Featured
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Personalized response-directed surgery and adjuvant therapy after neoadjuvant ipilimumab and nivolumab in high-risk stage III melanoma: the PRADO trial
Results from the PRADO extension cohort of the OpACIN-neo trial show that pathologic response rate to neoadjuvant ipilimumab and nivolumab can be used as a criterion for personalization of further treatment in stage III nodal melanoma, with the potential to reduce treatment morbidity and increase patient quality of life.
- Irene L. M. Reijers
- , Alexander M. Menzies
- & Christian U. Blank
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Article
| Open AccessSotigalimab and/or nivolumab with chemotherapy in first-line metastatic pancreatic cancer: clinical and immunologic analyses from the randomized phase 2 PRINCE trial
In a randomized phase 2 trial, sotigalimab, a CD40 agonist, did not significantly improve overall survival in patients with previously untreated metastatic pancreatic cancer when combined with chemotherapy or with nivolumab and chemotherapy. Multi-omic exploratory analyses provide insights into immunologic features associated with clinical benefit.
- Lacey J. Padrón
- , Deena M. Maurer
- & Robert H. Vonderheide
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Pembrolizumab in soft-tissue sarcomas with tertiary lymphoid structures: a phase 2 PEMBROSARC trial cohort
In a trial of patients with soft-tissue sarcomas, clinical outcome measures following anti-PD-1 treatment were better in a cohort prospectively selected for the presence of intratumoral tertiary lymphoid structures than in other cohorts where most patients lacked these structures.
- A. Italiano
- , A. Bessede
- & W. H. Fridman
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| Open AccessClaudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial interim results
In an interim analysis of a phase 1 trial, CAR T cells specific for Claudin18.2, a tight junction protein isoform highly expressed on gastrointestinal tract tumors, were well-tolerated and exhibited promising clinical activity in patients with gastrointestinal cancers.
- Changsong Qi
- , Jifang Gong
- & Lin Shen
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A T cell resilience model associated with response to immunotherapy in multiple tumor types
Gene signatures associated with T cell resilience to tumor-derived immunosuppressive signals predict responses to immune-checkpoint inhibitors and adoptive cell therapy and identify FIBP as a negative regulator of T cell activity
- Yu Zhang
- , Trang Vu
- & Peng Jiang
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Research Briefing |
PIK3CA hotspot mutation generates a shared neoantigen targetable by TCR gene therapy
PIK3CA gain-of-function mutations are among the most common alterations in human solid cancers. Through the use of stimulation-induced functional T cell receptor (TCR) sequencing (SIFT-seq), a panel of TCRs that bind a mutant PI3Kα shared neoantigen was identified, including a potential clinical candidate that engages cancer cells via a distinctive CDR3β loop.
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| Open AccessImmunogenicity and therapeutic targeting of a public neoantigen derived from mutated PIK3CA
A new high-throughput platform to find rare T cells that can recognize shared cancer neoantigens identifies T cell receptors specific for a conserved, immunogenic and therapeutically actionable epitope in mutant PI3Kα, one of the most common driver oncogenes
- Smita S. Chandran
- , Jiaqi Ma
- & Christopher A. Klebanoff
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Research Highlight |
New treatment option for early-stage lung cancer
A phase 3 trial confirms that addition of the checkpoint inhibitor nivolumab to neoadjuvant chemotherapy improves outcomes in patients with early-stage lung cancer.
- Karen O’Leary
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PSMA-targeting TGFβ-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: a phase 1 trial
CAR T cells targeting PSMA and engineered to be resistant to immunosuppressive TGFβ signaling exhibit dose-dependent toxicity and expansion following infusion, with some transient antitumor activity, in patients with metastatic castration-resistant prostate cancer
- Vivek Narayan
- , Julie S. Barber-Rotenberg
- & Naomi B. Haas
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| Open AccessAxicabtagene ciloleucel as first-line therapy in high-risk large B-cell lymphoma: the phase 2 ZUMA-12 trial
In a phase 2 trial, first-line treatment with axicabtagene ciloleucel, an autologous CD19-targeting CAR T-cell therapy, exhibited a high complete response rate and a manageable safety profile in adults with high-risk large B-cell lymphoma.
- Sattva S. Neelapu
- , Michael Dickinson
- & Julio C. Chavez
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Gut microbiome correlates of response and toxicity following anti-CD19 CAR T cell therapy
In an analysis of adult patients with hematologic malignancies who received anti-CD19 chimeric antigen receptor T cell therapy, baseline gut microbiome composition was correlated with clinical response and treatment with broad-spectrum antibiotics in the four weeks prior to infusion was associated with worse survival and increased neurotoxicity.
