Medical Abstracts

Filters applied: from 2021/2/1 - 2021/2/28.

1. Annu Rev Immunol. 2021 Feb 26. doi: 10.1146/annurev-immunol-093019-010426.

Online ahead of print.

The Innate Immune Response to Mycobacterium tuberculosis Infection.

Ravesloot-Chavez MM(1), Van Dis E(2), Stanley SA(2)(3).

Author information:

(1)Department of Plant and Microbial Biology, University of California,

Berkeley, California 94720, USA; email: mchavez@berkeley.edu.

(2)Division of Immunology and Pathogenesis, Department of Molecular and Cell

Biology, University of California, Berkeley, California 94720, USA; email:

sastanley@berkeley.edu, vandise@berkeley.edu.

(3)Division of Infectious Diseases and Vaccinology, School of Public Health,

University of California, Berkeley, California 94720, USA.

Infection with Mycobacterium tuberculosis causes >1.5 million deaths worldwide

annually. Innate immune cells are the first to encounter M. tuberculosis, and

their response dictates the course of infection. Dendritic cells (DCs) activate

the adaptive response and determine its characteristics. Macrophages are

responsible both for exerting cell-intrinsic antimicrobial control and for

initiating and maintaining inflammation. The inflammatory response to M.

tuberculosis infection is a double-edged sword. While cytokines such as TNF-α

and IL-1 are important for protection, either excessive or insufficient cytokine

production results in progressive disease. Furthermore, neutrophils-cells

normally associated with control of bacterial infection-are emerging as key

drivers of a hyperinflammatory response that results in host mortality. The

roles of other innate cells, including natural killer cells and innate-like T

cells, remain enigmatic. Understanding the nuances of both cell-intrinsic

control of infection and regulation of inflammation will be crucial for the

successful development of host-targeted therapeutics and vaccines. Expected

final online publication date for the Annual Review of Immunology, Volume 39 is

April 2021. Please see http://www.annualreviews.org/page/journal/pubdates for

revised estimates.

DOI: 10.1146/annurev-immunol-093019-010426

PMID: 33637017

2. Lancet. 2021 Feb 13;397(10274):592-604. doi: 10.1016/S0140-6736(21)00228-2.

Cemiplimab monotherapy for first-line treatment of advanced non-small-cell lung

cancer with PD-L1 of at least 50%: a multicentre, open-label, global, phase 3,

randomised, controlled trial.

Sezer A(1), Kilickap S(2), Gümü? M(3), Bondarenko I(4), Özgüro?lu M(5),

Gogishvili M(6), Turk HM(7), Cicin I(8), Bentsion D(9), Gladkov O(10), Clingan

P(11), Sriuranpong V(12), Rizvi N(13), Gao B(14), Li S(14), Lee S(14), McGuire

K(15), Chen CI(14), Makharadze T(16), Paydas S(17), Nechaeva M(18), Seebach

F(15), Weinreich DM(15), Yancopoulos GD(15), Gullo G(15), Lowy I(15), Rietschel

P(15).

Author information:

(1)Department of Medical Oncology, Ba?kent University, Adana, Turkey. Electronic

address: drasezer@hotmail.com.tr.

(2)Department of Medical Oncology, Hacettepe University Cancer Institute,

Ankara, Turkey.

(3)Department of Medical Oncology, School of Medicine, Istanbul Medeniyet

University, Istanbul, Turkey.

...

BACKGROUND: We aimed to examine cemiplimab, a programmed cell death 1 inhibitor,

in the first-line treatment of advanced non-small-cell lung cancer with

programmed cell death ligand 1 (PD-L1) of at least 50%.

METHODS: In EMPOWER-Lung 1, a multicentre, open-label, global, phase 3 study,

eligible patients recruited in 138 clinics from 24 countries (aged ≥18 years

with histologically or cytologically confirmed advanced non-small-cell lung

cancer, an Eastern Cooperative Oncology Group performance status of 0-1;

never-smokers were ineligible) were randomly assigned (1:1) to cemiplimab 350 mg

every 3 weeks or platinum-doublet chemotherapy. Crossover from chemotherapy to

cemiplimab was allowed following disease progression. Primary endpoints were

overall survival and progression-free survival per masked independent review

committee. Primary endpoints were assessed in the intention-to-treat population

and in a prespecified PD-L1 of at least 50% population (per US Food and Drug

Administration request to the sponsor), which consisted of patients with PD-L1

of at least 50% per 22C3 assay done according to instructions for use. Adverse

events were assessed in all patients who received at least one dose of the

assigned treatment. This study is registered with ClinicalTrials.gov,

NCT03088540 and is ongoing.

FINDINGS: Between June 27, 2017 and Feb 27, 2020, 710 patients were randomly

assigned (intention-to-treat population). In the PD-L1 of at least 50%

population, which consisted of 563 patients, median overall survival was not

reached (95% CI 17·9-not evaluable) with cemiplimab (n=283) versus 14·2 months

(11·2-17·5) with chemotherapy (n=280; hazard ratio [HR] 0·57 [0·42-0·77];

p=0·0002). Median progression-free survival was 8·2 months (6·1-8·8) with

cemiplimab versus 5·7 months (4·5-6·2) with chemotherapy (HR 0·54 [0·43-0·68];

p<0·0001). Significant improvements in overall survival and progression-free

survival were also observed with cemiplimab in the intention-to-treat population

despite a high crossover rate (74%). Grade 3-4 treatment-emergent adverse events

occurred in 98 (28%) of 355 patients treated with cemiplimab and 135 (39%) of

342 patients treated with chemotherapy.

INTERPRETATION: Cemiplimab monotherapy significantly improved overall survival

and progression-free survival compared with chemotherapy in patients with

advanced non-small-cell lung cancer with PD-L1 of at least 50%, providing a

potential new treatment option for this patient population.

FUNDING: Regeneron Pharmaceuticals and Sanofi.

Copyright © 2021 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S0140-6736(21)00228-2

PMID: 33581821

3. CA Cancer J Clin. 2021 Feb 4. doi: 10.3322/caac.21660. Online ahead of print.

Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality

worldwide for 36 cancers in 185 countries.

Sung H(1), Ferlay J(2), Siegel RL(1), Laversanne M(2), Soerjomataram I(2), Jemal

A(1), Bray F(2).

Author information:

(1)Surveillance and Health Equity Science, American Cancer Society, Atlanta,

Georgia.

(2)Section of Cancer Surveillance, International Agency for Research on Cancer,

Lyon, France.

This article provides an update on the global cancer burden using the GLOBOCAN

2020 estimates of cancer incidence and mortality produced by the International

Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer

cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million

cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020.

Female breast cancer has surpassed lung cancer as the most commonly diagnosed

cancer, with an estimated 2.3 million new cases (11.7%), followed by lung

(11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung

cancer remained the leading cause of cancer death, with an estimated 1.8 million

deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and

female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher

in transitioned versus transitioning countries for both sexes, whereas mortality

varied <2-fold for men and little for women. Death rates for female breast and

cervical cancers, however, were considerably higher in transitioning versus

transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000,

respectively). The global cancer burden is expected to be 28.4 million cases in

2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%)

versus transitioned (32% to 56%) countries due to demographic changes, although

this may be further exacerbated by increasing risk factors associated with

globalization and a growing economy. Efforts to build a sustainable

infrastructure for the dissemination of cancer prevention measures and provision

of cancer care in transitioning countries is critical for global cancer control.

