Medical Abstracts

Filters applied: from 2021/1/13 - 2021/1/31

1. Lancet Oncol. 2021 Jan 18:S1470-2045(20)30641-0. doi:

10.1016/S1470-2045(20)30641-0. Online ahead of print.

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),…

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.

…

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

2. Annu Rev Pathol. 2021 Jan 24;16:377-408. doi:

10.1146/annurev-pathol-042120-032916.

Perspectives and Advances in the Understanding of Tuberculosis.

Kinsella RL(1), Zhu DX(1), Harrison GA(1), Mayer Bridwell AE(1), Prusa J(1),

Chavez SM(1), Stallings CL(1).

Author information:

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

Medicine, Saint Louis, Missouri 63110, USA; email: stallings@wustl.edu.

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB),

remains a leading cause of death due to infection in humans. To more effectively

combat this pandemic, many aspects of TB control must be developed, including

better point of care diagnostics, shorter and safer drug regimens, and a

protective vaccine. To address all these areas of need, better understanding of

the pathogen, host responses, and clinical manifestations of the disease is

required. Recently, the application of cutting-edge technologies to the study of

Mtb pathogenesis has resulted in significant advances in basic biology, vaccine

development, and antibiotic discovery. This leaves us in an exciting era of Mtb

research in which our understanding of this deadly infection is improving at a

faster rate than ever, and renews hope in our fight to end TB. In this review,

we reflect on what is known regarding Mtb pathogenesis, highlighting recent

breakthroughs that will provide leverage for the next leaps forward in the

field.

DOI: 10.1146/annurev-pathol-042120-032916

PMID: 33497258

3. Immunity. 2021 Jan 23:S1074-7613(21)00026-1. doi: 10.1016/j.immuni.2021.01.003.

Online ahead of print.

Early innate and adaptive immune perturbations determine long-term severity of

chronic virus and Mycobacterium tuberculosis coinfection.

Xu W(1), Snell LM(1), Guo M(2), Boukhaled G(1), Macleod BL(1), Li M(3), Tullius

MV(4), Guidos CJ(5), Tsao MS(1), Divangahi M(6), Horwitz MA(7), Liu J(8), Brooks

DG(9).

Author information:

(1)Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G

2M9, Canada.

(2)Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G

2M9, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S

1A8, Canada.

(3)Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G

2M9, Canada; Department of Molecular Genetics, University of Toronto, Toronto,

ON M5S 1A8, Canada.

…

Chronic viral infections increase severity of Mycobacterium tuberculosis (Mtb)

coinfection. Here, we examined how chronic viral infections alter the pulmonary

microenvironment to foster coinfection and worsen disease severity. We developed

a coordinated system of chronic virus and Mtb infection that induced central

clinical manifestations of coinfection, including increased Mtb burden,

extra-pulmonary dissemination, and heightened mortality. These disease states

were not due to chronic virus-induced immunosuppression or exhaustion; rather,

increased amounts of the cytokine TNFα initially arrested pulmonary Mtb growth,

impeding dendritic cell mediated antigen transportation to the lymph node and

subverting immune-surveillance, allowing bacterial sanctuary. The cryptic Mtb

replication delayed CD4 T cell priming, redirecting T helper (Th) 1 toward Th17

differentiation and increasing pulmonary neutrophilia, which diminished

long-term survival. Temporally restoring CD4 T cell induction overcame these

diverse disease sequelae to enhance Mtb control. Thus, Mtb co-opts TNFα from the

chronic inflammatory environment to subvert immune-surveillance, avert early

immune function, and foster long-term coinfection.

Copyright © 2021 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.immuni.2021.01.003

PMID: 33515487

4. Nat Commun. 2021 Jan 29;12(1):704. doi: 10.1038/s41467-021-20928-8.

The oncogenicity of tumor-derived mutant p53 is enhanced by the recruitment of

PLK3.

Vaughan CA(1), Singh S(1), Subler MA(2), Windle JJ(2), Inoue K(3), Fry EA(3),

Pillappa R(4), Grossman SR(5)(6), Windle B(1)(5), Andrew Yeudall W(7)(8), Deb

SP(5)(9), Deb S(10)(11).

Author information:

(1)Philips Institute, Virginia Commonwealth University, Richmond, VA, 23298,

USA.

