Featured
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Article
| Open Access
Regorafenib plus nivolumab in unresectable hepatocellular carcinoma: the phase 2 RENOBATE trial
In the phase 2 RENOBATE trial, the combination of regorafenib and nivolumab as first-line treatment for unresectable hepatocellular carcinoma exhibited a safe profile and met the primary endpoint with a 31% overall response rate.
- Hyung-Don Kim
- , Seyoung Jung
- & Changhoon Yoo
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Article
| Open Access
Neoadjuvant atezolizumab plus chemotherapy in gastric and gastroesophageal junction adenocarcinoma: the phase 2 PANDA trial
A neoadjuvant treatment regimen of anti-PD-L1 monotherapy followed by anti-PD-L1 plus chemotherapy was well tolerated and led to a major pathologic response rate of 70% in patients with resectable gastric or gastroesophageal junction adenocarcinoma.
- Yara L. Verschoor
- , Joris van de Haar
- & Myriam Chalabi
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Article |
Thymus alterations and susceptibility to immune checkpoint inhibitor myocarditis
Thymic epithelial tumors are associated with increased risk of immune checkpoint inhibitor (ICI)-induced myotoxicities, and the presence of anti-acetylcholine-receptor antibodies has the potential to serve as a biomarker for ICI-induced myocarditis in patients with cancer.
- Charlotte Fenioux
- , Baptiste Abbar
- & Joe-Elie Salem
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Research Briefing |
Decoding antigen escape and multiple myeloma relapse after targeted immunotherapy
By integrating genomic and in vitro functional analysis, this study uncovers tumor-intrinsic mechanisms of resistance to immunotherapies that target B cell maturation antigen (BCMA) or the orphan G-protein-coupled-receptor GPRC5D in multiple myeloma (MM), highlighting a pivotal role for mutations in the genes encoding BCMA and GPRC5D in driving clinical relapse. These insights provide crucial guidance for the selection of therapeutic strategies and the development of next-generation targeted immunotherapies in MM.
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Article |
Nivolumab plus ipilimumab in advanced salivary gland cancer: a phase 2 trial
Treatment of patients with metastatic salivary gland cancer with anti-PD-1 and anti-CTLA-4 led to encouraging clinical benefit in certain histologic subtypes, with translational analyses showing pre-existing T cell clonal expansion in responding tumors.
- Joris L. Vos
- , Bharat Burman
- & Luc G. T. Morris
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Article |
Ipilimumab with or without nivolumab in PD-1 or PD-L1 blockade refractory metastatic melanoma: a randomized phase 2 trial
Patients with stage 4 or unresectable stage 3 melanoma refractory to first-line anti-programmed death protein 1 (PD-1) or anti-programmed cell death 1 ligand 1 have longer progression-free survival when treated with a combination of anti-cytotoxic T-lymphocyte protein 4 (CTLA-4) and anti-PD-1 versus anti-CTLA-4 alone.
- Ari VanderWalde
- , Shay L. Bellasea
- & Antoni Ribas
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Article
| Open Access
First-line durvalumab and tremelimumab with chemotherapy in RAS-mutated metastatic colorectal cancer: a phase 1b/2 trial
Treatment with anti-PDL1 and anti-CTLA4 in combination with mFOLFOX6 chemotherapy for patients with treatment-naive microsatellite stable metastatic colorectal cancer is safe, shows encouraging progression-free survival and induces a tumor-specific immune response.
- Marion Thibaudin
- , Jean-David Fumet
- & François Ghiringhelli
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Article |
Intratumoral dendritic cell–CD4+ T helper cell niches enable CD8+ T cell differentiation following PD-1 blockade in hepatocellular carcinoma
Response to anti-PD-1 in patients with hepatocellular carcinoma is associated with clonal expansion of intratumoral CXCL13+ CD4+ helper T cells and effector-like CD8+ T cells, and local dendritic cells enriched in expression of maturation and regulatory molecules help facilitate CD8+ T cell differentiation.