© 2021 American Cancer Society.

DOI: 10.3322/caac.21660

PMID: 33538338

4. Nature. 2021 Feb;590(7846):504-508. doi: 10.1038/s41586-020-03170-y. Epub 2021

Feb 3.

Elevated NSD3 histone methylation activity drives squamous cell lung cancer.

Yuan G(#)(1), Flores NM(#)(2), Hausmann S(2), Lofgren SM(2), Kharchenko V(3),

Angulo-Ibanez M(4)(5), Sengupta D(1), Lu X(2), Czaban I(3), Azhibek D(3), Vicent

S(6), Fischle W(3), Jaremko M(3), Fang B(7), Wistuba II(8), Chua KF(4)(5), Roth

JA(7), Minna JD(9)(10)(11), Shao NY(12), Jaremko ?(13), Mazur PK(14), Gozani

O(15).

Author information:

(1)Department of Biology, Stanford University, Stanford, CA, USA.

(2)Department of Experimental Radiation Oncology, The University of Texas MD

Anderson Cancer Center, Houston, TX, USA.

(3)Division of Biological and Environmental Science and Engineering, King

Abdullah University of Science and Technology, Thuwal, Saudi Arabia.

...

Comment in

Nature. 2021 Feb;590(7846):399-400.

Amplification of chromosomal region 8p11-12 is a common genetic alteration that

has been implicated in the aetiology of lung squamous cell carcinoma (LUSC)1-3.

The FGFR1 gene is the main candidate driver of tumorigenesis within this

region4. However, clinical trials evaluating FGFR1 inhibition as a targeted

therapy have been unsuccessful5. Here we identify the histone H3 lysine 36

(H3K36) methyltransferase NSD3, the gene for which is located in the 8p11-12

amplicon, as a key regulator of LUSC tumorigenesis. In contrast to other 8p11-12

candidate LUSC drivers, increased expression of NSD3 correlated strongly with

its gene amplification. Ablation of NSD3, but not of FGFR1, attenuated tumour

growth and extended survival in a mouse model of LUSC. We identify an

LUSC-associated variant NSD3(T1232A) that shows increased catalytic activity for

dimethylation of H3K36 (H3K36me2) in vitro and in vivo. Structural dynamic

analyses revealed that the T1232A substitution elicited localized mobility

changes throughout the catalytic domain of NSD3 to relieve auto-inhibition and

to increase accessibility of the H3 substrate. Expression of NSD3(T1232A) in

vivo accelerated tumorigenesis and decreased overall survival in mouse models of

LUSC. Pathological generation of H3K36me2 by NSD3(T1232A) reprograms the

chromatin landscape to promote oncogenic gene expression signatures.

Furthermore, NSD3, in a manner dependent on its catalytic activity, promoted

transformation in human tracheobronchial cells and growth of xenografted human

LUSC cell lines with amplification of 8p11-12. Depletion of NSD3 in

patient-derived xenografts from primary LUSCs containing NSD3 amplification or

the NSD3(T1232A)-encoding variant attenuated neoplastic growth in mice. Finally,

NSD3-regulated LUSC-derived xenografts were hypersensitive to bromodomain

inhibition. Thus, our work identifies NSD3 as a principal 8p11-12

amplicon-associated oncogenic driver in LUSC, and suggests that NSD3-dependency

renders LUSC therapeutically vulnerable to bromodomain inhibition.

DOI: 10.1038/s41586-020-03170-y

PMCID: PMC7895461

PMID: 33536620

5. Science. 2021 Feb 26;371(6532):eabc1944. doi: 10.1126/science.abc1944. Epub 2021

Jan 21.

Single-cell lineages reveal the rates, routes, and drivers of metastasis in

cancer xenografts.

Quinn JJ(#)(1)(2)(3), Jones MG(#)(1)(2)(4)(5)(6), Okimoto RA(7)(8), Nanjo

S(7)(8), Chan MM(1)(2)(9), Yosef N(10)(11)(12)(13), Bivona TG(14)(7)(8),

Weissman JS(14)(2)(15)(16).

Author information:

(1)Department of Cellular and Molecular Pharmacology, University of California,

San Francisco, San Francisco, CA, USA.

(2)Howard Hughes Medical Institute, University of California, San Francisco, San

Francisco, CA, USA.

(3)Inscripta, Inc., Boulder, CO, USA.

...

Detailed phylogenies of tumor populations can recount the history and chronology

of critical events during cancer progression, such as metastatic dissemination.

We applied a Cas9-based, single-cell lineage tracer to study the rates, routes,

and drivers of metastasis in a lung cancer xenograft mouse model. We report

deeply resolved phylogenies for tens of thousands of cancer cells traced over

months of growth and dissemination. This revealed stark heterogeneity in

metastatic capacity, arising from preexisting and heritable differences in gene

expression. We demonstrate that these identified genes can drive invasiveness

and uncovered an unanticipated suppressive role for KRT17 We also show that

metastases disseminated via multidirectional tissue routes and complex seeding

topologies. Overall, we demonstrate the power of tracing cancer progression at

subclonal resolution and vast scale.

Copyright © 2021 The Authors, some rights reserved; exclusive licensee American

Association for the Advancement of Science. No claim to original U.S. Government

Works.

DOI: 10.1126/science.abc1944

PMID: 33479121

6. Lancet Infect Dis. 2021 Feb 25:S1473-3099(20)30919-1. doi:

10.1016/S1473-3099(20)30919-1. Online ahead of print.

Quantifying the global number of tuberculosis survivors: a modelling study.

Dodd PJ(1), Yuen CM(2), Jayasooriya SM(3), van der Zalm MM(4), Seddon JA(5).

Author information:

(1)School of Health and Related Research, University of Sheffield, Sheffield,

UK. Electronic address: p.j.dodd@sheffield.ac.uk.

(2)Harvard Medical School, Harvard University, Boston, MA, USA; Division of

Global Health Equity, Brigham and Women's Hospital, Boston, MA, USA.

(3)Academic Unit of Primary Care, University of Sheffield, Sheffield, UK.

...

BACKGROUND: People who survive tuberculosis face clinical and societal

consequences after recovery, including increased risks of recurrent

tuberculosis, premature death, reduced lung function, and ongoing stigma. To

describe the size of this issue, we aimed to estimate the number of individuals

who developed first-episode tuberculosis between 1980 and 2019, the number who

survived to 2020, and the number who have been treated within the past 5 years

or 2 years.

METHODS: In this modelling study, we estimated the number of people who survived

treated tuberculosis using country-level WHO data on tuberculosis case

notifications, excluding those who died during treatment. We estimated the

number of individuals surviving untreated tuberculosis using the difference

between WHO country-level incidence estimates and notifications, applying

published age-stratified and HIV-stratified case fatality ratios. To estimate

survival with time, post-tuberculosis life tables were developed for each

country-year by use of UN World Population Prospects 2019 mortality rates and

published post-tuberculosis mortality hazard ratios.

