This twice-monthly newsletter highlights recently published research where Dana-Farber faculty are listed as first or senior authors. The information is pulled from PubMed and this issue notes papers published from March 1 - 15.
If you are a Dana-Farber faculty member and you think your paper is missing from Research News, please let us know by emailing [email protected].
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Annals of Oncology
MTAP Loss Is Frequent in Oncogene-Driven NSCLC and May Confer Sensitivity to Combined PRMT5 Inhibitors and Targeted Therapies
Aldea M, Lenahan S, Locquet MA, Liao L, Odintsov I, Wang X, Pecci F, Garbo E, Nakazawa S, Kulesza J, Tsai JA, Simon S, Rossato de Almeida G, Huang J, Paoloni F, Gariazzo E, Santo V, Marks JA, LoPiccolo J, Florez N, Nishino M, Ricciuti B, Luo J, Barbie DA, Rotow JK, Feng WW, Sholl L, Shaw AT, Jänne PA
BACKGROUND: Homozygous loss of MTAP (methylthioadenosine phosphorylase) occurs in approximately 15% of cancers and leads to partial PRMT5 inhibition, creating a selective vulnerability to PRMT5 inhibitors. The frequency and therapeutic relevance of MTAP loss in oncogene-driven non-small cell lung cancers (NSCLCs) remain underexplored.
METHODS: MTAP status was assessed by next-generation sequencing (NGS) or immunohistochemistry (IHC) in >13,000 NSCLC samples in four cohorts. Prevalence was assessed across oncogenic drivers and temporal dynamics in pre- and post-treatment biopsies. Clinical outcomes were analyzed in EGFR- and ALK-rearranged NSCLC treated with first-line osimertinib and alectinib, respectively. The MTA-cooperative PRMT5 inhibitor BMS-986504 was tested alone and in combination with targeted therapies (TT) in MTAP-deleted models in vitro, ex vivo and in vivo.
RESULTS: MTAP loss was frequent in ALK-rearranged (27% and 33% by NGS; 36% and 45% IHC), RET-rearranged (18.5% and 26% by NGS; 35% by IHC), and EGFR-mutant NSCLC (17% and 24% by NGS; 24% and 29% by IHC), with CDKN2A co-deletion in 98% of cases. MTAP loss was typically present prior to TT. MTAP loss did not significantly impact response or overall survival with first-line osimertinib or alectinib in EGFR mutant and ALK-rearranged NSCLC, respectively. In preclinical studies, BMS-986504 showed nanomolar activity in 11/18 MTAP-deleted models, including 5/8 EGFR- and 5/5 ALK-driven models, regardless of TT sensitivity. Synergistic or additive effects with TT were observed in 11/18 models. In ex vivo ALK-rearranged spheroids resistant to crizotinib, the combination of BMS-986504 and alectinib improved antitumor activity over monotherapy. In an osimertinib-resistant, EGFR mutant PDX model, BMS-986504 with or without osimertinib controlled tumor growth, without weight loss.
CONCLUSIONS: MTAP loss is frequent in oncogene-driven NSCLC, particularly in ALK-, RET-, and EGFR-altered subtypes. MTA-cooperative PRMT5 inhibition demonstrates broad activity in MTAP-deleted, oncogene-driven models and, and may enhance targeted therapy efficacy in selected settings.
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Annals of Oncology
Nivolumab Plus Ipilimumab Versus Sunitinib for First-Line Treatment of Advanced Renal Cell Carcinoma: Final Analysis of Efficacy and Safety from the Phase III CheckMate 214 Trial
Choueiri TK, McDermott DF
BACKGROUND: Nivolumab plus ipilimumab (NIVO+IPI) demonstrated significant long-term survival and response benefits in patients with previously untreated advanced renal cell carcinoma (aRCC) in the phase III CheckMate 214 trial (NCT02231749). We report final efficacy and safety results with 9.3 years median follow-up.
PATIENTS AND METHODS: Patients (N=1096) were randomized to NIVO 3 mg/kg plus IPI 1 mg/kg Q3W × four doses, followed by NIVO (3 mg/kg or 240 mg Q2W or 480 mg Q4W); or sunitinib (SUN) (50 mg) QD (4 weeks on, 2 weeks off).
ENDPOINTS: overall survival (OS), and independent radiology review committee-assessed progression-free survival (PFS) and objective response rate (ORR) in IMDC intermediate/poor-risk (primary), intention-to-treat (secondary), and IMDC favorable-risk (exploratory) patients.
RESULTS: With a median (range) follow-up of 9.3 (8.6-9.9) years, the hazard ratio (HR; 95% confidence interval [CI]) for OS with NIVO+IPI versus SUN was 0.71 (0.62-0.82) in intention-to-treat patients, 0.69 (0.59-0.81) in intermediate/poor-risk patients, and 0.80 (0.59-1.09) in favorable-risk patients; 108-month OS probabilities were 31.4% versus 19.5%, 30.2% versus 18.7%, and 35.3% versus 21.8%, respectively. PFS probabilities at 96 months were 22.7% versus 9.0% (intention-to-treat), 25.4% versus 8.5% (intermediate/poor-risk), and 12.5% versus 11.3% (favorable-risk). Probabilities of remaining in response at 96 months with NIVO+IPI versus SUN were 48.0% versus 19.0% (intention-to-treat), 50.0% versus 23.0% (intermediate/poor-risk), and 36.0% versus not estimable (favorable-risk). Incidence of any-grade (grade 3-4) treatment-related adverse events (AEs) was 94.1% (48.6%) with NIVO+IPI versus 97.6% (64.1%) with SUN. Exploratory post hoc analyses reported include descriptive analyses of OS by immune-mediated AE discontinuation status.
