells [senescent immune phenotype (SIP)] was assessed by flow cytometry on blood from patients with aNSCLC before single-agent ICI (discovery cohort). A SIP cut-off was identified by log-rank maximization method and patients with aNSCLC treated with ICI (validation cohort) or PCT were classified accordingly. Proliferation and functional properties of SIP+ CD8+ T cells were assessed in vitro.
Results:
In the ICI discovery cohort (N = 37), SIP cut-off was 39.5%, 27% of patients were SIP+. In the ICI validation cohort (N = 46), SIP+ status was found in 28% of patients and significantly correlated with worse objective response rate (ORR; 0% vs. 30%, P = 0.04), median progression-free survival (PFS) [1.8 (95% confidence interval (CI), 1.3-NR) vs. 6.4 (95% CI, 2–19) months, P = 0.009] and median overall survival, OS [2.8 (95% CI, 2.0-NR) vs. 20.8 (95% CI, 6.0-NR) months, P = 0.02]. SIP+ status was significantly associated with circulating specific immunephenotypes, in vitro lower CD8+ T cells proliferation, lower IL2 and higher TNFα and IFNγ production. In the ICI-pooled population (N = 83), SIP+ status did not correlate with any clinical characteristics and it was associated with significantly worse ORR, PFS, and OS. In PCT cohort (N = 61), 11% of patients were SIP+. SIP status did not correlate with outcomes upon PCT.
Conclusions:
Circulating T-cell immunosenescence is observed in up to 28% of patients with aNSCLC and correlates with lack of benefit from ICI but not from PCT.

See related commentary by Salas-Benito et al., p. 374
Data from Trametinib Activity in Patients with Solid Tumors and Lymphomas Harboring BRAF Non-V600 Mutations or Fusions: Results from NCI-MATCH (EAY131)
Authors: Johnson Douglas B. , Zhao Fengmin , Noel Marcus , Riely Gregory J. , Mitchell Edith P. , Wright John J. , Chen Helen X. , Gray Robert J. , Li Shuli , McShane Lisa M. , Rubinstein Larry V. , Patton David , Williams P. Mickey , Hamilton Stanly R. , Conley Barbara A. , Arteaga Carlos L. , Harris Lyndsay N. , O'Dwyer Peter J. , Chen Alice P. , Flaherty Keith T.
Published: April 2023

AbstractPurpose:
Substantial preclinical evidence and case reports suggest that MEK inhibition is an active approach in tumors with BRAF mutations outside the V600 locus, and in BRAF fusions. Thus, Subprotocol R of the NCI-MATCH study tested the MEK inhibitor trametinib in this population.
Patients and Methods:
The NCI-MATCH study performed genomic profiling on tumor samples from patients with solid tumors and lymphomas progressing on standard therapies or with no standard treatments. Patients with prespecified fusions and non-V600 mutations in BRAF were assigned to Subprotocol R using the NCI-MATCHBOX algorithm. The primary endpoint was objective response rate (ORR).
Results:
Among 50 patients assigned, 32 were eligible and received therapy with trametinib. Of these, 1 had a BRAF fusion and 31 had BRAF mutations (13 and 19 with class 2 and 3 mutations, respectively). There were no complete responses; 1 patient (3%) had a confirmed partial response (patient with breast ductal adenocarcinoma with BRAF G469E mutation) and 10 patients had stable disease as best response (clinical benefit rate 34%). Median progression-free survival (PFS) was 1.8 months, and median overall survival was 5.7 months. Exploratory subgroup analyses showed that patients with colorectal adenocarcinoma (n = 8) had particularly poor PFS. No new toxicity signals were identified.
Conclusions:
Trametinib did not show promising clinical activity in patients with tumors harboring non-V600 BRAF mutations, and the subprotocol did not meet its primary endpoint.
Data from Regulation of CEACAM5 and Therapeutic Efficacy of an Anti-CEACAM5–SN38 Antibody–drug Conjugate in Neuroendocrine Prostate Cancer
Authors: DeLucia Diana C. , Cardillo Thomas M. , Ang Lisa , Labrecque Mark P. , Zhang Ailin , Hopkins James E. , De Sarkar Navonil , Coleman Ilsa , da Costa Rui M. Gil , Corey Eva , True Lawrence D. , Haffner Michael C. , Schweizer Michael T. , Morrissey Colm , Nelson Peter S. , Lee John K.
Published: April 2023