FINDINGS: Between 1980 and 2019, we estimate that 363 million people (95%

uncertainty interval [UI] 287 million-438 million) developed tuberculosis, of

whom 172 million (169 million-174 million) were treated. Individuals who

developed tuberculosis between 1980 and 2019 had lived 3480 million life-years

(95% UI 3040 million-3920 million) after tuberculosis by 2020, with survivors

younger than 15 years at the time of tuberculosis development contributing 12%

(95% UI 7-17) of these life-years. We estimate that 155 million tuberculosis

survivors (95% UI 138 million-171 million) were alive in 2020, the largest

proportion (47% [37-57]) of whom were in the WHO South-East Asia region. Of the

tuberculosis survivors who were alive in 2020, we estimate that 18% (95% UI

16-20) were treated in the past 5 years and 8% (7-9) were treated in the past 2

years.

INTERPRETATION: The number of tuberculosis survivors alive in 2020 is more than

ten times the estimated annual tuberculosis incidence. Interventions to

alleviate respiratory morbidity, screen for and prevent recurrent tuberculosis,

and reduce stigma should be immediately prioritised for recently treated

tuberculosis survivors.

FUNDING: UK Medical Research Council, the UK Department for International

Development, the National Institute for Health Research, and the European and

Developing Countries Clinical Trials Partnership.

Copyright © 2021 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1473-3099(20)30919-1

PMID: 33640076

7. Cancer Discov. 2021 Feb 25:candisc.1598.2020. doi: 10.1158/2159-8290.CD-20-1598.

Online ahead of print.

Activity and Safety of Mobocertinib (TAK-788) in Previously Treated Non-Small

Cell Lung Cancer With EGFR Exon 20 Insertion Mutations From a Phase 1/2 Trial.

Riely GJ(1), Neal JW(2), Camidge DR(3), Spira AI(4), Piotrowska Z(5), Costa

DB(6), Tsao AS(7), Patel JD(8), Gadgeel SM(9), Bazhenova L(10), Zhu VW(11), West

HL(12), Mekhail T(13), Gentzler RD(14), Nguyen D(15), Vincent S(16), Zhang

S(17), Lin J(18), Bunn V(19), Jin S(20), Li S(21), Janne PA(22).

Author information:

(1)Medicine, Memorial Sloan Kettering Cancer Center rielyg@mskcc.org.

(2)Division of Oncology, Department of Medicine, Stanford Cancer Institute,

Stanford University.

(3)Cancer Center, University of Colorado Denver.

...

Mobocertinib, an oral epidermal growth factor receptor (EGFR) inhibitor

targeting EGFR gene mutations including exon 20 insertions (EGFRex20ins) in

non-small cell lung cancer, was evaluated in a phase 1/2

dose-escalation/expansion trial (ClinicalTrials.gov NCT02716116). Dose

escalation identified 160 mg daily as the recommended phase 2 dose and maximum

tolerated dose. Among 136 patients treated with 160 mg daily, the most common

any grade treatment-related adverse events (TRAEs; >25%) were diarrhea (83%),

nausea (43%), rash (33%), and vomiting (26%), with diarrhea (21%) the only grade

{greater than or equal to}3 TRAE >5%. Among 28 EGFRex20ins patients treated at

160 mg daily, the investigator-assessed confirmed response rate was 43% (12/28;

95% confidence interval (CI): 24-63%) with median duration of response of 14

months (5.0-not reached), and median progression-free survival of 7.3 months

(4.4-15.6). Mobocertinib demonstrated antitumor activity in patients with

diverse EGFRex20ins variants with a safety profile consistent with other EGFR

inhibitors.

Copyright ©2021, American Association for Cancer Research.

DOI: 10.1158/2159-8290.CD-20-1598

PMID: 33632775

8. Lancet Infect Dis. 2021 Feb 17:S1473-3099(20)30653-8. doi:

10.1016/S1473-3099(20)30653-8. Online ahead of print.

BCG-induced non-specific effects on heterologous infectious disease in Ugandan

neonates: an investigator-blind randomised controlled trial.

Prentice S(1), Nassanga B(2), Webb EL(3), Akello F(2), Kiwudhu F(2), Akurut

H(2), Elliott AM(4), Arts RJW(5), Netea MG(6), Dockrell HM(7), Cose S(8);

Delayed BCG Study Team.

Author information:

(1)Clinical Research Department, London School of Hygiene and Tropical Medicine,

London, UK; MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda. Electronic

address: sarah.prentice@nhs.net.

(2)MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda.

(3)Department of Infectious Disease Epidemiology, London School of Hygiene and

Tropical Medicine, London, UK.

...

BACKGROUND: Trials done in infants with low birthweight in west Africa suggest

that BCG vaccination reduces all-cause mortality in the neonatal period,

probably because of heterologous protection against non-tuberculous infections.

This study investigated whether BCG alters all-cause infectious disease

morbidity in healthy infants in a different high-mortality setting, and explored

whether the changes are mediated via trained innate immunity.

METHODS: This was an investigator-blind, randomised, controlled trial done at

one hospital in Entebbe, Uganda. Infants who were born unwell (ie, those who

were not well enough to be discharged directly home from the labour ward because

they required medical intervention), with major congenital malformations, to

mothers with HIV, into families with known or suspected tuberculosis, or for

whom cord blood samples could not be taken, were excluded from the study. Any

other infant well enough to be discharged directly from the labour ward was

eligible for inclusion, with no limitation on gestational age or birthweight.

Participants were recruited at birth and randomly assigned (1:1) to receive

standard dose BCG 1331 (BCG-Danish) on the day of birth or at age 6 weeks

(computer-generated randomisation, block sizes of 24, stratified by sex).

Investigators and clinicians were masked to group assignment; parents were not

masked. Participants were clinically followed up to age 10 weeks and contributed

blood samples to one of three immunological substudies. The primary clinical

outcome was physician-diagnosed non-tuberculous infectious disease incidence.

Primary immunological outcomes were histone trimethylation at the promoter

region of TNF, IL6, and IL1B; ex-vivo production of TNF, IL-6, IL-1β, IL-10, and

IFNγ after heterologous stimulation; and transferrin saturation and hepcidin

levels. All outcomes were analysed in the modified intention-to-treat population

of all randomly assigned participants except those whose for whom consent was

withdrawn. This trial is registered with the International Standard Randomised

Controlled Trial Number registry (#59683017).

FINDINGS: Between Sept 25, 2014, and July 31, 2015, 560 participants were

enrolled and randomly assigned to receive BCG at birth (n=280) or age 6 weeks

(n=280). 12 participants assigned to receive BCG at birth and 11 participants

assigned to receive BCG at age 6 weeks were withdrawn from the study by their

parents shortly after randomisation and were not included in analyses. During

the first 6 weeks of life before the infants in the delayed vaccination group

received BCG vaccination, physician-diagnosed non-tuberculous infectious disease

incidence was lower in infants in the BCG at birth group than in the delayed

group (98 presentations in the BCG at birth group vs 129 in the delayed BCG

group; hazard ratio [HR] 0·71 [95% CI 0·53-0·95], p=0·023). After BCG in the

delayed group (ie, during the age 6-10 weeks follow-up), there was no

significant difference in non-tuberculous infectious disease incidence between

the groups (88 presentations vs 76 presentations; HR 1·10 [0·87-1·40], p=0·62).