CONCLUSIONS: In the longest phase III follow-up of a first-line checkpoint inhibitor combination in aRCC (>9 years), NIVO+IPI maintained a substantial survival benefit with durable responses versus SUN. Grade 3-4 treatment-related AEs were lower with NIVO+IPI versus SUN at 9 years. NIVO+IPI remains a first-line standard of care in aRCC.
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Blood
Graft Manipulation and GVHD: What Goes Around Comes Around
Soiffer RJ
In this issue of Blood, Meyer et al report the results of a prospective randomized trial comparing Orca-T, a T-cell deconstructed and reconstructed allogeneic mobilized peripheral blood graft, with a conventional unmanipulated peripheral blood graft using tacrolimus plus methotrexate as graft-versus-host disease (GVHD) prophylaxis. The Orca-T product comprised a CD34-selected T-cell–depleted graft with the additional infusion of freshly isolated donor regulatory T cells on day 0 and conventional T cells on day +2 or +3. This trial was performed in HLA-matched transplants after myeloablative conditioning; with a median follow-up of nearly a year, Orca-T achieved its primary end point, superior chronic GVHD–free survival compared with the control arm (78.0% vs 38.4%; P< .001). Notably, nonrelapse mortality (NRM) was lower in the Orca-T arm than in the control arm (3.4% vs 13.2%; P = .03); with limited follow-up, there were no significant differences in relapse rates, disease-free survival (DFS), or overall survival (OS) between the 2 arms.
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Blood
Hemophagocytic Lymphohistiocytosis in Adults
Hsu JI, Nikiforow S, Berliner N
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hematologic disorder characterized by unchecked immune activation and hyperinflammation, resulting in end-organ tissue damage and high mortality rates in untreated patients. Since the first description of this condition in 1939, our understanding of HLH has continued to deepen, with increasing appreciation of the differences and similarities between primary (familial) HLH and secondary (acquired) HLH. Primary HLH typically presents in the early years of life on the backdrop of inherited genetic mutations affecting cytotoxic immune cell function, whereas secondary HLH more commonly presents in adults and is a heterogeneous disorder with various potential triggers ranging from infections to malignancy, autoimmune disease, immunodeficiency, and medications. However, they converge in a common pathway of widespread systemic inflammation, which clinically manifests with fevers, organomegaly, cytopenias, laboratory derangements, and rapid development of multiorgan failure. As such, early recognition and intervention is critical to prevent irreversible organ damage and death in both primary and secondary HLH. In this review, we focus our attention on adult-onset secondary HLH and explore the latest updates on the pathophysiology, precipitants, clinical presentation, diagnosis, and management of this life-threatening condition. Primary HLH is reviewed separately as a companion article in this review series.
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Blood
Real-World Outcomes for Lisocabtagene Maraleucel in Patients with Relapsed or Refractory Large B-Cell Lymphoma
Crombie JL, Frigault MJ
This study assessed real-world effectiveness and safety of lisocabtagene maraleucel (liso-cel) in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL), including those with high-risk disease, secondary central nervous system (sCNS) involvement, comorbidities, and poor fitness, using data in the Center for International Blood and Marrow Transplant Research Registry from 5 Feb 2021 to 4 Feb 2025. Eligible patients (N=1116) received liso-cel and had ≥1 effectiveness and safety assessment after infusion, including 195 in the second-line setting, 71 with sCNS, and 257 with transformed LBCL. Median age was 71.1 years (range, 21.5‒91.2), with 72.3% ≥65 years. Within the overall population, 6.6% had Eastern Cooperative Oncology Group performance status of ≥2, 53.4% had ≥1 comorbidity, and median number of prior lines of therapy was 3 (range, 1‒16). Median study follow-up was 12.6 months (95% confidence interval [CI], 12.5‒12.8). Among effectiveness-evaluable patients (n=1109), objective response rate was 81.2% and complete response rate was 71.3%. Duration of response, progression-free survival, and overall survival rates (95% CI) at 12 months were 60.2% (56.4‒63.9), 51.2% (48.0‒54.4), and 67.6% (64.5‒70.6), respectively. Cytokine release syndrome was reported in 51.0% of patients, with grade ≥3 events in 2.5%. Immune effector cell-associated neurotoxicity syndrome was reported in 26.6% of patients, with grade ≥3 events in 9.2%. The 12-month nonrelapse mortality rate was 6.1% (95% CI, 4.6‒7.8). These real-world data reinforce the effectiveness and safety of liso-cel in this broad population of patients with R/R LBCL, including younger patients and those with high-risk disease features.