AbstractPurpose:
Neuroendocrine prostate cancer (NEPC) is an aggressive form of castration-resistant prostate cancer (CRPC) for which effective therapies are lacking. We previously identified carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) as a promising NEPC cell surface antigen. Here we investigated the scope of CEACAM5 expression in end-stage prostate cancer, the basis for CEACAM5 enrichment in NEPC, and the therapeutic potential of the CEACAM5 antibody–drug conjugate labetuzumab govitecan in prostate cancer.
Experimental Design:
The expression of CEACAM5 and other clinically relevant antigens was characterized by multiplex immunofluorescence of a tissue microarray comprising metastatic tumors from 34 lethal metastatic CRPC (mCRPC) cases. A genetically defined neuroendocrine transdifferentiation assay of prostate cancer was developed to evaluate mechanisms of CEACAM5 regulation in NEPC. The specificity and efficacy of labetuzumab govitecan was determined in CEACAM5+ prostate cancer cell lines and patient-derived xenografts models.
Results:
CEACAM5 expression was enriched in NEPC compared with other mCRPC subtypes and minimally overlapped with prostate-specific membrane antigen, prostate stem cell antigen, and trophoblast cell surface antigen 2 expression. We focused on a correlation between the expression of the pioneer transcription factor ASCL1 and CEACAM5 to determine that ASCL1 can drive neuroendocrine reprogramming of prostate cancer which is associated with increased chromatin accessibility of the CEACAM5 core promoter and CEACAM5 expression. Labetuzumab govitecan induced DNA damage in CEACAM5+ prostate cancer cell lines and marked antitumor responses in CEACAM5+ CRPC xenograft models including chemotherapy-resistant NEPC.
Conclusions:
Our findings provide insights into the scope and regulation of CEACAM5 expression in prostate cancer and strong support for clinical studies of labetuzumab govitecan for NEPC.
Data from Restoration of Temozolomide Sensitivity by PARP Inhibitors in Mismatch Repair Deficient Glioblastoma is Independent of Base Excision Repair
Authors: Higuchi Fumi , Nagashima Hiroaki , Ning Jianfang , Koerner Mara V.A. , Wakimoto Hiroaki , Cahill Daniel P.
Published: April 2023