(2)Department of Human and Molecular Genetics, Virginia Commonwealth University,

Richmond, VA, 23298, USA.

(3)Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC,

27101, USA.

…

p53 mutations with single amino acid changes in cancer often lead to dominant

oncogenic changes. Here, we have developed a mouse model of gain-of-function

(GOF) p53-driven lung cancer utilizing conditionally active LSL p53-R172H and

LSL K-Ras-G12D knock-in alleles that can be activated by Cre in lung club cells.

Mutation of the p53 transactivation domain (TAD) (p53-L25Q/W26S/R172H)

eliminating significant transactivation activity resulted in loss of

tumorigenicity, demonstrating that transactivation mediated by or dependent on

TAD is required for oncogenicity by GOF p53. GOF p53 TAD mutations significantly

reduce phosphorylation of nearby p53 serine 20 (S20), which is a target for PLK3

phosphorylation. Knocking out PLK3 attenuated S20 phosphorylation along with

transactivation and oncogenicity by GOF p53, indicating that GOF p53 exploits

PLK3 to trigger its transactivation capability and exert oncogenic functions.

Our data show a mechanistic involvement of PLK3 in mutant p53 pathway of

oncogenesis.

DOI: 10.1038/s41467-021-20928-8

PMID: 33514736

5. J Clin Oncol. 2021 Jan 29:JCO2003579. doi: 10.1200/JCO.20.03579. Online ahead of print.

Pembrolizumab Plus Ipilimumab or Placebo for Metastatic Non-Small-Cell Lung

Cancer With PD-L1 Tumor Proportion Score ≥ 50%: Randomized, Double-Blind Phase

III KEYNOTE-598 Study.

Boyer M(1), ?endur MAN(2), Rodríguez-Abreu D(3), Park K(4), Lee DH(5), Çiçin

I(6), Yumuk PF(7), Orlandi FJ(8), Leal TA(9), Molinier O(10), Soparattanapaisam

N(11), Langleben A(12), Califano R(13), Medgyasszay B(14), Hsia TC(15), Otterson

GA(16), Xu L(17), Piperdi B(17), Samkari A(17), Reck M(18); KEYNOTE-598

Investigators.

Author information:

(1)Chris O'Brien Lifehouse, Camperdown, NSW, Australia.

(2)Ankara Y?ld?r?m Beyaz?t University, Faculty of Medicine and Ankara City

Hospital, Ankara, Turkey.

(3)Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria,

Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain.

…

PURPOSE: Pembrolizumab monotherapy is standard first-line therapy for metastatic

non-small-cell lung cancer (NSCLC) with programmed death ligand 1 (PD-L1) tumor

proportion score (TPS) ≥ 50% without actionable driver mutations. It is not

known whether adding ipilimumab to pembrolizumab improves efficacy over

pembrolizumab alone in this population.

METHODS: In the randomized, double-blind, phase III KEYNOTE-598 trial

(ClinicalTrials.gov identifier: NCT03302234), eligible patients with previously

untreated metastatic NSCLC with PD-L1 TPS ≥ 50% and no sensitizing EGFR or ALK

aberrations were randomly allocated 1:1 to ipilimumab 1 mg/kg or placebo every 6

weeks for up to 18 doses; all participants received pembrolizumab 200 mg every 3

weeks for up to 35 doses. Primary end points were overall survival and

progression-free survival.

RESULTS: Of the 568 participants, 284 were randomly allocated to each group.

Median overall survival was 21.4 months for pembrolizumab-ipilimumab versus 21.9

months for pembrolizumab-placebo (hazard ratio, 1.08; 95% CI, 0.85 to 1.37; P =

.74). Median progression-free survival was 8.2 months for

pembrolizumab-ipilimumab versus 8.4 months for pembrolizumab-placebo (hazard

ratio, 1.06; 95% CI, 0.86 to 1.30; P = .72). Grade 3-5 adverse events occurred

in 62.4% of pembrolizumab-ipilimumab recipients versus 50.2% of

pembrolizumab-placebo recipients and led to death in 13.1% versus 7.5%. The

external data and safety monitoring committee recommended that the study be

stopped for futility and that participants discontinue ipilimumab and placebo.