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Cancer Cell
A Context-Augmented Large Language Model for Accurate Precision Oncology Medicine Recommendations
Jun H, Tanaka Y, Johri S, Camp SY, Bao EL, Carvalho FLF, Gui DY, Jordan AC, Labaki C, Martin SD, Nagy M, O'Meara TA, Pappa T, Pimenta EM, Saad E, Yang DD, Gillani R, Tewari AK, Reardon B, Van Allen E
The rapid expansion of molecularly informed therapies in oncology, coupled with evolving regulatory food and drug administration (FDA) approvals, poses a challenge for oncologists seeking to integrate precision oncology medicine into patient care. Large language models (LLMs) have clinical potential, but their reliance on general knowledge limits their ability to provide up-to-date and niche treatment recommendations. Here, we developed a retrieval-augmented generation (RAG)-LLM workflow using the molecular oncology almanac (MOAlmanac) and benchmarked it against an LLM-only approach for biomarker-driven treatment recommendations. Our RAG-LLM achieved up to 95% accuracy on synthetic queries and 93% on real-world queries collected from practicing oncologists. Finally, our study explored several prompting and retrieval strategies to enhance performance. Taken together, this approach may serve as valuable guidance for deploying LLMs to support cancer patients' treatment decisions in precision oncology clinical settings.
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Cancer Cell
The Cellular Orchestra of CAR T Success
Samur MK, Munshi NC
The treatment landscape for multiple myeloma (MM) has been reshaped by chimeric antigen receptor (CAR) T cell therapies targeting B cell maturation antigen (BCMA). With the availability of idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), patients who have exhausted conventional therapies now have paradigm-shifting alternatives. However, striking heterogeneity in depth and durability of responses, as well as toxicity, is still present. The cellular and immunologic mechanisms that separate durable complete responses (CRs) from early relapses and predict severe inflammatory and hematologic toxicity have remained poorly defined. In this issue of Cancer Cell, Rade et al. publish a longitudinal single-cell atlas study and present an integrated view of the impact of CAR T cell composition, immune and non-immune microenvironmental interactions, and tumor cell characteristics, including soluble biomarkers, providing a high-resolution view of the cellular mechanisms underlying both therapeutic success and toxicity.
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Cancer Cell
Vascular STING Activation Facilitates NK Cell Anti-Tumor Immunity in Small Cell Lung Cancer
Campisi M, Dryg I, Stornante C, Wolff J, Weirather J, Weaver N, Tarannum M, Gillanders I, Bers A, Bobilev E, Lineberry MS, Schol P, Chen M, Ota K, Park SR, Fahey CG, Thai TC, Li Y, Li Z, Li ZH, Padrick C, Ivanova E, Ha M, Yang S, Olszewski H, Kivlehan S, Lizotte P, Hagen K, Gjeci I, Haller W, Zasadil LM, El Zarif T, Knelson EH, Brea EJ, Odintsov I, Tuladhar B, Ngo K, Pfaff K, Freedman M, Hodi FS, Tolstorukov MY, Oser MG, Sheffer M, Mitsiades CS, Gokhale PC, Paweletz CP, Romee R, Rodig S, Barbie DA, Mahadevan NR
Small cell lung cancer (SCLC) typically displays a "cold" tumor microenvironment with a paucity of immune infiltrate. Neuroendocrine SCLC cells also profoundly repress MHC-I expression, rendering them vulnerable to NK cell-mediated cytotoxicity. Here, we confirm that neuroendocrine SCLC cells are sensitive to NK cell-mediated attack, yet the quantitative spatial profiling of the SCLC immune microenvironment in patient samples reveals that effector immune cells, including NK cells, are excluded from MHC-Ilow/neg SCLC regions. To study this biology, we develop dynamic single-cell RNA sequencing of microphysiological immune tumor environments (DynaMITE-seq) and integrate findings with spatial transcriptomics in patient tissue, unveiling the microvasculature as a major checkpoint restricting NK cell extravasation/recruitment. We demonstrate that the activation of vascular Stimulator of Interferon Genes (STING) signaling restores NK cell infiltration and killing of neuroendocrine SCLC, suggesting a strategy to overcome this key SCLC immunologic barrier and prime therapeutic response to DLL3-targeted CAR-NK cell therapy.