AbstractPurpose:
Emergence of mismatch repair (MMR) deficiency is a frequent mechanism of acquired resistance to the alkylating chemotherapeutic temozolomide (TMZ) in gliomas. Poly(ADP-ribose) polymerase inhibitors (PARPi) have been shown to potentiate TMZ cytotoxicity in several cancer types, including gliomas. We tested whether PARP inhibition could re-sensitize MSH6-null MMR-deficient gliomas to TMZ, and assessed the role of the base excision repair (BER) DNA damage repair pathway in PARPi-mediated effects.
Experimental Design:
Isogenic pairs of MSH6 wild-type and MSH6-inactivated human glioblastoma (GBM) cells (including both IDH1/2 wild-type and IDH1 mutant), as well as MSH6-null cells derived from a patient with recurrent GBM were treated with TMZ, the PARPi veliparib or olaparib, and combination thereof. Efficacy of PARPi combined with TMZ was assessed in vivo. We used genetic and pharmacological approaches to dissect the contribution of BER.
Results:
While having no detectable effect in MSH6 wild-type GBMs, PARPi selectively restored TMZ sensitivity in MSH6-deficient GBM cells. This genotype-specific restoration of activity translated in vivo, where combination treatment of veliparib and TMZ showed potent suppression of tumor growth of MSH6-inactivated orthotopic xenografts, compared with TMZ monotherapy. Unlike PARPi, genetic and pharmacological blockage of BER pathway did not re-sensitize MSH6-inactivated GBM cells to TMZ. Similarly, CRISPR PARP1 knockout did not re-sensitize MSH6-inactivated GBM cells to TMZ.
Conclusions:
PARPi restoration of TMZ chemosensitivity in MSH6-inactivated glioma represents a promising strategy to overcome acquired chemoresistance caused by MMR deficiency. Mechanistically, this PARPi-mediated synthetic phenotype was independent of BER blockage and was not recapitulated by loss of PARP1.
Data from Tumor Mutational Burden and PTEN Alterations as Molecular Correlates of Response to PD-1/L1 Blockade in Metastatic Triple-Negative Breast Cancer
Authors: Barroso-Sousa Romualdo , Keenan Tanya E. , Pernas Sonia , Exman Pedro , Jain Esha , Garrido-Castro Ana C. , Hughes Melissa , Bychkovsky Brittany , Umeton Renato , Files Janet L. , Lindeman Neal I. , MacConaill Laura E. , Hodi F. Stephen , Krop Ian E. , Dillon Deborah , Winer Eric P. , Wagle Nikhil , Lin Nancy U. , Mittendorf Elizabeth A. , Van Allen Eliezer M. , Tolaney Sara M.
Published: April 2023

AbstractPurpose:
Few patients with metastatic triple-negative breast cancer (mTNBC) benefit from immune checkpoint inhibitors (ICI). On the basis of immunotherapy response correlates in other cancers, we evaluated whether high tumor mutational burden (TMB) ≥10 nonsynonymous mutations/megabase and PTEN alterations, defined as nonsynonymous mutations or 1 or 2 copy deletions, were associated with clinical benefit to anti-PD-1/L1 therapy in mTNBC.
Experimental Design:
We identified patients with mTNBC, who consented to targeted DNA sequencing and were treated with ICIs on clinical trials between April 2014 and January 2019 at Dana-Farber Cancer Institute (Boston, MA). Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were correlated with tumor genomic features.
Results:
Sixty-two women received anti-PD-1/L1 inhibitors alone (23%) or combined with targeted therapy (19%) or chemotherapy (58%). High TMB (18%) was associated with significantly longer PFS (12.5 vs. 3.7 months; P = 0.04), while PTEN alterations (29%) were associated with significantly lower ORR (6% vs. 48%; P = 0.01), shorter PFS (2.3 vs. 6.1 months; P = 0.01), and shorter OS (9.7 vs. 20.5 months; P = 0.02). Multivariate analyses confirmed that these associations were independent of performance status, prior lines of therapy, therapy regimen, and visceral metastases. The survival associations were additionally independent of PD-L1 in patients with known PD-L1 and were not found in mTNBC cohorts treated with chemotherapy (n = 90) and non-ICI regimens (n = 169).
Conclusions:
Among patients with mTNBC treated with anti-PD-1/L1 therapies, high TMB and PTEN alterations were associated with longer and shorter survival, respectively. These observations warrant validation in larger datasets.
Data from Preclinical Characterization of HPN536, a Trispecific, T-Cell–Activating Protein Construct for the Treatment of Mesothelin-Expressing Solid Tumors
Authors: Molloy Mary Ellen , Austin Richard J. , Lemon Bryan D. , Aaron Wade H. , Ganti Vaishnavi , Jones Adrie , Jones Susan D. , Strobel Kathryn L. , Patnaik Purbasa , Sexton Kenneth , Tatalick Laurie , Yu Timothy Z. , Baeuerle Patrick A. , Law Che-Leung , Wesche Holger
Published: April 2023