CONCLUSION: Adding ipilimumab to pembrolizumab does not improve efficacy and is

associated with greater toxicity than pembrolizumab monotherapy as first-line

treatment for metastatic NSCLC with PD-L1 TPS ≥ 50% and no targetable EGFR or

ALK aberrations. These data do not support use of pembrolizumab-ipilimumab in

place of pembrolizumab monotherapy in this population.

DOI: 10.1200/JCO.20.03579

PMID: 33513313

6. Lancet Infect Dis. 2021 Jan 25:S1473-3099(20)30914-2. doi:

10.1016/S1473-3099(20)30914-2. Online ahead of print.

Biomarker-guided tuberculosis preventive therapy (CORTIS): a randomised

controlled trial.

Scriba TJ(1), Fiore-Gartland A(2), Penn-Nicholson A(1), Mulenga H(1), Kimbung

Mbandi S(1), Borate B(2), Mendelsohn SC(1), Hadley K(1), Hikuam C(1), Kaskar

M(1), Musvosvi M(1), Bilek N(1), Self S(2), Sumner T(3), White RG(3), Erasmus

M(1), Jaxa L(1), Raphela R(1), Innes C(4), Brumskine W(4), Hiemstra A(5),

Malherbe ST(5), Hassan-Moosa R(6), Tameris M(1), Walzl G(5), Naidoo K(6),

Churchyard G(7), Hatherill M(8); CORTIS-01 Study Team.

Author information:

(1)South African Tuberculosis Vaccine Initiative, Institute of Infectious

Disease and Molecular Medicine, Division of Immunology, Department of Pathology,

University of Cape Town, Cape Town, South Africa.

(2)Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research

Center, Seattle, WA, USA.

(3)TB Modelling Group, TB Centre, Centre for Mathematical Modelling of

Infectious Diseases, Department of Infectious Disease Epidemiology, London

School of Hygiene & Tropical Medicine, London, UK.

…

BACKGROUND: Targeted preventive therapy for individuals at highest risk of

incident tuberculosis might impact the epidemic by interrupting transmission. We

tested performance of a transcriptomic signature of tuberculosis (RISK11) and

efficacy of signature-guided preventive therapy in parallel, using a hybrid

three-group study design.

METHODS: Adult volunteers aged 18-59 years were recruited at five geographically

distinct communities in South Africa. Whole blood was sampled for RISK11 by

quantitative RT-PCR assay from eligible volunteers without HIV, recent previous

tuberculosis (ie, <3 years before screening), or comorbidities at screening.

RISK11-positive participants were block randomised (1:2; block size 15) to

once-weekly, directly-observed, open-label isoniazid and rifapentine for 12

weeks (ie, RISK11 positive and 3HP positive), or no treatment (ie, RISK11

positive and 3HP negative). A subset of eligible RISK11-negative volunteers were

randomly assigned to no treatment (ie, RISK11 negative and 3HP negative).

Diagnostic discrimination of prevalent tuberculosis was tested in all

participants at baseline. Thereafter, prognostic discrimination of incident

tuberculosis was tested in the untreated RISK11-positive versus RISK11-negative

groups, and treatment efficacy in the 3HP-treated versus untreated

RISK11-positive groups, during active surveillance through 15 months. The

primary endpoint was microbiologically confirmed pulmonary tuberculosis. The

primary outcome measures were risk ratio [RR] for tuberculosis of

RISK11-positive to RISK11-negative participants, and treatment efficacy. This

trial is registered with ClinicalTrials.gov, NCT02735590.

FINDINGS: 20?207 volunteers were screened, and 2923 participants were enrolled,

including RISK11-positive participants randomly assigned to 3HP (n=375) or no

3HP (n=764), and 1784 RISK11-negative participants. Cumulative probability of

prevalent or incident tuberculosis disease was 0·066 (95% CI 0·049 to 0·084) in

RISK11-positive (3HP negative) participants and 0·018 (0·011 to 0·025) in

RISK11-negative participants (RR 3·69, 95% CI 2·25-6·05) over 15 months.