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Cancer Discovery
PTEN Loss Promotes PI3Kβ Phosphorylation and EPHA2/SRC/p-PI3KβY962 Complex Assembly to Drive Tumorigenesis
Tang S, Bergholz JS, Jiang T, Wang W, Ji R, Li Y, He X, Jing Q, Johnson JL, Yaron-Barir TM, Cantley LC, Roberts TM, Zhao JJ
Loss of the tumor-suppressor PTEN drives cancer progression and therapeutic resistance, yet no targeted therapies exist for PTEN-deficient tumors. In this study, we identify a critical druggable mechanism in which PTEN loss induces PI3Kβ phosphorylation for tumorigenesis. Using the BioID interactome, we uncovered a phosphorylation-dependent PI3Kβ-EPHA2 interaction in PTEN-null cells, driven by p-PI3KβY962. PTEN functions as a tyrosine phosphatase that normally dephosphorylates p-PI3KβY962. In PTEN-deficient contexts, enhanced p-PI3KβY962 forms a complex with EPHA2 and SRC, in which both kinases contribute to PI3Kβ phosphorylation, activating oncogenic pERK/c-MYC and pAKT pathways. We developed a selective p-PI3KβY962 antibody detecting p-PI3KβY962 in PTEN-deficient tumors across preclinical models and clinical tumor specimens. Disrupting p-PI3KβY962 suppressed tumor growth in multiple PTEN-null models. Dasatinib, an FDA-approved SRC/EPHA2 inhibitor, effectively reduced p-PI3KβY962 and inhibited tumor progression in PTEN-null but not PTEN wild-type tumors. These findings establish p-PI3KβY962 as a druggable target and biomarker for developing targeted therapy in PTEN-deficient cancers beyond conventional PI3K kinase inhibition.
SIGNIFICANCE: We revealed a critical new mechanism that PTEN loss induces PI3Kβ phosphorylation and EPHA2/SRC/p-PI3KβY962 complex signaling to drive tumorigenesis. This work directs pharmaceutical development of p-PI3KβY962 inhibitors and biomarker-driven clinical trials repurposing dasatinib for PTEN-deficient solid tumor treatment, with potential to significantly improve outcomes of broad patients with PTEN-deficient tumors.
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Cell
Giant DNA Viruses Encode a Hallmark Translation Initiation Complex of Eukaryotic Life
Fels JM, Hill AB, Han R, Garcia JM, Kranzusch PJ, Lee ASY
In contrast to living organisms, viruses were long thought to lack protein synthesis machinery and instead depend on host factors to translate viral transcripts. Here, we discover that giant DNA viruses encode a distinct and functional IF4F translation-initiation complex to drive protein synthesis, thereby blurring the line between cellular and acellular biology. During infection, eukaryotic IF4F on host ribosomes is replaced by an essential viral IF4F that regulates viral translation, virion formation, and replication plasticity during altered host states. Structural dissection of viral IF4F reveals that the mRNA cap-binding subunit mediates exclusive interactions with viral mRNAs, constituting a molecular switch from translating host to viral proteins. Thus, our study establishes that viruses express a eukaryotic translation-initiation complex for protein synthesis, illuminating a series of evolutionary innovations in a core process of life.
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Cell
Persistent T Cell Activation and Cytotoxicity Against Glioblastoma Following Single Oncolytic Virus Treatment in a Clinical Trial
Meylan M, Tian Y, Wu L, Ling AL, Barlow GL, Nguyen LD, Pyrdol J, Marx S, Westphal L, Michel J, Gonzalez Castro LN, Dumont S, Santos A, Suvà ML, Chiocca EA, Wucherpfennig KW
A recent first-in-human clinical trial demonstrated that survival in glioblastoma (GBM) patients following rQNestin34.5v.2 oncolytic virus treatment was associated with immune activation signatures. This study was registered at ClinicalTrials.gov (NCT03152318). Here, we provide in situ evidence of ongoing T cell-mediated cytotoxicity against tumor cells at late time points following single treatment, with deep and persistent T cell infiltration into tumor regions. Shorter distances between cleaved caspase-3+ tumor cells and granzyme B+ T cells were associated with longer progression-free survival following treatment. Pre-existing tumor-infiltrating T cells expanded locally upon treatment, correlating with longer overall patient survival. T cells with an early activation program closely interacted with tumor cells and were strongly enriched upon treatment. Viral remnants were restricted to necrotic regions, while T cells infiltrated deeply into live tumor regions. These data demonstrate that single oncolytic virus treatment can expand pre-existing T cell clones and trigger persistent T cell-mediated immunity against GBM.
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JAMA Oncology
Extensive Oral Ulcerations After Stem Cell Transplant
Kuchibhotla N, Koreth J, Sroussi H
Case: A 69-year-old male patient presented to the oral medicine and oncology clinic with substantial oral discomfort and dysphagia. He reported a 6-day history of new-onset muted taste and oral pain, both of which progressively worsened leading up to his clinic visit. His medical history was notable for myelodysplastic syndrome, for which he underwent an allogeneic hematopoietic stem cell transplant (HSCT) approximately 18 months prior, using a reduced-intensity conditioning regimen. His haplo-identical donor was his daughter. He thereafter received posttransplant cyclophosphamide (PTCy), tacrolimus, and mycophenolate mofetil for graft-vs-host disease (GVHD) prophylaxis. At the time of the visit, the patient was taking ruxolitinib, 5 mg, once daily. Additional medical history included hypertension and hyperlipidemia managed with metoprolol and pravastatin, respectively. Intraoral examination revealed intense erythema and extensive ulcerations involving the labial and buccal mucosae, lateral borders, the ventrum of the tongue, hard palatal mucosa, and the soft palate, as shown in the Figure. Given the concern for hepatic GVHD, relevant laboratory reports were reviewed. They revealed a normal serum bilirubin (0.2 mg/dL [to convert mg/dL to μmol/L, multiply by 17.104]; reference range, 0.2-1.2 mg/dL) and mildly elevated aspartate aminotransferase levels (44 U/L [to convert U/L to μkat/L, multiply by 0.0167]; reference, <41 U/L).