AbstractPurpose:
Mesothelin (MSLN) is a glycophosphatidylinositol-linked tumor antigen overexpressed in a variety of malignancies, including ovarian, pancreatic, lung, and triple-negative breast cancer. Early signs of clinical efficacy with MSLN-targeting agents have validated MSLN as a promising target for therapeutic intervention, but therapies with improved efficacy are still needed to address the significant unmet medical need posed by MSLN-expressing cancers.
Experimental Design:
We designed HPN536, a 53-kDa, trispecific, T-cell–activating protein-based construct, which binds to MSLN-expressing tumor cells, CD3ϵ on T cells, and to serum albumin. Experiments were conducted to assess the potency, activity, and half-life of HPN536 in in vitro assays, rodent models, and in nonhuman primates (NHP).
Results:
HPN536 binds to MSLN-expressing tumor cells and to CD3ϵ on T cells, leading to T-cell activation and potent redirected target cell lysis. A third domain of HPN536 binds to serum albumin for extension of plasma half-life. In cynomolgus monkeys, HPN536 at doses ranging from 0.1 to 10 mg/kg demonstrated MSLN-dependent pharmacologic activity, was well tolerated, and showed pharmacokinetics in support of weekly dosing in humans.
Conclusions:
HPN536 is potent, is well tolerated, and exhibits extended half-life in NHPs. It is currently in phase I clinical testing in patients with MSLN-expressing malignancies (NCT03872206).
Data from Genomic Analysis of Circulating Tumor DNA in 3,334 Patients with Advanced Prostate Cancer Identifies Targetable BRCA Alterations and AR Resistance Mechanisms
Authors: Tukachinsky Hanna , Madison Russell W. , Chung Jon H. , Gjoerup Ole V. , Severson Eric A. , Dennis Lucas , Fendler Bernard J. , Morley Samantha , Zhong Lei , Graf Ryon P. , Ross Jeffrey S. , Alexander Brian M. , Abida Wassim , Chowdhury Simon , Ryan Charles J. , Fizazi Karim , Golsorkhi Tony , Watkins Simon P. , Simmons Andrew , Loehr Andrea , Venstrom Jeffrey M. , Oxnard Geoffrey R.
Published: April 2023

AbstractPurpose:
Comprehensive genomic profiling (CGP) is of increasing value for patients with metastatic castration-resistant prostate cancer (mCRPC). mCRPC tends to metastasize to bone, making tissue biopsies challenging to obtain. We hypothesized CGP of cell-free circulating tumor DNA (ctDNA) could offer a minimally invasive alternative to detect targetable genomic alterations (GA) that inform clinical care.
Experimental Design:
Using plasma from 3,334 patients with mCRPC (including 1,674 screening samples from TRITON2/3), we evaluated the landscape of GAs detected in ctDNA and assessed concordance with tissue-based CGP.
Results:
A total of 3,129 patients (94%) had detectable ctDNA with a median ctDNA fraction of 7.5%; BRCA1/2 was mutated in 295 (8.8%). In concordance analysis, 72 of 837 patients had BRCA1/2 mutations detected in tissue, 67 (93%) of which were also identified using ctDNA, including 100% of predicted germline variants. ctDNA harbored some BRCA1/2 alterations not identified by tissue testing, and ctDNA was enriched in therapy resistance alterations, as well as possible clonal hematopoiesis mutations (e.g., in ATM and CHEK2). Potential androgen receptor resistance alterations were detected in 940 of 2,213 patients (42%), including amplifications, polyclonal and compound mutations, rearrangements, and novel deletions in exon 8.
Conclusions:
Genomic analysis of ctDNA from patients with mCRPC recapitulates the genomic landscape detected in tissue biopsies, with a high level of agreement in detection of BRCA1/2 mutations, but more acquired resistance alterations detected in ctDNA. CGP of ctDNA is a compelling clinical complement to tissue CGP, with reflex to tissue CGP if negative for actionable variants.