BCG at birth inhibited the increase in histone trimethylation at the TNF

promoter in peripheral blood mononuclear cells occurring in the first 6 weeks of

life. H3K4me3 geometric mean fold-increases were 3·1 times lower at the TNF

promoter (p=0·018), 2·5 times lower at the IL6 promoter (p=0·20), and 3·1 times

lower at the IL1B promoter (p=0·082) and H3K9me3 geometric mean fold-increases

were 8·9 times lower at the TNF promoter (p=0·0046), 1·2 times lower at the IL6

promoter (p=0·75), and 4·6 times lower at the IL1B promoter (p=0·068), in

BCG-vaccinated (BCG at birth group) versus BCG-naive (delayed BCG group)

infants. No clear effect of BCG on ex-vivo production of TNF, IL-6, IL-1β,

IL-10, and IFNγ after heterologous stimulation, or transferrin saturation and

hepcidin concentration, was detected (geometric mean ratios between 0·68 and

1·68; p≥0·038 for all comparisons).

INTERPRETATION: BCG vaccination protects against non-tuberculous infectious

disease during the neonatal period, in addition to having tuberculosis-specific

effects. Prioritisation of BCG on the first day of life in high-mortality

settings might have significant public-health benefits through reductions in

all-cause infectious morbidity and mortality.

FUNDING: Wellcome Trust.

TRANSLATIONS: For the Luganda and Swahili translations of the abstract see

Supplementary Materials section.

Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open

Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All

rights reserved.

DOI: 10.1016/S1473-3099(20)30653-8

PMID: 33609457

9. Nat Commun. 2021 Feb 19;12(1):1193. doi: 10.1038/s41467-021-21467-y.

An annotation-free whole-slide training approach to pathological classification

of lung cancer types using deep learning.

Chen CL(#)(1)(2)(3), Chen CC(#)(4), Yu WH(4), Chen SH(4), Chang YC(5), Hsu

TI(6), Hsiao M(6), Yeh CY(7), Chen CY(8)(9).

Author information:

(1)Department of Pathology, School of Medicine, College of Medicine, Taipei

Medical University, Taipei, Taiwan.

(2)Department of Pathology, Taipei Medical University Hospital, Taipei, Taiwan.

(3)Research Center for Artificial Intelligence in Medicine, Taipei Medical

University, Taipei, Taiwan.

...

Deep learning for digital pathology is hindered by the extremely high spatial

resolution of whole-slide images (WSIs). Most studies have employed patch-based

methods, which often require detailed annotation of image patches. This

typically involves laborious free-hand contouring on WSIs. To alleviate the

burden of such contouring and obtain benefits from scaling up training with

numerous WSIs, we develop a method for training neural networks on entire WSIs

using only slide-level diagnoses. Our method leverages the unified memory

mechanism to overcome the memory constraint of compute accelerators. Experiments

conducted on a data set of 9662 lung cancer WSIs reveal that the proposed method

achieves areas under the receiver operating characteristic curve of 0.9594 and

0.9414 for adenocarcinoma and squamous cell carcinoma classification on the

testing set, respectively. Furthermore, the method demonstrates higher

classification performance than multiple-instance learning as well as strong

localization results for small lesions through class activation mapping.

DOI: 10.1038/s41467-021-21467-y

PMID: 33608558

10. Nat Commun. 2021 Feb 18;12(1):1141. doi: 10.1038/s41467-021-21475-y.

Gastrointestinal microbiota composition predicts peripheral inflammatory state

during treatment of human tuberculosis.

Wipperman MF(#)(1)(2), Bhattarai SK(#)(3), Vorkas CK(1)(4), Maringati VS(3),

Taur Y(5), Mathurin L(6), McAulay K(7), Vilbrun SC(6), Francois D(6), Bean J(1),

Walsh KF(7), Nathan C(8), Fitzgerald DW(7), Glickman MS(9)(10)(11), Bucci

V(12)(13)(14).

Author information:

(1)Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY,

USA.

(2)Clinical and Translational Science Center, Weill Cornell Medicine, New York,

NY, USA.

(3)Department of Microbiology and Physiological Systems, University of

Massachusetts Medical School, Worcester, MA, USA.

...

The composition of the gastrointestinal microbiota influences systemic immune

responses, but how this affects infectious disease pathogenesis and antibiotic

therapy outcome is poorly understood. This question is rarely examined in humans

due to the difficulty in dissociating the immunologic effects of

antibiotic-induced pathogen clearance and microbiome alteration. Here, we

analyze data from two longitudinal studies of tuberculosis (TB) therapy (35 and

20 individuals) and a cross sectional study from 55 healthy controls, in which

we collected fecal samples (for microbiome analysis), sputum (for determination

of Mycobacterium tuberculosis (Mtb) bacterial load), and peripheral blood (for

transcriptomic analysis). We decouple microbiome effects from pathogen

sterilization by comparing standard TB therapy with an experimental TB treatment

that did not reduce Mtb bacterial load. Random forest regression to the

microbiome-transcriptome-sputum data from the two longitudinal datasets reveals

that renormalization of the TB inflammatory state is associated with Mtb

pathogen clearance, increased abundance of Clusters IV and XIVa Clostridia, and

decreased abundance of Bacilli and Proteobacteria. We find similar associations

when applying machine learning to peripheral gene expression and microbiota

profiling in the independent cohort of healthy individuals. Our findings

indicate that antibiotic-induced reduction in pathogen burden and changes in the

microbiome are independently associated with treatment-induced changes of the

inflammatory response of active TB, and the response to antibiotic therapy may

be a combined effect of pathogen killing and microbiome driven immunomodulation.

DOI: 10.1038/s41467-021-21475-y

PMID: 33602926

11. J Clin Oncol. 2021 Feb 16:JCO2003570. doi: 10.1200/JCO.20.03570. Online ahead of

print.

Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO

and OH (CCO) Joint Guideline Update.

Hanna NH(1), Robinson AG(2), Temin S(3), Baker S Jr(4), Brahmer JR(5), Ellis

PM(6), Gaspar LE(7)(8), Haddad RY(9), Hesketh PJ(10), Jain D(11), Jaiyesimi

I(12), Johnson DH(13), Leighl NB(14), Moffitt PR(15), Phillips T(16), Riely

GJ(17), Rosell R(18), Schiller JH(19), Schneider BJ(20), Singh N(21), Spigel

DR(22), Tashbar J(23), Masters G(24).

Author information:

(1)Indiana University Simon Comprehensive Cancer Center, Indianapolis, IN.

(2)Kingston General Hospital, School of Medicine, Queen's University, ON,

Canada.

(3)American Society of Clinical Oncology, Alexandria, VA.

PURPOSE: To provide evidence-based recommendations updating the 2017 ASCO

guideline on systemic therapy for patients with stage IV non-small-cell lung

cancer (NSCLC) with driver alterations. A guideline update for systemic therapy

for patients with stage IV NSCLC without driver alterations was published

separately.

METHODS: The American Society of Clinical Oncology and Ontario Health (Cancer

Care Ontario) NSCLC Expert Panel updated recommendations based on a systematic

review of randomized controlled trials (RCTs) from December 2015 to January 2020

and meeting abstracts from ASCO 2020.