- Assaf Magen
- , Pauline Hamon
- & Miriam Merad
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Research Briefing |
Stress response in tumor-infiltrating T cells is linked to immunotherapy resistance
A newly composed single-cell transcriptomic atlas of tumor-infiltrating T cells across 16 cancer types revealed previously undescribed T cell states and heterogeneity. A unique T cell stress response state, TSTR, was linked to immunotherapy resistance. Our high-resolution T cell reference maps, web portal, and annotation tool can assist efforts to develop T cell therapies.
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Resource |
Pan-cancer T cell atlas links a cellular stress response state to immunotherapy resistance
A single-cell analysis of tumor-infiltrating T cells from 16 cancer types identifies new T cell subsets and a stress response cell state enriched in tumors resistant to immunotherapy.
- Yanshuo Chu
- , Enyu Dai
- & Linghua Wang
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Resource
| Open Access
An integrated tumor, immune and microbiome atlas of colon cancer
A large, publicly available dataset integrating RNA, whole-exome, T cell receptor and 16S rRNA sequencing from patients with colon cancer enables the discovery of a prognostic score consisting of tumor, immune and microbial features.
- Jessica Roelands
- , Peter J. K. Kuppen
- & Davide Bedognetti
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Article |
Anti-GD2 CAR-NKT cells in relapsed or refractory neuroblastoma: updated phase 1 trial interim results
In updated results from a phase 1 trial of GD2-specific CAR-NKT cells in patients with neuroblastoma, no dose-limiting toxicities were observed across multiple dose levels; the maximum tolerated dose was not reached; and there was evidence of anti-tumor activity.
- Andras Heczey
- , Xin Xu
- & Leonid S. Metelitsa
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Article
| Open Access
Neoadjuvant chemotherapy plus nivolumab with or without ipilimumab in operable non-small cell lung cancer: the phase 2 platform NEOSTAR trial
The combination of neoadjuvant nivolumab, ipilimumab and chemotherapy showed promising efficacy in patients with resectable non-small cell lung cancer, with higher tumor immune cell infiltration and tertiary lymphoid structures after treatment compared with neoadjuvant nivolumab plus chemotherapy.
- Tina Cascone
- , Cheuk H. Leung
- & Boris Sepesi
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Article
| Open Access
Whole-body CD8+ T cell visualization before and during cancer immunotherapy: a phase 1/2 trial
A CD8-specific, one-armed antibody positron emission tomography tracer enables the visualization of the immune response in patients with solid tumors before and after starting immunotherapy.
- Laura Kist de Ruijter
- , Pim P. van de Donk
- & Elisabeth G. E. de Vries
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Meeting Report |
Advancing T cell–based cancer therapy with single-cell technologies
To accelerate the development of T cell–based immunotherapies that are effective for more patients with cancer, there is an urgent need to decipher the precise attributes of the ideal therapeutic T cell. In March 2021, the Parker Institute of Cancer Immunotherapy and 10x Genomics partnered to bring together a group of T cell immunotherapy researchers and single-cell-technology innovators for a day’s workshop. Participants evaluated the current cutting edge of knowledge, identified areas for focused technology development, and put forward a call to action to the field. Insights were provided on how to best leverage single-cell technologies and key areas for future development were proposed — with the goal of facilitating a better understanding of T cell research and translation of this research into effective cancer immunotherapies. The key points of discussion that emerged from this workshop are summarized here.
- Samantha L. Bucktrout
- , Nicholas E. Banovich
- & Abbey Cutchin
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Article |
Distinct cellular dynamics associated with response to CAR-T therapy for refractory B cell lymphoma
Single-cell transcriptomics analyses of pretreatment and post-treatment peripheral blood mononuclear cells from patients treated with CD19 chimeric antigen receptor (CAR)-T products reveal a role for CAR-T regulatory cells in treatment relapse.
- Nicholas J. Haradhvala
- , Mark B. Leick
- & Marcela V. Maus
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Article
| Open Access
Tumor immune contexture is a determinant of anti-CD19 CAR T cell efficacy in large B cell lymphoma
Analysis of tumor biopsies from the pivotal phase 1/2 ZUMA-1 trial identifies pre-treatment T cell–related characteristics that are associated with clinical response and neurologic toxicity after anti-CD19 CAR T cell therapy in patients with large B cell lymphoma.