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Journal of Clinical Oncology
Pembrolizumab With or Without Lenvatinib as First-Line Therapy for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Phase III LEAP-010 Study
Haddad RI
PURPOSE: The PD-1 inhibitor pembrolizumab is approved as first-line treatment for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). In LEAP-010 (ClinicalTrials.gov identifier: NCT04199104), the multikinase inhibitor lenvatinib plus pembrolizumab was evaluated as first-line therapy in participants with PD-L1 combined positive score (CPS) ≥1 R/M HNSCC.
METHODS: In this phase III, randomized, placebo-controlled, double-blind study, participants 18 years and older with PD-L1 CPS ≥1 R/M HNSCC deemed incurable by local therapy were randomly assigned 1:1 to lenvatinib 20 mg plus pembrolizumab 200 mg IV once every 3 weeks for ≤35 cycles or placebo orally once daily plus pembrolizumab 200 mg IV once every 3 weeks for ≤35 cycles. Primary end points were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Per the prespecified analysis plan, ORR and PFS were reported from the first interim analysis (IA1; data cutoff: July 6, 2022), and OS from IA2 (data cutoff: May 30, 2023).
RESULTS: Five hundred eleven participants were randomly assigned to lenvatinib plus pembrolizumab (n = 256) or placebo plus pembrolizumab (n = 255). The median time from random assignment to data cutoff was 11.5 months for IA1 and 21.3 months for IA2. At IA1, the median PFS was 6.2 months for lenvatinib plus pembrolizumab versus 2.8 months for placebo plus pembrolizumab (hazard ratio [HR], 0.64 [95% CI, 0.50 to 0.81]; P = .0001040); the ORR was 46.1% versus 25.4%, respectively (difference = 20.2% [95% CI, 10.5 to 29.6]; P = .0000251). At IA2, the median OS was 15.0 months for lenvatinib plus pembrolizumab versus 17.9 months for placebo plus pembrolizumab (HR,1.15 [95% CI, 0.91 to 1.45]; P = .882). At IA2, 170 (66.9%) participants receiving lenvatinib plus pembrolizumab had grade 3-4 all-cause adverse events compared with 97 (38.3%) participants on placebo plus pembrolizumab.
CONCLUSION: In participants with PD-L1 CPS ≥1 R/M HNSCC, first-line lenvatinib plus pembrolizumab significantly improved ORR and PFS, but not OS, compared with placebo plus pembrolizumab. The safety profile was consistent with published data.
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Journal of Clinical Oncology
TBCRC 048 (Olaparib Expanded) Expansion Cohorts: Phase II Study of Olaparib Monotherapy for Patients with Metastatic Breast Cancer with Germline Mutations in PALB2 or Somatic Mutations in BRCA1 or BRCA2
Tung NM, Li T, DeMeo M, Vieira JP, Wulf G, Garber JE
PURPOSE: Translational Breast Cancer Research Consortium 048 was a proof-of-principle trial demonstrating responses to the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib in patients (pts) with metastatic breast cancer (MBC) with germline (g) PALB2 or somatic (s) BRCA mutations (sBRCAm). Here we report results from the expansion cohorts in a larger sample of pts with gPALB2m or sBRCAm.
METHODS: Eligible pts had MBC of any subtype with measurable disease and a gPALB2m or sBRCAm. Pts received olaparib 300 mg twice a day until progression. The primary end point was overall response rate. Secondary end points include clinical benefit rate (CBR) at 18 weeks, progression-free survival (PFS), duration of response (DOR), and whether among sBRCAm carriers the mutant allele frequency (MAF) is significantly higher in responders than in nonresponders.
RESULTS: Fifty-four pts with gPALB2m (N = 24) or sBRCAm (N = 30) were enrolled. Forty-two (78%) had estrogen receptor-positive human epidermal growth factor receptor 2-negative (HER2-) MBC, seven (13%) had triple-negative breast cancer, and five (9%) had HER2+ disease. Among pts with a gPALB2m, the overall response rate (ORR) was 75% (80% CI, 60.2 to 86.3), CBR was 83.3% (90% CI, 65.8 to 94.1), the median PFS was 9.4 months (90% CI, 8.3 to 13.1), and the median DOR was 7.0 months (90% CI, 5.6 to 10.4). Among pts with sBRCAm (15 sBRCA1 and 15 sBRCA2), the ORR was 36.7% (80% CI, 24.7 to 50), CBR was 53.3% (90% CI, 37 to 69.1), the median PFS was 5.5 months (90% CI, 2.8 to 8.3), and the median DOR was 11.2 months (90% CI, 4.4 to not reached). One additional pt had an unconfirmed partial response. Although clinically meaningful, the ORR in pts with sBRCAm did not achieve the prespecified target. Among sBRCAm carriers, the mean MAF did not differ significantly between responders (46%) and nonresponders (39%; P = .7).
CONCLUSION: Olaparib is active in pts with MBC with gPALB2m and sBRCAm, significantly expanding the population of pts with breast cancer likely to benefit from PARP inhibitors beyond gBRCA1/2m carriers.