RESULTS: This guideline update reflects changes in evidence since the previous

update. Twenty-seven RCTs, 26 observational studies, and one meta-analysis

provide the evidence base (total 54). Outcomes of interest included efficacy and

safety. Additional literature suggested by the Expert Panel is discussed.

RECOMMENDATIONS: All patients with nonsquamous NSCLC should have the results of

testing for potentially targetable mutations (alterations) before implementing

therapy for advanced lung cancer, regardless of smoking status recommendations,

when possible, following other existing high-quality testing guidelines. Most

patients should receive targeted therapy for these alterations: Targeted

therapies against ROS-1 fusions, BRAF V600e mutations, RET fusions, MET exon 14

skipping mutations, and NTRK fusions should be offered to patients, either as

initial or second-line therapy when not given in the first-line setting. New or

revised recommendations include the following: Osimertinib is the optimal

first-line treatment for patients with activating epidermal growth factor

receptor mutations (exon 19 deletion, exon 21 L858R, and exon 20 T790M);

alectinib or brigatinib is the optimal first-line treatment for patients with

anaplastic lymphoma kinase fusions. For the first time, to our knowledge, the

guideline includes recommendations regarding RET, MET, and NTRK alterations.

Chemotherapy is still an option at most stages.Additional information is

available at www.asco.org/thoracic-cancer-guidelines.

DOI: 10.1200/JCO.20.03570

PMID: 33591844

12. Lancet Infect Dis. 2021 Feb 12:S1473-3099(20)30770-2. doi:

10.1016/S1473-3099(20)30770-2. Online ahead of print.

QT effects of bedaquiline, delamanid, or both in patients with

rifampicin-resistant tuberculosis: a phase 2, open-label, randomised, controlled

trial.

Dooley KE(1), Rosenkranz SL(2), Conradie F(3), Moran L(4), Hafner R(5), von

Groote-Bidlingmaier F(6), Lama JR(7), Shenje J(8), De Los Rios J(7), Comins

K(6), Morganroth J(9), Diacon AH(10), Cramer YS(2), Donahue K(11), Maartens

G(12); AIDS Clinical Trials Group (ACTG) A5343 DELIBERATE Study Team.

Collaborators: Alli O, Gottesman J, Guevara M, Hikuam C, Hovind L, Karlsson M,

McClaren J, McIlleron H, Murtaugh W, Rolls B, Shahkolahi A, Stone L, Tegha G,

Tenai J, Upton C, Wimbish C.

Author information:

(1)Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic

address: kdooley1@jhmi.edu.

(2)Frontier Science Foundation, Brookline, MA, USA.

(3)University of Witwatersrand, Johannesburg, South Africa.

...

BACKGROUND: Bedaquiline and delamanid are the first drugs of new classes

registered for tuberculosis treatment in 40 years. Each can prolong the QTc

interval, with maximum effects occurring weeks after drug initiation. The

cardiac safety and microbiological activity of these drugs when co-administered

are not well-established. Our aim was to characterise the effects of

bedaquiline, delamanid, or both on the QTc interval, longitudinally over 6

months of multidrug treatment, among patients with multidrug-resistant or

rifampicin-resistant tuberculosis taking multidrug background therapy.

METHODS: ACTG A5343 is a phase 2, open-label, randomised, controlled trial in

which adults with multidrug-resistant or rifampicin-resistant tuberculosis

receiving multidrug background treatment were randomly assigned 1:1:1 by

centrally, computer-generated randomisation, by means of permuted blocks to

receive bedaquiline, delamanid, or both for 24 weeks. Participants were enrolled

at TASK in Cape Town and the South African Tuberculosis Vaccine Initiative in

Worcester, both in South Africa, and Hospital Maria Auxiliadora in Peru.

Individuals with QTc greater than 450 ms were excluded. HIV-positive

participants received dolutegravir-based antiretroviral therapy. Clofazimine was

disallowed, and levofloxacin replaced moxifloxacin. ECG in triplicate and sputum

cultures were done fortnightly. The primary endpoint was mean QTcF change from

baseline (averaged over weeks 8-24); cumulative culture conversation at week

8-24 was an exploratory endpoint. Analyses included all participants who

initiated study tuberculosis treatment (modified intention-to-treat population).

This trial is registered with ClinicalTrials.gov, NCT02583048 and is ongoing.

FINDINGS: Between Aug 26, 2016 and July 13, 2018, of 174 screened, 84

participants (28 in each treatment group, and 31 in total with HIV) were

enrolled. Two participants did not initiate study treatment (one in the

delamanid group withdrew consent and one in the bedaquiline plus delamanid

group) did not meet the eligibility criterion). Mean change in QTc from baseline

was 12·3 ms (95% CI 7·8-16·7; bedaquiline), 8·6 ms (4·0-13·1; delamanid), and

20·7 ms (16·1-25·3) (bedaquiline plus delamanid). There were no grade 3 or 4

adverse QTc prolongation events and no deaths during study treatment. Cumulative

culture conversion by week 8 was 21 (88%) of 24 (95% CI 71-97; bedaquiline), 20

(83%) of 24 (65-95; delamanid), and 19 (95%) of 20 (79-100; bedaquiline plus

delamanid) and was 92% (77-99) for bedaquiline, 91% (76-99), for delamanid, and

95% (79-100) for bedaquiline plus delamanid at 24 weeks.

INTERPRETATION: Combining bedaquiline and delamanid has a modest, no more than

additive, effect on the QTc interval, and initial microbiology data are

encouraging. This study provides supportive evidence for use of these agents

together in patients with multidrug-resistant or rifampicin-resistant

tuberculosis with normal baseline QTc values.

FUNDING: Division of AIDS, National Institutes of Health.

Copyright © 2021 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1473-3099(20)30770-2

PMID: 33587897

13. Sci Transl Med. 2021 Feb 3;13(579):eabd7618. doi: 10.1126/scitranslmed.abd7618.

Fourteen-day PET/CT imaging to monitor drug combination activity in treated

individuals with tuberculosis.

Xie YL(1), de Jager VR(2), Chen RY(3)(4), Dodd LE(5), Paripati P(6), Via

LE(3)(4), Follmann D(5), Wang J(7), Lumbard K(7), Lahouar S(6), Malherbe ST(8),

Andrews J(9), Yu X(3), Goldfeder LC(3), Cai Y(3), Arora K(3), Loxton AG(8),

Vanker N(2), Duvenhage M(7), Winter J(10), Song T(4), Walzl G(8), Diacon

AH(2)(11), Barry CE 3rd(12)(4).

Author information:

(1)Division of Infectious Diseases, Department of Medicine, Rutgers New Jersey

Medical School, Newark, NJ 07103, USA.

(2)TASK Applied Science, Cape Town 7500, South Africa.

(3)Tuberculosis Research Section, Laboratory of Clinical Immunology and

Microbiology, Division of Intramural Research, National Institute of Allergy and

Infectious Disease, National Institutes of Health, Bethesda, MD 20892, USA.

...