See related commentary by Hawkey and Armstrong, p. 2961
Data from Uncovering Clinically Relevant Gene Fusions with Integrated Genomic and Transcriptomic Profiling of Metastatic Cancers
Authors: Tsang Erica S. , Grisdale Cameron J. , Pleasance Erin , Topham James T. , Mungall Karen , Reisle Caralyn , Choo Caleb , Carreira Marcus , Bowlby Reanne , Karasinska Joanna M. , MacMillan Daniel , Williamson Laura M. , Chuah Eric , Moore Richard A. , Mungall Andrew J. , Zhao Yongjun , Tessier-Cloutier Basile , Ng Tony , Sun Sophie , Lim Howard J. , Schaeffer David F. , Renouf Daniel J. , Yip Stephen , Laskin Janessa , Marra Marco A. , Jones Steven J.M. , Loree Jonathan M.
Published: April 2023

AbstractPurpose:
Gene fusions are important oncogenic drivers and many are actionable. Whole-genome and transcriptome (WGS and RNA-seq, respectively) sequencing can discover novel clinically relevant fusions.
Experimental Design:
Using WGS and RNA-seq, we reviewed the prevalence of fusions in a cohort of 570 patients with cancer, and compared prevalence to that predicted with commercially available panels. Fusions were annotated using a consensus variant calling pipeline (MAVIS) and required that a contig of the breakpoint could be constructed and supported from ≥2 structural variant detection approaches.
Results:
In 570 patients with advanced cancer, MAVIS identified 81 recurrent fusions by WGS and 111 by RNA-seq, of which 18 fusions by WGS and 19 by RNA-seq were noted in at least 3 separate patients. The most common fusions were EML4-ALK in thoracic malignancies (9/69, 13%), and CMTM8-CMTM7 in colorectal cancer (4/73, 5.5%). Combined genomic and transcriptomic analysis identified novel fusion partners for clinically relevant genes, such as NTRK2 (novel partners: SHC3, DAPK1), and NTRK3 (novel partners: POLG, PIBF1).
Conclusions:
Utilizing WGS/RNA-seq facilitates identification of novel fusions in clinically relevant genes, and detected a greater proportion than commercially available panels are expected to find. A significant benefit of WGS and RNA-seq is the innate ability to retrospectively identify variants that becomes clinically relevant over time, without the need for additional testing, which is not possible with panel-based approaches.
Data from Safety, Antitumor Activity, and T-cell Responses in a Dose-Ranging Phase I Trial of the Oncolytic Peptide LTX-315 in Patients with Solid Tumors
Authors: Spicer James , Marabelle Aurélien , Baurain Jean-Francois , Jebsen Nina Louise , Jøssang Dag Erik , Awada Ahmad , Kristeleit Rebecca , Loirat Delphine , Lazaridis George , Jungels Christiane , Brunsvig Paal , Nicolaisen Berit , Saunders Andrew , Patel Hamina , Galon Jérôme , Hermitte Fabienne , Camilio Ketil André , Mauseth Brynjar , Sundvold Vibeke , Sveinbjørnsson Baldur , Rekdal Øystein
Published: April 2023