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Lancet Oncology
Towards Response-Adapted Neoadjuvant Breast Cancer Treatment
Nader-Marta G, Mayer EL
The therapeutic landscape of early-stage HER2-positive breast cancer has been transformed over the past two decades. The introduction of HER2-directed therapy, including the antibody trastuzumab, has fundamentally altered the natural history of this disease, converting an aggressive breast cancer subtype associated with poor outcomes into one with high rates of pathological complete response and excellent long-term survival. These gains were initially achieved using intensive multi-agent regimens incorporating HER2-directed therapies with anthracyclines, taxanes, and platinum chemotherapy in both the adjuvant and neoadjuvant settings. However, with greater understanding of how tumour heterogeneity affects treatment sensitivity, uniform application of intensive regimens might result in overtreatment for a substantial subset of patients who could achieve excellent clinical outcomes with a less burdensome approach. In response, contemporary research has focused on tailoring systemic therapy while preserving treatment efficacy, including a reduction in chemotherapy intensity or duration and, in the preoperative setting, response-adapted approaches informed by early indicators of treatment sensitivity.
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Nature
A Glucocorticoid-FAS Axis Controls Immune Evasion During Metastatic Seeding
Cassandras M, Sanchez X, Hsu L, Huang Y, Getzler AJ, Ganguly D, Baldominos P, Codinachs I, Chuong J, Martin EE, Smith BE, Marina E, Spasic M, Qin X, Parsons HA, Mayer EL, Sarosiek KA, Dougan SK, Mittendorf EA, McAllister SS, Hsu YC, Agudo J
Metastasis is the major cause of death for patients with triple-negative breast cancer and other solid malignancies. Metastases arise from cancer cells that disseminate from the original tumour, survive systemic immune surveillance and colonize new organs1. Little is known about how initial disseminated tumour cells (DTCs) overcome anti-tumour immunity after seeding a new organ. Here we use a visible antigen in a model of triple-negative breast cancer with cognate CD8+ T cells to study the mechanisms of immune evasion in early metastatic seeding. Analysis of surviving DTCs revealed glucocorticoid receptor (GR) activation as a key driver of resistance to both CD8+ T cells and natural killer cells. Niche profiling using an optimized labelling tool identified FAS-FASL as a key pan-cytotoxic pathway against DTCs, which is repressed by GR activation. Pharmacological inhibition of GR in combination with immunotherapy reduced metastatic burden and expanded lifespan in mice. Thus, we identified a mechanism of immune evasion that operates specifically in DTCs, illustrating the unique immune-cancer interactions at this stage in the metastatic cascade. Our findings suggest that there are therapeutic opportunities to eliminate DTCs, separately from treatments aimed at primary tumours, and GR inhibition is one promising target.
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Nature
Multidimensional Profiling of Heterogeneity in Supratentorial Ependymomas
Jeong D, Danielli SG, Jiang L, Katiyar S, Lo Cascio C, Neyazi S, de Biagi-Junior CAO, Couvillon E, Castellani S, Pazyra-Murphy M, Mullally M, Englinger B, Nascimento A, Cruzeiro GAV, Marques JG, Haase RD, Nguyen CM, Baumgartner AC, Rozowsky JS, Hack OA, Shaw ML, Baird L, Alexandrescu S, Filbin MG
Supratentorial ependymomas are aggressive childhood brain cancers that retain features of neurodevelopmental cell types1 and segregate into molecularly and clinically distinct subgroups2,3, suggesting different developmental roots. The developmental signatures, as well as microenvironmental factors, underlying aberrant cellular transformation and behaviour across each supratentorial ependymoma subgroup are unclear. Here we integrated single-cell and spatial transcriptomics, as well as in vitro and in vivo live-cell imaging, to define supratentorial ependymoma cell states, spatial organization and dynamic behaviour within the neural microenvironment. We find that individual tumour subgroups have two distinct progenitor-like cell states-neuroepithelial-like and embryonic-like-that are reminiscent of early human brain development and diverge in the extent of their neuronal or ependymal differentiation. We further identify several modes of spatial organization of these tumours, including a high-order architecture that is influenced by mesenchymal and hypoxia signatures, and local neighbourhood structures. Finally, we identify a role for brain-resident cells in shifting supratentorial ependymoma cellular heterogeneity towards neuronal-like cells that co-opt immature neuronal morphology and migratory mechanisms, and a subset of neuroepithelial-like cells that are both proliferative and highly migratory. Collectively, these findings provide a multidimensional framework to integrate transcriptional and phenotypic characterization of tumour heterogeneity in supratentorial ependymoma and its potential clinical implications.