- Nathalie Scholler
- , Regis Perbost
- & Jérôme Galon
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Article
| Open Access
Immunogenicity 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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Article |
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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Article
| Open Access
Durvalumab 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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Article |
Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung cancer: a phase 1 trial
Adoptive cell therapy with tumor-infiltrating lymphocytes in metastatic lung cancer patients is safe and elicits antitumor activity, including ongoing complete responses, in association with polyclonal T cell responses against tumor antigens.
- Benjamin C. Creelan
- , Chao Wang
- & Scott J. Antonia
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Article |
An ex vivo tumor fragment platform to dissect response to PD-1 blockade in cancer
An ex vivo platform of patient-derived tumor fragments enables the assessment of intratumoral immune reactivation after PD-1 blockade that is predictive of clinical outcomes in patients with cancer.
- Paula Voabil
- , Marjolein de Bruijn
- & Daniela S. Thommen
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News & Views |
Context matters in CAR T cell tonic signaling
Unexpected clinical results unearth a new facet in CAR design that could facilitate the development of more-effective CAR T cell therapies.
- Kristen Hege
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Article |
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
| Open Access
Transcriptional mediators of treatment resistance in lethal prostate cancer
Single-cell transcriptomic analysis of metastatic castration-resistant prostate cancer uncovers pervasive coexpression of androgen receptor isoforms and cancer cell–intrinsic and microenvironmental programs of treatment resistance
- Meng Xiao He
- , Michael S. Cuoco
- & Eliezer M. Van Allen
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Letter |
TCR-engineered T cells targeting E7 for patients with metastatic HPV-associated epithelial cancers
In a first-in-human phase 1 trial of patients with HPV-associated metastatic epithelial cancers, T cells targeting HPV-16 E7 were well tolerated, with one observed dose-limiting toxicity, and elicited objective clinical responses in 6 of 12 treated patients.
- Nisha B. Nagarsheth
- , Scott M. Norberg
- & Christian S. Hinrichs
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Article |
Opposing immune and genetic mechanisms shape oncogenic programs in synovial sarcoma
Single-cell transcriptional profiling of primary human synovial sarcoma tumors suggests that combinatorial treatment with HDAC and CDK4/CDK6 inhibitors could enhance tumor immunogenicity.
- Livnat Jerby-Arnon
- , Cyril Neftel
- & Aviv Regev
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Article |
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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News & Views |
Liver metastases inhibit immunotherapy efficacy
Liver metastases lead to resistance to immunotherapy through the ‘siphoning’ of tumor antigen–specific CD8+ T cells into the liver, which results in a systemic ‘immune desert’ incapable of controlling tumor burden.
- Katherine E. Lindblad
- & Amaia Lujambio
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Article |
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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Article |
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 |
A single-cell landscape of high-grade serous ovarian cancer
Single-cell transcriptomics analysis of malignant ascites samples from patients with high-grade serous ovarian cancer reveals inter- and intra-patient heterogeneity in malignant cells, cancer-associated fibroblasts and macrophages.
- Benjamin Izar
- , Itay Tirosh
- & Aviv Regev
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Article |
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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Letter |
Geospatial immune variability illuminates differential evolution of lung adenocarcinoma
Multiregion spatial histology, exome and transcriptome data from patients with non-small cell lung cancer suggest that cancer subclones from immune cold regions diversify later than subclones from immune hot regions
- Khalid AbdulJabbar
- , Shan E. Ahmed Raza
- & Yinyin Yuan
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Article |
Systemic dysfunction and plasticity of the immune macroenvironment in cancer models
Primary tumor presence and progression shape the systemic immune landscape and immune responses to pathogens in multiple murine tumor models.