AbstractPurpose:
LTX-315 is a first-in-class, 9-mer membranolytic peptide that has shown potent immunomodulatory properties in preclinical models. We conducted a phase I dose-escalating study of intratumoral LTX-315 administration in patients with advanced solid tumors.
Patients and Methods:
Thirty-nine patients were enrolled, receiving LTX-315 injections into accessible tumors. The primary objective was to assess the safety and tolerability of this approach, with antitumor and immunomodulatory activity as secondary objectives. Tumor biopsies were collected at baseline and posttreatment for analysis of immunologic parameters.
Results:
The most common treatment-related grade 1–2 adverse events were vascular disorders including transient hypotension (18 patients, 46%), flushing (11 patients, 28%), and injection site reactions in 38% of patients. The most common grade 3 LTX-315–related toxicities were hypersensitivity or anaphylaxis (4 patients, 10%). Analysis of immune endpoints in serial biopsies indicated that LTX-315 induces necrosis and CD8+ T-cell infiltration into the tumor microenvironment. Sequencing of the T-cell receptor repertoire in peripheral blood identified significant expansion of T-cell clones after treatment, of which 49% were present in available tumor biopsies after treatment, suggesting that they were tumor associated. Substantial volume reduction (≥30%) of injected tumors occurred in 29% of the patients, and 86% (12/14 biopsies) had an increase in intralesional CD8+ T cells posttreatment. No partial responses by immune-related response criteria were seen, but evidence of abscopal effect was demonstrated following treatment with LTX-315.
Conclusions:
LTX-315 has an acceptable safety profile, is clinically active, induces changes in the tumor microenvironment and contributes to immune-mediated anticancer activity.
Data from Hematopoietic Stem Cell Transplantation Positively Affects the Natural History of Cancer in Nijmegen Breakage Syndrome
Authors: Wolska-Kusnierz Beata , Pastorczak Agata , Fendler Wojciech , Wakulinska Anna , Dembowska-Baginska Bozena , Heropolitanska-Pliszka Edyta , Piątosa Barbara , Pietrucha Barbara , Kałwak Krzysztof , Ussowicz Marek , Pieczonka Anna , Drabko Katarzyna , Lejman Monika , Koltan Sylwia , Gozdzik Jolanta , Styczynski Jan , Fedorova Alina , Miakova Natalia , Deripapa Elena , Kostyuchenko Larysa , Krenova Zdenka , Hlavackova Eva , Gennery Andrew R. , Sykora Karl-Walter , Ghosh Sujal , Albert Michael H. , Balashov Dmitry , Eapen Mary , Svec Peter , Seidel Markus G. , Kilic Sara S. , Tomaszewska Agnieszka , Wiesik-Szewczyk Ewa , Kreins Alexandra , Greil Johann , Buechner Jochen , Lund Bendik , Gregorek Hanna , Chrzanowska Krystyna , Mlynarski Wojciech
Published: April 2023

AbstractPurpose:
Nijmegen breakage syndrome (NBS) is a DNA repair disorder with a high predisposition to hematologic malignancies.
Experimental Design:
We describe the natural history of NBS, including cancer incidence, risk of death, and the potential effectiveness of hematopoietic stem cell transplantation (HSCT) in preventing both pathologies: malignancy and immunodeficiency.
Results:
Among 241 patients with NBS enrolled in the study from 11 countries, 151 (63.0%) patients were diagnosed with cancer. Incidence rates for primary and secondary cancer, tumor characteristics, and risk factors affecting overall survival (OS) were estimated. The cumulative cancer incidence was 40.21% ± 3.5% and 77.78% ± 3.4% at 10 years and 20 years of follow-up, respectively. Most of the tumors n = 95 (62.9%) were non-Hodgkin lymphomas. Overall, 20 (13.2%) secondary malignancies occurred at a median age of 18 (interquartile range, 13.7–21.5) years. The probability of 20-year overall survival (OS) for the whole cohort was 44.6% ± 4.5%. Patients who developed cancer had a shorter 20-year OS than those without malignancy (29.6% vs. 86.2%; P < 10−5). A total of 49 patients with NBS underwent HSCT, including 14 patients transplanted before malignancy. Patients with NBS with diagnosed cancer who received HSCT had higher 20-year OS than those who did not (42.7% vs. 30.3%; P = 0.038, respectively). In the group of patients who underwent preemptive transplantation, only 1 patient developed cancer, which is 6.7 times lower as compared with nontransplanted patients [incidence rate ratio 0.149 (95% confidence interval, 0.138–0.162); P < 0.0001].
Conclusions:
There is a beneficial effect of HSCT on the long-term survival of patients with NBS transplanted in their first complete remission of cancer.