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Nature Chemical Biology
A Druggable Redox Switch on SHP1 Controls Macrophage Inflammation
Ng MY, Burger N, Shin S, Takeda H, Cheah Xin Yan M, Zhang B, Xiao H, Wei SM, Seo HS, Dhe-Paganon S, Mills EL, Che J, Chouchani ET
Immunological proteins are major disease targets, yet most remain undrugged. Post-translational redox modification of cysteine residues has emerged as an important mode of immune cell regulation, particularly in macrophage cytokine responses. Here we develop a strategy for systematic discovery and small-molecule functionalization of redox-regulated cysteines on immunological proteins. Using deep redox proteomics, we annotate 788 in vivo redox-regulated cysteines across diverse immune-relevant protein domains. We demonstrate how these sites enable cysteine-directed pharmacology through discovery of a novel cysteine activation site on the immune regulator SHP1. Targeting C102, we develop a highly selective covalent agonist, SCA, which binds the N-SH2 domain to relieve autoinhibition and activate SHP1. In mouse and human macrophages, SCA selectively engages SHP1 C102, antagonizing interleukin-1 receptor-associated kinase signaling and lipopolysaccharide-induced proinflammatory cytokine production. Together, this work identifies a druggable cysteine redox switch controlling macrophage cytokine responses and provides a compendium of redox-regulated sites for therapeutic development.
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Nature Medicine
Clinical Development of Cancer Vaccines
Kagan JC, Fritsch EF, Wu CJ
The limitations of current immune checkpoint inhibitor therapies highlight a need for improved strategies to expand tumor-reactive T cell repertoires in a way that is safe, selective and efficient. Cancer vaccines hold potential to achieve this goal, but the profound success of vaccines for infectious diseases has not yet translated to the cancer setting. Recently, however, encouraging preliminary results from phase 1 and 2 clinical trials have renewed enthusiasm and spurred the initiation of large-scale cancer vaccine trials. In this Review, we highlight insights from recent clinical trials, translational studies and preclinical models, which reveal critical factors for optimizing cancer vaccines. Key strategies include definition of improved proxies to estimate vaccine efficacy, selection of high-quality antigens-particularly neoantigens-using modular vaccine platforms with innate immunostimulatory capabilities, and a focus on early-stage cancer, as exemplified by (neo)adjuvant therapies. We discuss each of these in detail, outlining a roadmap for future cancer vaccine development.
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New England Journal of Medicine
A Feverish Pace
Shashikumar SA, Vaidya A, Kovac VJ, Allbee AW, Odejide OO
Case Presentation: A 52-year-old man presented to his primary care clinic with a 3-week history of fevers, drenching night sweats, fatigue, myalgias, and dyspnea on exertion. He reported poor appetite and a weight loss of 6.8 kg that had occurred during the previous 3 weeks. Two weeks before the onset of symptoms, he had traveled to Colorado for a family event. He had not gone hiking during his trip, and he reported not having had close contact with birds, wildlife, or exotic animals. He had no pets and had no history of international travel.
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Proceedings of the National Academy of Sciences of the U.S.A.
HPV16 E6 Oncoprotein Promotes Microhomology-Mediated Viral Integration by Increasing PolΘ Protein Expression
Zhu G, Asada S, Sun L, Mukkavalli S, D'Andrea AD
Integration of the high-risk human papillomavirus 16 (HPV16) genome into the host chromosome, frequently driven by microhomology-mediated end joining (MMEJ), is a critical step in the carcinogenesis of HPV-associated tumors. However, the mechanisms by which viral oncoproteins manipulate the error-prone MMEJ pathway remain poorly defined. Here, we demonstrate that the HPV16 E6 oncoprotein upregulates MMEJ to facilitate viral genome integration. This heightened MMEJ activity is driven by a marked increase in the protein levels of DNA polymerase theta (PolΘ), a central enzyme of the MMEJ pathway. Mechanistically, we show that the elevation of PolΘ levels in response to HPV16 E6 expression is dependent on the host E3 ubiquitin ligase UBE3A/E6AP but is independent of p53 degradation. E6 redirects UBE3A to enhance the ubiquitination and degradation of RAD23A, a shuttle protein required for delivering polyubiquitinated PolΘ to the proteasome. Consequently, the loss of functional RAD23A phenocopies the effect of HPV16 E6, leading to PolΘ protein stabilization and increased MMEJ activity. By elucidating the E6-UBE3A-RAD23A-PolΘ axis, our findings reveal a mechanism through which HPV manipulates the host DNA repair machinery to promote its integration and oncogenic potential.