Early bactericidal activity studies monitor daily sputum bacterial counts in

individuals with tuberculosis (TB) for 14 days during experimental drug

treatment. The rate of change in sputum bacterial load over time provides an

informative, but imperfect, estimate of drug activity and is considered a

critical step in development of new TB drugs. In this clinical study, 160

participants with TB received isoniazid, pyrazinamide, or rifampicin, components

of first-line chemotherapy, and moxifloxacin individually and in combination. In

addition to standard bacterial enumeration in sputum, participants underwent

2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography and computerized

tomography ([18F]FDG-PET/CT) at the beginning and end of the 14-day drug

treatment. Quantitating radiological responses to drug treatment provided

comparative single and combination drug activity measures across lung lesion

types that correlated more closely with established clinical outcomes when

combined with sputum enumeration compared to sputum enumeration alone.

Rifampicin and rifampicin-containing drug combinations were most effective in

reducing both lung lesion volume measured by CT imaging and lesion-associated

inflammation measured by PET imaging. Moxifloxacin was not superior to

rifampicin in any measure by PET/CT imaging, consistent with its performance in

recent phase 3 clinical trials. PET/CT imaging revealed synergy between

isoniazid and pyrazinamide and demonstrated that the activity of pyrazinamide

was limited to lung lesion, showing the highest FDG uptake during the first 2

weeks of drug treatment. [18F]FDG-PET/CT imaging may be useful for measuring the

activity of single drugs and drug combinations during evaluation of potential

new TB drug regimens before phase 3 trials.

Copyright © 2021 The Authors, some rights reserved; exclusive licensee American

Association for the Advancement of Science. No claim to original U.S. Government

Works.

DOI: 10.1126/scitranslmed.abd7618

PMID: 33536283

14. J Clin Invest. 2021 Feb 1;131(3):e136222. doi: 10.1172/JCI136222.

The knowns and unknowns of latent Mycobacterium tuberculosis infection.

Boom WH(1)(2)(3), Schaible UE(4)(5), Achkar JM(6)(7).

Author information:

(1)Department of Medicine.

(2)Department of Pathology, and.

(3)Department of Molecular Biology and Microbiology, Case Western Reserve

University and University Hospitals Cleveland Medical Center, Cleveland, Ohio,

USA.

(4)Division of Cellular Microbiology, Research Center Borstel-Leibniz Lung

Center, Borstel, Germany.

(5)German Center for Infection Research, partner site

Hamburg-Lübeck-Borstel-Riems, Germany.

(6)Department of Medicine and.

(7)Department of Microbiology and Immunology, Albert Einstein College of

Medicine, Bronx, New York, USA.

Humans have been infected with Mycobacterium tuberculosis (Mtb) for thousands of

years. While tuberculosis (TB), one of the deadliest infectious diseases, is

caused by uncontrolled Mtb infection, over 90% of presumed infected individuals

remain asymptomatic and contain Mtb in a latent TB infection (LTBI) without ever

developing disease, and some may clear the infection. A small number of heavily

Mtb-exposed individuals appear to resist developing traditional LTBI. Because

Mtb has mechanisms for intracellular survival and immune evasion, successful

control involves all of the arms of the immune system. Here, we focus on immune

responses to Mtb in humans and nonhuman primates and discuss new concepts and

outline major knowledge gaps in our understanding of LTBI, ranging from the

earliest events of exposure and infection to success or failure of Mtb control.

DOI: 10.1172/JCI136222

PMCID: PMC7843221

PMID: 33529162

Conflict of interest statement: Conflict of interest: The authors have declared

that no conflict of interest exists.

15. Cell Metab. 2021 Feb 2;33(2):300-318.e12. doi: 10.1016/j.cmet.2020.12.016. Epub

2021 Jan 8.

Caloric Restriction Promotes Immunometabolic Reprogramming Leading to Protection

from Tuberculosis.

Palma C(1), La Rocca C(2), Gigantino V(3), Aquino G(3), Piccaro G(4), Di

Silvestre D(5), Brambilla F(5), Rossi R(5), Bonacina F(6), Lepore MT(2), Audano

M(6), Mitro N(6), Botti G(7), Bruzzaniti S(8), Fusco C(9), Procaccini C(10), De

Rosa V(10), Galgani M(11), Alviggi C(12), Puca A(13), Grassi F(14),

Rezzonico-Jost T(14), Norata GD(15), Mauri P(16), Netea MG(17), de Candia P(18),

Matarese G(19).

Author information:

(1)Dipartimento Malattie Infettive, Istituto Superiore di Sanità, 00161 Roma,

Italy. Electronic address: carla.palma@iss.it.

(2)Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale

delle Ricerche (IEOS-CNR), 80131 Napoli, Italy.

(3)Pathology Unit, Istituto Nazionale Tumori, Fondazione G. Pascale, IRCCS,

80131 Naples, Italy.

...

There is a strong relationship between metabolic state and susceptibility to

Mycobacterium tuberculosis (MTB) infection, with energy metabolism setting the

basis for an exaggerated immuno-inflammatory response, which concurs with MTB

pathogenesis. Herein, we show that controlled caloric restriction (CR), not

leading to malnutrition, protects susceptible DBA/2 mice against pulmonary MTB

infection by reducing bacterial load, lung immunopathology, and generation of

foam cells, an MTB reservoir in lung granulomas. Mechanistically, CR induced a

metabolic shift toward glycolysis, and decreased both fatty acid oxidation and

mTOR activity associated with induction of autophagy in immune cells. An

integrated multi-omics approach revealed a specific CR-induced metabolomic,

transcriptomic, and proteomic signature leading to reduced lung damage and

protective remodeling of lung interstitial tightness able to limit MTB

spreading. Our data propose CR as a feasible immunometabolic manipulation to

control MTB infection, and this approach offers an unexpected strategy to boost

immunity against MTB.

Copyright © 2020 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.cmet.2020.12.016

PMID: 33421383

16. Cell Host Microbe. 2021 Feb 10;29(2):165-178.e8. doi:

10.1016/j.chom.2020.11.013. Epub 2020 Dec 18.

The immune landscape in tuberculosis reveals populations linked to disease and

latency.

Esaulova E(1), Das S(2), Singh DK(3), Choreño-Parra JA(4), Swain A(1), Arthur

L(1), Rangel-Moreno J(5), Ahmed M(2), Singh B(3), Gupta A(2), Fernández-López

LA(4), de la Luz Garcia-Hernandez M(5), Bucsan A(6), Moodley C(6), Mehra S(6),

García-Latorre E(7), Zuniga J(8), Atkinson J(9), Kaushal D(10), Artyomov MN(11),

Khader SA(12).

Author information:

(1)Department of Pathology and Immunology, Washington University School of

Medicine, St Louis, MO 63110, USA.

(2)Department of Molecular Microbiology, Washington University School of

Medicine, St. Louis, MO 63110, USA.

(3)Southwest National Primate Research Center, Texas Biomedical Research

Institute, San Antonio, TX 78227, USA.

...

Comment in

Cell Host Microbe. 2021 Feb 10;29(2):158-159.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) latently infects

approximately one-fourth of the world's population. The immune mechanisms that

govern progression from latent (LTBI) to active pulmonary TB (PTB) remain poorly

defined. Experimentally Mtb-infected non-human primates (NHP) mirror the disease

observed in humans and recapitulate both PTB and LTBI. We characterized the lung

immune landscape in NHPs with LTBI and PTB using high-throughput technologies.