- Melody Smith
- , Anqi Dai
- & Marco Ruella
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Article
| Open AccessNivolumab plus ipilimumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial
A randomized trial in treatment-naive patients with metastatic renal cell carcinoma shows that the addition of a live bacterial product to an immunotherapy combination elicits promising clinical benefit in association with an enrichment of bacterial species, circulating cytokines and immune cell populations in responders.
- Nazli Dizman
- , Luis Meza
- & Sumanta K. Pal
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T cell characteristics associated with toxicity to immune checkpoint blockade in patients with melanoma
Clonally diverse and activated memory CD4+ T cells at baseline are associated with the development of severe immune-related adverse events, irrespective of the affected organ system, in patients with melanoma treated with immune checkpoint inhibitors.
- Alexander X. Lozano
- , Aadel A. Chaudhuri
- & Aaron M. Newman
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HLA-independent T cell receptors for targeting tumors with low antigen density
HLA-independent T cell receptors, in which the heavy and light chains of a chimeric antigen receptor are incorporated into the endogenous T cell receptor locus, are more effective than CD28-based chimeric antigen receptors at targeting tumors with low antigen expression.
- Jorge Mansilla-Soto
- , Justin Eyquem
- & Michel Sadelain
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Research Highlight |
CAR-T cell therapies for large B cell lymphoma
CAR-T cell therapies may represent a viable treatment for relapsed or refractory disease, but further studies will be needed to refine patient selection.
- Karen O’Leary
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Article
| Open AccessGenomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency
Hypermutation and microsatellite burden determine responses and long-term survival following PD-1 blockade in children and young adults with refractory cancers resulting from germline DNA replication repair deficiency.
- Anirban Das
- , Sumedha Sudhaman
- & Uri Tabori
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Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: the phase 2 ELARA trial
In a prespecified interim analysis of a pivotal phase 2 trial, tisagenlecleucel, an autologous CD19-targeting CAR-T cell therapy, produced a high rate of complete responses with a manageable safety profile in adults with relapsed or refractory follicular lymphoma
- Nathan Hale Fowler
- , Michael Dickinson
- & Catherine Thieblemont
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| Open AccessDurvalumab with platinum-pemetrexed for unresectable pleural mesothelioma: survival, genomic and immunologic analyses from the phase 2 PrE0505 trial
In a phase 2 trial, the combination of chemotherapy with durvalumab, an anti-PD-L1 antibody, exhibited promising clinical activity in patients with previously untreated, unresectable mesothelioma, with additional analyses providing insights into genomic and immunologic features potentially associated with response.
- Patrick M. Forde
- , Valsamo Anagnostou
- & Suresh S. Ramalingam
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| Open AccessCAR T cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia: a phase 1 trial
Bicistronic CAR T cells targeting CD19 and CD22 exhibit clinical activity and low toxicity in pediatric and young adult patients with B cell acute lymphoblastic leukemia, with relapses associated with limited CAR T cell persistence.
- Shaun Cordoba
- , Shimobi Onuoha
- & Persis J. Amrolia
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Neoadjuvant talimogene laherparepvec plus surgery versus surgery alone for resectable stage IIIB–IVM1a melanoma: a randomized, open-label, phase 2 trial
Intralesional injection of an oncolytic virus prior to surgery shows favorable clinical activity over surgery alone in patients with locally advanced, resectable melanoma, supporting further evaluation in the neoadjuvant setting for this population.
- R. Dummer
- , D. E. Gyorki
- & M. I. Ross
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Research Highlight |
A compelling microbial SagA
Certain gut microbes produce a protein called ‘SagA’, which enhances the efficacy of cancer immunotherapy in mice
- Karen O’Leary
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News & Views |
The expanding universe of checkpoint inhibitors for nasopharyngeal cancer
Three phase 3 studies show that an immune-checkpoint inhibitor combined with chemotherapy improves progression-free survival in recurrent or metastatic nasopharyngeal cancer.
- Brigette B. Y. Ma
- , Edwin P. Hui
- & Anthony T. C. Chan
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Toripalimab or placebo plus chemotherapy as first-line treatment in advanced nasopharyngeal carcinoma: a multicenter randomized phase 3 trial
Interim analysis from the randomized phase 3 JUPITER-02 trial shows that the addition of anti-PD-1 toripalimab to standard gemcitabine/cisplatin as a first-line treatment for patients with recurrent or metastatic nasopharyngeal carcinoma has manageable toxicity and improves progression-free survival, suggesting a potential new treatment standard in this setting.
- Hai-Qiang Mai
- , Qiu-Yan Chen
- & Rui-Hua Xu
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| Open AccessCAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial
Bispecific CAR T cells targeting CD19 and CD22 exhibit clinical activity and low toxicity in patients with large B cell lymphoma and B cell acute lymphoblastic leukemia, with relapses associated with loss of CD19 but not CD22.