- Breanna M. Allen
- , Kamir J. Hiam
- & Matthew H. Spitzer
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Article |
Chemotherapy-induced ileal crypt apoptosis and the ileal microbiome shape immunosurveillance and prognosis of proximal colon cancer
Local microbiome composition influences treatment efficacy of chemotherapy in colon cancer via modulation of tolerogenic versus immunogenic ileal intestinal epithelial cell death, which in turn influences follicular helper T cell priming.
- Maria Paula Roberti
- , Satoru Yonekura
- & Laurence Zitvogel
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Letter |
Common germline variants of the human APOE gene modulate melanoma progression and survival
Heritable APOE variants in patients with melanoma influence anti-tumor immunity and modulate metastatic progression and response to immunotherapy.
- Benjamin N. Ostendorf
- , Jana Bilanovic
- & Sohail F. Tavazoie
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Letter |
BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: the COMBAT trial
Results from the phase IIa COMBAT trial combining CXCR4 and PD-1 inhibition in patients with metastatic cancer show encouraging clinical responses in association with enhanced antitumor immune activation.
- Bruno Bockorny
- , Valerya Semenisty
- & Manuel Hidalgo
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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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Perspective |
Learning from clinical trials of neoadjuvant checkpoint blockade
The emerging success of neoadjuvant therapy is creating opportunities for understanding successful immune responses and improving therapies using this unique pool of knowledge.
- Judith M. Versluis
- , Georgina V. Long
- & Christian U. Blank
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Article |
TMEM30A loss-of-function mutations drive lymphomagenesis and confer therapeutically exploitable vulnerability in B-cell lymphoma
Integrative analysis in patients with diffuse large B-cell lymphoma uncovers that biallelic mutations on TMEM30A are associated with a favorable outcome and enhanced sensitivity to CD47 blockade.
- Daisuke Ennishi
- , Shannon Healy
- & Christian Steidl
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Perspective |
Single-cell genomic approaches for developing the next generation of immunotherapies
Amit and colleagues discuss where single-cell genomic technologies can be applied both in trial design and in the clinical trial stage to improve the development of immunotherapies.
- Ido Yofe
- , Rony Dahan
- & Ido Amit
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Letter |
Immune profiling of human tumors identifies CD73 as a combinatorial target in glioblastoma
Analysis of a mass cytometry dataset for different human solid tumors coupled with murine reverse translational experiments suggests that targeting CD73 could enhance the efficacy of checkpoint inhibitor therapy in glioblastoma.
- Sangeeta Goswami
- , Thomas Walle
- & Padmanee Sharma
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Matters Arising |
IMPRES does not reproducibly predict response to immune checkpoint blockade therapy in metastatic melanoma
- Jason A. Carter
- , Philip Gilbo
- & Gurinder S. Atwal
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Letter |
Evolutionary divergence of HLA class I genotype impacts efficacy of cancer immunotherapy
The degree of sequence divergence between patient MHC class I alleles influences the response to immune checkpoint blockade therapy independently of tumor mutational burden.
- Diego Chowell
- , Chirag Krishna
- & Timothy A. Chan
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Article |
Spatial heterogeneity of the T cell receptor repertoire reflects the mutational landscape in lung cancer
A survey of T cell repertoire evolution in the tumors, healthy tissue and blood of patients with early-stage untreated lung cancer offers an opportunity to monitor and identify neoantigen-specific T cells for personalized immunotherapy.
- Kroopa Joshi
- , Marc Robert de Massy
- & Benny Chain
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Article |
Stress–glucocorticoid–TSC22D3 axis compromises therapy-induced antitumor immunity
Stress reduces the effects of various cancer therapies, such as chemotherapy and immunotherapy, in mice; this is mediated, at least partially, through Tsc22d3 upregulation in tumor-infiltrating dendritic cells, which leads to immunosuppression.
- Heng Yang
- , Lin Xia
- & Yuting Ma
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Review Article |
Clinical lessons learned from the first leg of the CAR T cell journey
Clinical application of CAR T cells to cancer therapy has met with much success, but future trials must build on current understanding to overcome therapy resistance
- Robbie G. Majzner
- & Crystal L. Mackall
A spatial architecture-embedding HLA signature to predict clinical response to immunotherapy in renal cell carcinoma