Tuberculosis prevalence was 47 (4·1%) of 1139 versus 14 (0·78%) of 1984 in

RISK11-positive compared with RISK11-negative participants, respectively

(diagnostic RR 5·13, 95% CI 2·93 to 9·43). Tuberculosis incidence over 15 months

was 2·09 (95% CI 0·97 to 3·19) vs 0·80 (0·30 to 1·30) per 100 person years in

RISK11-positive (3HP-negative) participants compared with RISK11-negative

participants (cumulative incidence ratio 2·6, 95% CI 1·2 to 5·9). Serious

adverse events related to 3HP included one hospitalisation for seizures

(unintentional isoniazid overdose) and one death of unknown cause (possibly

temporally related). Tuberculosis incidence over 15 months was 1·94 (95% CI 0·35

to 3·50) versus 2·09 (95% CI 0·97 to 3·19) per 100 person-years in 3HP-treated

RISK11-positive participants compared with untreated RISK11-positive

participants (efficacy 7·0%, 95% CI -145 to 65).

INTERPRETATION: The RISK11 signature discriminated between individuals with

prevalent tuberculosis, or progression to incident tuberculosis, and individuals

who remained healthy, but provision of 3HP to signature-positive individuals

after exclusion of baseline disease did not reduce progression to tuberculosis

over 15 months.

FUNDING: Bill and Melinda Gates Foundation, South African Medical Research

Council.

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)30914-2

PMID: 33508224

7. Lancet Infect Dis. 2021 Jan 25:S1473-3099(20)30928-2. doi:

10.1016/S1473-3099(20)30928-2. Online ahead of print.

Transcriptomic signatures for diagnosing tuberculosis in clinical practice: a

prospective, multicentre cohort study.

Hoang LT(1), Jain P(1), Pillay TD(1), Tolosa-Wright M(1), Niazi U(2), Takwoingi

Y(3), Halliday A(4), Berrocal-Almanza LC(1), Deeks JJ(3), Beverley P(1), Kon

OM(5), Lalvani A(6).

Author information:

(1)Tuberculosis Research Centre, National Heart and Lung Institute, Imperial

College London, London, UK.

(2)Guy's and St Thomas' National Health Service Foundation Trust and King's

College London National Institute for Health Research Biomedical Research Centre

Translational Bioinformatics Platform, Guy's Hospital, London, UK.

(3)Test Evaluation Research Group, Institute of Applied Health Research,

University of Birmingham, Birmingham, UK; National Institute of Health Research

Birmingham Biomedical Research Centre, University Hospitals Birmingham National

Health Service Foundation Trust and University of Birmingham, Birmingham, UK.

…

BACKGROUND: Blood transcriptomic signatures for diagnosis of tuberculosis have

shown promise in case-control studies, but none have been prospectively designed

or validated in adults presenting with the full clinical spectrum of suspected

tuberculosis, including extrapulmonary tuberculosis and common differential

diagnoses that clinically resemble tuberculosis. We aimed to evaluate the

diagnostic accuracy of transcriptomic signatures in patients presenting with

clinically suspected tuberculosis in routine practice.

METHODS: The Validation of New Technologies for Diagnostic Evaluation of

Tuberculosis (VANTDET) study was nested within a prospective, multicentre cohort

study in secondary care in England (IDEA 11/H0722/8). Patients (aged ≥16 years)

suspected of having tuberculosis in the routine clinical inpatient and

outpatient setting were recruited at ten National Health Service hospitals in

England for IDEA and were included in VANTDET if they provided consent for

genomic analysis. Patients had whole blood taken for microarray analysis to

measure abundance of transcripts and were followed up for 6-12 months to

determine final diagnoses on the basis of predefined diagnostic criteria. The

diagnostic accuracy of six signatures derived from the cohort and three

previously published transcriptomic signatures with potentially high diagnostic

performance were assessed by calculating area under the receiver-operating

characteristic curves (AUC-ROC), sensitivities, and specificities.

FINDINGS: Between Nov 25, 2011, and Dec 31, 2013, 1162 participants were

enrolled. 628 participants (aged ≥16 years) were included in the analysis, of

whom 212 (34%) had culture-confirmed tuberculosis, 89 (14%) had highly probable

tuberculosis, and 327 (52%) had tuberculosis excluded. The novel signature with

highest performance for identifying all active tuberculosis gave an AUC-ROC of

0·87 (95% CI 0·81-0·92), sensitivity of 77% (66-87), and specificity of 84%

(74-91). The best-performing published signature gave an AUC-ROC of 0·83

(0·80-0·86), sensitivity of 78% (73-83), and specificity of 76% (70-80). For

detecting highly probable tuberculosis, the best novel signature yielded results

of 0·86 (0·71-0·95), 77% (56-94%), and 77% (57-95%). None of the relevant

cohort-derived or previously published signatures achieved the WHO-defined

targets of paired sensitivity and specificity for a non-sputum-based diagnostic

test.