- Jay Y. Spiegel
- , Shabnum Patel
- & David B. Miklos
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Research Highlight |
A new treatment combination for liver cancer
Gefitinib with lenvatinib shows promising antitumor activity in patients whose cancers had progressed on lenvatinib monotherapy.
- Karen O’Leary
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Article |
Locoregional infusion of HER2-specific CAR T cells in children and young adults with recurrent or refractory CNS tumors: an interim analysis
In an interim analysis of a phase 1 trial, repeated intracranial infusions of HER2-specific CAR T cells were well tolerated with no observed dose-limiting toxicities in three young adult patients with CNS tumors.
- Nicholas A. Vitanza
- , Adam J. Johnson
- & Julie R. Park
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Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade
Clinical benefit or intestinal toxicity resulting from combined immune checkpoint blockade in patients with melanoma associates with prevalent commensal bacteria and can be decoupled by IL-1R inhibition.
- Miles C. Andrews
- , Connie P. M. Duong
- & Jennifer A. Wargo
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Brief Communication
| Open AccessCytokine release syndrome in a patient with colorectal cancer after vaccination with BNT162b2
A rare case of cytokine release syndrome in a patient on anti-PD-1 blockade that was likely related to BNT162b2 vaccination supports prospective monitoring of patients with cancer after COVID-19 vaccine administration.
- Lewis Au
- , Annika Fendler
- & Samra Turajlic
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A single-cell map of intratumoral changes during anti-PD1 treatment of patients with breast cancer
Transcriptomic and proteomic profiling of breast cancer biopsies identifies baseline features of the tumor immune microenvironment associated with T cell clonal expansion following neoadjuvant anti-PD-1 treatment.
- Ayse Bassez
- , Hanne Vos
- & Diether Lambrechts
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Letter |
Evolution of delayed resistance to immunotherapy in a melanoma responder
Genetic and protein expression analyses of serially collected tumor biopsies from a patient with melanoma treated with immune checkpoint inhibitors provide insights into tumor microenvironment changes that occur during treatment resistance.
- David Liu
- , Jia-Ren Lin
- & Genevieve M. Boland
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Antigen-independent activation enhances the efficacy of 4-1BB-costimulated CD22 CAR T cells
A bedside-to-bench analysis identifies single-chain variable fragment linker length as an important component of chimeric antigen receptor (CAR) structure and suggests that, in contrast to CD28-based CAR T cells, tonic signaling can be beneficial for 4-1BB-based CAR T cell function.
- Nathan Singh
- , Noelle V. Frey
- & Marco Ruella
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Research Highlight |
Immunotherapy for esophageal cancer
Anti-PD-1 after surgery improves the survival of patients with esophageal cancers in a clinical trial.
- Saheli Sadanand
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Research Highlight |
CAR T cells drive multiple myeloma out
Engineered T cells that recognize a protein expressed on myeloma cells show promise in a clinical trial.
- Saheli Sadanand
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Brief Communication |
Homozygous BCMA gene deletion in response to anti-BCMA CAR T cells in a patient with multiple myeloma
Biallelic loss of BCMA caused a patient with multiple myeloma to relapse after anti-BCMA CAR T cell treatment. Baseline heterozygous BCMA deletions might be a risk factor for this form of resistance.
- Matteo C. Da Vià
- , Oliver Dietrich
- & Leo Rasche
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Personal neoantigen vaccines induce persistent memory T cell responses and epitope spreading in patients with melanoma
Personalized neoantigen vaccination in patients with melanoma elicits durable and specific memory T cell clones that have cytotoxic gene signatures and can diversify to include nonvaccine neoantigen specificities.
- Zhuting Hu
- , Donna E. Leet
- & Patrick A. Ott
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Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination
Liver metastases reduce clinical and preclinical immune-checkpoint inhibitor efficacy through hepatic siphoning of circulating activated CD8+ T cells, but therapeutic benefit can be improved by combining immunotherapy with liver-directed radiotherapy.
- Jiali Yu
- , Michael D. Green
- & Weiping Zou
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Brief Communication |
Anti-GD2 CAR-NKT cells in patients with relapsed or refractory neuroblastoma: an interim analysis
In an interim analysis of a first-in-human phase 1 trial of patients with neuroblastoma, highly pure GD2-specific CAR-NKT cells were well tolerated with no observed dose-limiting toxicities.
- Andras Heczey
- , Amy N. Courtney
- & Leonid S. Metelitsa
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Letter |
Neoadjuvant PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable high-risk urothelial carcinoma
Neoadjuvant combination of immune checkpoint therapy in patients with cisplatin-ineligible bladder cancer achieves clinical efficacy and uncovers immune features as potential predictive biomarkers of treatment response.