Three defining features of PTB in macaque lungs include the influx of

plasmacytoid dendritic cells (pDCs), an Interferon (IFN)-responsive macrophage

population, and activated T cell responses. In contrast, a CD27+ Natural killer

(NK) cell subset accumulated in the lungs of LTBI macaques. This NK cell

population was also detected in the circulation of LTBI individuals. This

comprehensive analysis of the lung immune landscape will improve the

understanding of TB immunopathogenesis, providing potential targets for

therapies and vaccines for TB control.

Copyright © 2020 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.chom.2020.11.013

PMCID: PMC7878437

PMID: 33340449

17. Nat Med. 2021 Feb 18. doi: 10.1038/s41591-020-01224-2. Online ahead of print.

Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell

lung cancer: the phase 2 randomized NEOSTAR trial.

Cascone T(1), William WN Jr(2)(3), Weissferdt A(4)(5), Leung CH(6), Lin HY(6),

Pataer A(5), Godoy MCB(7), Carter BW(7), Federico L(8), Reuben A(2), Khan

MAW(9),...

Author information:

(1)Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson

Cancer Center, Houston, TX, USA. tcascone@mdanderson.org.

(2)Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson

Cancer Center, Houston, TX, USA.

(3)Oncology Center, Hospital BP, a Beneficencia Portuguesa de São Paulo, São

Paulo, Brazil.

...

Ipilimumab improves clinical outcomes when combined with nivolumab in metastatic

non-small cell lung cancer (NSCLC), but its efficacy and impact on the immune

microenvironment in operable NSCLC remain unclear. We report the results of the

phase 2 randomized NEOSTAR trial (NCT03158129) of neoadjuvant nivolumab or

nivolumab + ipilimumab followed by surgery in 44 patients with operable NSCLC,

using major pathologic response (MPR) as the primary endpoint. The MPR rate for

each treatment arm was tested against historical controls of neoadjuvant

chemotherapy. The nivolumab + ipilimumab arm met the prespecified primary

endpoint threshold of 6 MPRs in 21 patients, achieving a 38% MPR rate (8/21). We

observed a 22% MPR rate (5/23) in the nivolumab arm. In 37 patients resected on

trial, nivolumab and nivolumab + ipilimumab produced MPR rates of 24% (5/21) and

50% (8/16), respectively. Compared with nivolumab, nivolumab + ipilimumab

resulted in higher pathologic complete response rates (10% versus 38%), less

viable tumor (median 50% versus 9%), and greater frequencies of effector,

tissue-resident memory and effector memory T cells. Increased abundance of gut

Ruminococcus and Akkermansia spp. was associated with MPR to dual therapy. Our

data indicate that neoadjuvant nivolumab + ipilimumab-based therapy enhances

pathologic responses, tumor immune infiltrates and immunologic memory, and

merits further investigation in operable NSCLC.

DOI: 10.1038/s41591-020-01224-2

PMID: 33603241

18. Lancet Oncol. 2021 Feb;22(2):198-211. doi: 10.1016/S1470-2045(20)30641-0. Epub

2021 Jan 18.

First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in

patients with non-small-cell lung cancer (CheckMate 9LA): an international,

randomised, open-label, phase 3 trial.

Paz-Ares L(1), Ciuleanu TE(2), Cobo M(3), Schenker M(4), Zurawski B(5), Menezes

J(6), Richardet E(7), Bennouna J(8), Felip E(9), Juan-Vidal O(10), Alexandru

A(11), Sakai H(12), Lingua A(13), Salman P(14), Souquet PJ(15), De Marchi P(16),

Martin C(17), Pérol M(18), Scherpereel A(19), Lu S(20), John T(21), Carbone

DP(22), Meadows-Shropshire S(23), Agrawal S(23), Oukessou A(23), Yan J(23), Reck

M(24).

Author information:

(1)Hospital Universitario 12 de Octubre, CNIO-H12o Lung Cancer Unit, Universidad

Complutense & CiberOnc, Madrid, Spain. Electronic address: lpazaresr@seom.org.

(2)Institutul Oncologic Prof Dr Ion Chiricuta and UMF Iuliu Hatieganu,

Cluj-Napoca, Romania.

(3)Unidad de Gestión Clínica Intercentros de Oncología Médica, Hospitales

Universitarios Regional y Virgen de la Victoria, IBIMA, Málaga, Spain.

...

Comment in

Lancet Oncol. 2021 Feb;22(2):157-159.

BACKGROUND: First-line nivolumab plus ipilimumab has shown improved overall

survival in patients with advanced non-small-cell lung cancer (NSCLC). We aimed

to investigate whether the addition of a limited course (two cycles) of

chemotherapy to this combination would further enhance the clinical benefit.

METHODS: This randomised, open-label, phase 3 trial was done at 103 hospitals in

19 countries. Eligible patients were aged 18 years or older with

treatment-naive, histologically confirmed stage IV or recurrent NSCLC, and an

Eastern Cooperative Oncology Group performance status of 0-1. Patients were

randomly assigned (1:1) by an interactive web response system via permuted

blocks (block size of four) to nivolumab (360 mg intravenously every 3 weeks)

plus ipilimumab (1 mg/kg intravenously every 6 weeks) combined with

histology-based, platinum doublet chemotherapy (intravenously every 3 weeks for

two cycles; experimental group), or chemotherapy alone (every 3 weeks for four

cycles; control group). Randomisation was stratified by tumour histology, sex,

and PD-L1 expression. The primary endpoint was overall survival in all randomly

assigned patients. Safety was analysed in all treated patients. Results reported

here are from a pre-planned interim analysis (when the study met its primary

endpoint) and an exploratory longer-term follow-up analysis. This study is

active but no longer recruiting patients, and is registered with

ClinicalTrials.gov, number NCT03215706.

FINDINGS: Between Aug 24, 2017, and Jan 30, 2019, 1150 patients were enrolled

and 719 (62·5%) randomly assigned to nivolumab plus ipilimumab with two cycles

of chemotherapy (n=361 [50%]) or four cycles of chemotherapy alone (n=358

[50%]). At the pre-planned interim analysis (median follow-up 9·7 months [IQR

6·4-12·8]), overall survival in all randomly assigned patients was significantly

longer in the experimental group than in the control group (median 14·1 months

[95% CI 13·2-16·2] vs 10·7 months [9·5-12·4]; hazard ratio [HR] 0·69 [96·71% CI 0·55-0·87]; p=0·00065). With 3·5 months longer median follow-up (median 13·2

months [IQR 6·4-17·0]), median overall survival was 15·6 months (95% CI

13·9-20·0) in the experimental group versus 10·9 months (9·5-12·6) in the

control group (HR 0·66 [95% CI 0·55-0·80]). The most common grade 3-4

treatment-related adverse events were neutropenia (in 24 [7%] patients in the

experimental group vs 32 [9%] in the control group), anaemia (21 [6%] vs 50

[14%]), diarrhoea (14 [4%] vs two [1%]), increased lipase (22 [6%] vs three

[1%]), and asthenia (tjree [1%] vs eight [2%]). Serious treatment-related

adverse events of any grade occurred in 106 (30%) patients in the experimental

group and 62 (18%) in the control group. Seven (2%) deaths in the experimental

group (acute kidney failure, diarrhoea, hepatotoxicity, hepatitis, pneumonitis,

sepsis with acute renal insufficiency, and thrombocytopenia; one patient each)

and six (2%) deaths in the control group (anaemia, febrile neutropenia,

pancytopenia, pulmonary sepsis, respiratory failure, and sepsis; one patient

each) were treatment related.