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American Journal of Hematology
Final Report of a Phase II Study of Ibrutinib and Venetoclax in Previously Untreated Waldenström Macroglobulinemia
Castillo JJ, Branagan AR, Guijosa A, von Keudell G, Ramirez-Gamero A, Chory H, Kobs M, Budano N, Nguyen J, Eurell A, Boyajian C, Meid K, Guerrera ML, Kofides A, Liu S, Liu X, Tsakmaklis N, Hunter ZR, Patterson CJ, Treon SP, Sarosiek S
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American Journal of Hematology
Venetoclax or Pirtobrutinib in Relapsed/Refractory Waldenström Macroglobulinemia: Clinical and Molecular Predictors and Sequencing Implications
Guijosa A, Tsakamaklis N, Kobs M, Kofides A, Budano N, Nguyen J, Eurell A, Meid K, Guerrera ML, Hunter ZR, Treon SP, Sarosiek S, Castillo JJ
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Annals of Surgical Oncology
Axillary Management and Outcomes After Neoadjuvant Endocrine Therapy in the Randomized PELOPS Trial
Weiss A, Jin Q, Tayob N, Wrabel E, DeMeo M, Carter J, Constantine M, Faggen M, Block C, Mittendorf EA, Jeselsohn R, Metzger Filho O, King TA
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Blood Advances
Venetoclax/FluBu2 RIC Transplant Followed by All-Oral Venetoclax/Decitabine Maintenance for Poor-Risk MDS/AML
Garcia JS, Kim HT, Murdock HM, Bosch-Vilaseca A, Panaro KM, Lim F, Fiorilla J, Auriemma E, Brock J, Gooptu M, Ho VT, Cutler CS, Shapiro R, Kelkar AH, Abel GA, DeAngelo DJ, Stone RM, Bat-Erdene D, Ryan J, Fell G, Letai A, Ritz J, Lindsley RC, Antin JH, Soiffer RJ
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Breast Cancer Research and Treatment
A Phase II Study of Atezolizumab in Combination with Stereotactic Radiation for Patients with Triple-Negative Breast Cancer and Brain Metastasis
Giordano A, Graham N, Aizer AA, Tayob N, Pereslete AM, Schoenfeld JD, Leone JP, Davis R, Erick TK, Mayer EL, Tolaney SM, Lin NU
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Cancer Epidemiology, Biomarkers and Prevention
Germline Predisposition to Oncogenic Alkylating Damage in Colorectal Cancer
Gurjao C, Cazaubiel J, Reardon B, Hofree M, Ugai T, Meyerhardt JA, Nowak JA, Giovannucci E, Ogino S, Giannakis M
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Cancer Research
Cancer Susceptibility to Stapled Oncolytic Peptides is Dictated by Membrane Cholesterol and Inflammatory Signaling
Adhikary U, Tesar B, Patel K, Schmidt MJ, Levy HR, Zacharakis E, Godes M, Gokhale PC, Hebert KM, Neuberg DS, Bird GH, Walensky LD
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Cancer Research Communications
Diagnostic Outcomes among Patients with Positive Multi-Cancer Early Detection Test Results
O'Donnell EK, Kauffman TL, Asnis S, Kelly VA, Matthews E, Kartsounis M, Dharaneeswaran H, Beckwith JB, Bennett C, Marto M, Parmigiani G, Rebbeck TR, Ghobrial IM, Syngal S, Marinac CR
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Cold Spring Harbor Perspectives in Medicine
Epigenetic Therapies
Bourgeois W, Armstrong SA, Heikamp EB
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ESMO Open
Progression Patterns and Clinical Outcomes in Patients with Cutaneous Squamous-Cell Carcinoma Following Anti-PD-1 Therapy Failure
Khaddour K, Kote P, Liu M, Giobbie-Hurder A, Dryg I, Goyal A, Guenette JP, Schoenfeld JD, Margalit DN, Tishler RB, Rettig EM, Sethi RKV, Annino DJ, Goguen LA, Uppaluri R, Yoon C, de Simone M, Ran NA, Stevens J, Waldman AH, Ruiz ES, Cohen JV, Silk AW, Hanna GJ
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Leukemia
Off-Trial Outcomes of Zanubrutinib in Waldenström Macroglobulinemia: The Prognostic Impact of CXCR4 and TP53 Alterations
Guijosa A, Tsakmaklis N, Kobs M, Kofides A, Guerrera ML, von Keudell G, Branagan A, Hunter ZR, Treon SP, Sarosiek S, Castillo JJ
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Nature Biomedical Engineering
DNA Origami Vaccine Nanoparticles Improve Humoral and Cellular Immune Responses to Infectious Diseases
Zeng YC, Young OJ, Xiong Q, Si L, Ku MW, Bernier SG, Dembele H, Isinelli G, Gilboa T, Swank Z, Seok SH, Rajwar A, Jiang A, Zhai Y, Wintersinger CM, Graveline AR, Vernet A, Sanchez M, Bardales S, Ryu JH, Kwon IC, Goyal G, Ingber DE, Shih WM
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NPJ Precision Oncology
Graph Neural Network Modeling of Spatial Tumor-Immune Interactions Identifies Prognostic Cellular Niches in Non‑Small Cell Lung Cancer
Hoebel KV, Lindsay JR, Altreuter J, Alessi JV, Weirather JL, Dryg I, Giobbie-Hurder A, Li Z, Yu KH, Awad MM, Rodig SJ, Lotter W
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NPJ Precision Oncology
Quantitative HER2 Tissue and Plasma Profiling Predicts the Activity of Trastuzumab Deruxtecan for Breast Cancer
Tarantino P, Kim SE, Hughes ME, Kusmick RJ, Smith K, Garcia-Cortes D, Gomez Tejeda Zanudo J, Pereslete AM, Li T, Gupta H, D'Amico O, Martini A, Morganti S, Spindel J, Cook C, McLaughlin C, Dvir K, Garrido-Castro AC, Sammons S, Files J, Sendrick K, Buck S, Dillon D, Jeselsohn R, Li YY, Cherniack AD, Tayob N, Lin NU, Tolaney SM
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