- Jianjun Gao
- , Neema Navai
- & Padmanee Sharma
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Characteristics of anti-CD19 CAR T cell infusion products associated with efficacy and toxicity in patients with large B cell lymphomas
Single-cell transcriptomics reveals that the heterogeneity of anti-CD19 CAR T cell infusion products contributes to variability in clinical response, early molecular response and development of immune effector cell-associated neurotoxicity syndrome in patients with large B cell lymphomas.
- Qing Deng
- , Guangchun Han
- & Michael R. Green
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Letter |
Combined PD-1, BRAF and MEK inhibition in advanced BRAF-mutant melanoma: safety run-in and biomarker cohorts of COMBI-i
Clinical activity and biomarker analysis from the COMBI-i trial evaluating PD-1, BRAF and MEK inhibition in patients with metastatic melanoma demonstrate high response rates and uncover molecular correlates of long-term treatment benefit.
- Reinhard Dummer
- , Celeste Lebbé
- & Georgina V. Long
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A peripheral immune signature of responsiveness to PD-1 blockade in patients with classical Hodgkin lymphoma
In a phase II clinical trial of patients with classical Hodgkin lymphoma, peripheral CD4+ T cell receptor diversity and the abundance of mature natural killer cells and CD3−CD68+CD4+GrB+ innate cells were associated with favorable responses to anti-PD-1 monotherapy.
- Fathima Zumla Cader
- , Xihao Hu
- & Margaret A. Shipp
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Letter |
Single-arm, open-label phase 2 trial of pembrolizumab in patients with leptomeningeal carcinomatosis
In a phase 2 clinical trial cohort of patients with leptomeningeal disease, anti-PD-1 monotherapy was safe and associated with a 3-month overall survival of 60%.
- Priscilla K. Brastianos
- , Eudocia Quant Lee
- & Ryan J. Sullivan
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Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma
A pooled genetic, transcriptomic and immunopathologic analysis of over 500 tumors from patients with advanced renal cell cancer suggests that response to PD-1 blockade depends on both CD8+ T cell infiltration and enrichment of tumor-intrinsic somatic alterations.
- David A. Braun
- , Yue Hou
- & Toni K. Choueiri
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News & Views |
IL-8 and cancer prognosis on immunotherapy
Interleukin-8, produced by intratumoral and circulating myeloid cells, correlates with an immunosuppressive myeloid-enriched tumor microenvironment and adverse cancer prognosis.
- Ziad Bakouny
- & Toni K. Choueiri
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Letter |
High systemic and tumor-associated IL-8 correlates with reduced clinical benefit of PD-L1 blockade
In a retrospective analysis of data from three clinical trials, increased baseline peripheral and tumor IL-8 levels were associated with worse clinical outcomes in patients with metastatic urothelial carcinoma and metastatic renal cell carcinoma treated with anti-PD-L1 therapy.
- Kobe C. Yuen
- , Li-Fen Liu
- & Sanjeev Mariathasan
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Brief Communication |
Elevated serum interleukin-8 is associated with enhanced intratumor neutrophils and reduced clinical benefit of immune-checkpoint inhibitors
In a retrospective analysis of data from four phase 3 clinical trials, elevated baseline serum IL-8 levels were associated with worse clinical outcomes in patients with multiple tumor types treated with anti-PD-1 monotherapy or anti-PD-1 and anti-CTLA-4 combinatorial therapy.
- Kurt A. Schalper
- , Michael Carleton
- & Ignacio Melero
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Article |
Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma
Intraventricularly delivered monovalent and trivalent CAR T cells exhibit greater therapeutic efficacy as compared with intravenously delivered CAR T cells in medulloblastoma xenograft mouse models and show potency in ependymoma xenograft mouse models.
- Laura K. Donovan
- , Alberto Delaidelli
- & Michael D. Taylor
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Article |
Safety and feasibility of CRISPR-edited T cells in patients with refractory non-small-cell lung cancer
In a first-in-human phase I trial of patients with advanced lung cancer, infusions of autologous T cells edited to delete the PD-1 gene via CRISPR–Cas9 were well tolerated and did not lead to severe treatment-related adverse events.
- You Lu
- , Jianxin Xue
- & Tony Mok
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Letter |
Locoregionally administered B7-H3-targeted CAR T cells for treatment of atypical teratoid/rhabdoid tumors
CAR T cells administered intracerebroventricularly or intratumorally exhibit more rapid kinetics, reduced systemic toxicity and greater therapeutic potency as compared to intravenously delivered CAR T cells in atypical teratoid/rhabdoid tumor xenograft mouse models.
- Johanna Theruvath
- , Elena Sotillo
- & Crystal L. Mackall