INTERPRETATION: Nivolumab plus ipilimumab with two cycles of chemotherapy

provided a significant improvement in overall survival versus chemotherapy alone

and had a favourable risk-benefit profile. These data support this regimen as a

new first-line treatment option for patients with advanced NSCLC.

FUNDING: Bristol Myers Squibb.

Copyright © 2021 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1470-2045(20)30641-0

PMID: 33476593 [Indexed for MEDLINE]

19. Cancer Cell. 2021 Feb 8;39(2):193-208.e10. doi: 10.1016/j.ccell.2020.11.005.

Epub 2020 Dec 24.

Immunogenic Chemotherapy Enhances Recruitment of CAR-T Cells to Lung Tumors and

Improves Antitumor Efficacy when Combined with Checkpoint Blockade.

Srivastava S(1), Furlan SN(2), Jaeger-Ruckstuhl CA(3), Sarvothama M(3), Berger

C(3), Smythe KS(3), Garrison SM(3), Specht JM(4), Lee SM(4), Amezquita RA(5),

Voillet V(5), Muhunthan V(3), Yechan-Gunja S(3), Pillai SPS(6), Rader C(7),

Houghton AM(3), Pierce RH(3), Gottardo R(5), Maloney DG(4), Riddell SR(4).

Author information:

(1)Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle,

WA, USA. Electronic address: ssrivas2@fredhutch.org.

(2)Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle,

WA, USA; Department of Pediatrics, University of Washington, Seattle, WA, USA.

(3)Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle,

WA, USA.

...

Adoptive therapy using chimeric antigen receptor-modified T cells (CAR-T cells)

is effective in hematologic but not epithelial malignancies, which cause the

greatest mortality. In breast and lung cancer patients, CAR-T cells targeting

the tumor-associated antigen receptor tyrosine kinase-like orphan receptor 1

(ROR1) infiltrate tumors poorly and become dysfunctional. To test strategies for

enhancing efficacy, we adapted the KrasLSL-G12D/+;p53f/f autochthonous model of

lung adenocarcinoma to express the CAR target ROR1. Murine ROR1 CAR-T cells

transferred after lymphodepletion with cyclophosphamide (Cy) transiently control

tumor growth but infiltrate tumors poorly and lose function, similar to what is

seen in patients. Adding oxaliplatin (Ox) to the lymphodepletion regimen

activates tumor macrophages to express T-cell-recruiting chemokines, resulting

in improved CAR-T cell infiltration, remodeling of the tumor microenvironment,

and increased tumor sensitivity to anti-PD-L1. Combination therapy with Ox/Cy

and anti-PD-L1 synergistically improves CAR-T cell-mediated tumor control and

survival, providing a strategy to improve CAR-T cell efficacy in the clinic.

Copyright © 2020 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.ccell.2020.11.005

PMCID: PMC7878409

PMID: 33357452

20. J Clin Invest. 2021 Feb 1;131(3):e130319. doi: 10.1172/JCI130319.

The integrated stress response mediates necrosis in murine Mycobacterium

tuberculosis granulomas.

Bhattacharya B(1), Xiao S(2), Chatterjee S(1), Urbanowski M(2), Ordonez A(2),

Ihms EA(2), Agrahari G(1), Lun S(2), Berland R(1)(3), Pichugin A(4), Gao Y(5),

Connor J(6), Ivanov AR(7), Yan BS(8), Kobzik L(9), Koo BB(1), Jain S(2), Bishai

W(2), Kramnik I(1)(10).

Author information:

(1)The National Emerging Infectious Diseases Laboratory, Boston University

School of Medicine, Boston, Massachusetts, USA.

(2)Center for TB Research, Johns Hopkins University School of Medicine,

Baltimore, Maryland, USA.

(3)Department of Integrative Physiology and Pathobiology, Tufts University

School of Medicine, Boston, Massachusetts, USA.

...

The mechanism by which only some individuals infected with Mycobacterium

tuberculosis develop necrotic granulomas with progressive disease while others

form controlled granulomas that contain the infection remains poorly defined.

Mice carrying the sst1-suscepible (sst1S) genotype develop necrotic inflammatory

lung lesions, similar to human tuberculosis (TB) granulomas, which are linked to

macrophage dysfunction, while their congenic counterpart (B6) mice do not. In

this study we report that (a) sst1S macrophages developed aberrant, biphasic

responses to TNF characterized by superinduction of stress and type I interferon

pathways after prolonged TNF stimulation; (b) the late-stage TNF response was

driven via a JNK/IFN-β/protein kinase R (PKR) circuit; and (c) induced the

integrated stress response (ISR) via PKR-mediated eIF2α phosphorylation and the

subsequent hyperinduction of ATF3 and ISR-target genes Chac1, Trib3, and Ddit4.

The administration of ISRIB, a small-molecule inhibitor of the ISR, blocked the

development of necrosis in lung granulomas of M. tuberculosis-infected sst1S

mice and concomitantly reduced the bacterial burden. Hence, induction of the ISR

and the locked-in state of escalating stress driven by the type I IFN pathway in

sst1S macrophages play a causal role in the development of necrosis in TB

granulomas. Interruption of the aberrant stress response with inhibitors such as

ISRIB may offer novel host-directed therapy strategies.

DOI: 10.1172/JCI130319

PMCID: PMC7843230

PMID: 33301427

21. J Exp Med. 2021 Feb 1;218(2):e20200887. doi: 10.1084/jem.20200887.

Type I interferon signaling mediates Mycobacterium tuberculosis-induced

macrophage death.

Zhang L(1), Jiang X(1), Pfau D(1), Ling Y(1), Nathan CF(1).

Author information:

(1)Department of Microbiology and Immunology, Weill Cornell Medicine, New York,

NY.

Macrophages help defend the host against Mycobacterium tuberculosis (Mtb), the

major cause of tuberculosis (TB). Once phagocytized, Mtb resists killing by

macrophages, replicates inside them, and leads to their death, releasing Mtb

that can infect other cells. We found that the death of Mtb-infected mouse

macrophages in vitro does not appear to proceed by a currently known pathway.

Through genome-wide CRISPR-Cas9 screening, we identified a critical role for

autocrine or paracrine signaling by macrophage-derived type I IFNs in the death

of Mtb-infected macrophages in vitro, and blockade of type I IFN signaling

augmented the effect of rifampin, a first-line TB drug, in Mtb-infected mice.

Further definition of the pathway of type I IFN-mediated macrophage death may

allow for host-directed therapy of TB that is more selective than systemic

blockade of type I IFN signaling.

© 2020 Zhang et al.

DOI: 10.1084/jem.20200887

PMCID: PMC7608065

PMID: 33125053