INTERPRETATION: In a clinically representative cohort in routine practice in a

low-incidence setting, transcriptomic signatures did not have adequate accuracy

for diagnosis of tuberculosis, including in patients with highly probable

tuberculosis where the unmet need is greatest. These findings suggest that

transcriptomic signatures have little clinical utility for diagnostic assessment

of suspected tuberculosis.

FUNDING: National Institute for Health Research.

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

Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd..

All rights reserved.

DOI: 10.1016/S1473-3099(20)30928-2

PMID: 33508221

8. Nat Commun. 2021 Jan 27;12(1):602. doi: 10.1038/s41467-021-20930-0.

Human antibodies targeting a Mycobacterium transporter protein mediate

protection against tuberculosis.

Watson A(#)(1), Li H(#)(2)(3), Ma B(#)(4), Weiss R(1), Bendayan D(5), Abramovitz

L(1), Ben-Shalom N(1), Mor M(1), Pinko E(5), Bar Oz M(6), Wang Z(2), Du F(7), Lu

Y(7), Rybniker J(8)(9), Dahan R(10), Huang H(11), Barkan D(6), Xiang Y(12),

Javid B(13)(14), Freund NT(15).

Author information:

(1)Department of Clinical Microbiology and Immunology, Sackler Faculty of

Medicine, Tel Aviv University, Tel Aviv-Yafo, Israel.

(2)Centre for Global Health and Infectious Diseases, Collaborative Innovation

Centre for the Diagnosis and Treatment of Infectious Diseases, Tsinghua

University School of Medicine, Beijing, China.

(3)College of Veterinary Medicine, China Agricultural University, Beijing,

China.

…

Mycobacterium tuberculosis (Mtb) exposure drives antibody responses, but whether

patients with active tuberculosis elicit protective antibodies, and against

which antigens, is still unclear. Here we generate monoclonal antibodies from

memory B cells of one patient to investigate the B cell responses during active

infection. The antibodies, members of four distinct B cell clones, are directed

against the Mtb phosphate transporter subunit PstS1. Antibodies p4-36 and p4-163

reduce Mycobacterium bovis-BCG and Mtb levels in an ex vivo human whole blood

growth inhibition assay in an FcR-dependent manner; meanwhile, germline versions

of p4-36 and p4-163 do not bind Mtb. Crystal structures of p4-36 and p4-170,

complexed to PstS1, are determined at 2.1 Å and 2.4 Å resolution, respectively,

to reveal two distinctive PstS1 epitopes. Lastly, a prophylactic p4-36 and

p4-163 treatment in Mtb-infected Balb/c mice reduces bacterial lung burden by

50%. Our study shows that inhibitory anti-PstS1 B cell responses arise during

active tuberculosis.

DOI: 10.1038/s41467-021-20930-0

PMID: 33504803

9. Sci Transl Med. 2021 Jan 27;13(578):eabc7488. doi: 10.1126/scitranslmed.abc7488.

Whole-exome sequencing reveals germline-mutated small cell lung cancer subtype

with favorable response to DNA repair-targeted therapies.

Tlemsani C(1), Takahashi N(1), Pongor L(1), Rajapakse VN(1), Tyagi M(2), Wen

X(2), Fasaye GA(2), Schmidt KT(3), Desai P(1), Kim C(4), Rajan A(5), Swift S(5),

Sciuto L(1), Vilimas R(1), Webb S(1), Nichols S(1), Figg WD(3), Pommier Y(1),

Calzone K(2), Steinberg SM(6), Wei JS(2), Guha U(5), Turner CE(7), Khan J(2),

Thomas A(8).

Author information:

(1)Developmental Therapeutics Branch, Center for Cancer Research, NCI, Bethesda,

MD 20892, USA.

(2)Genetics Branch, Center for Cancer Research, NCI, Bethesda, MD 20892, USA.

(3)Genitourinary Malignancies Branch, Center for Cancer Research, NCI, Bethesda,

MD 20892, USA.

…

Because tobacco is a potent carcinogen, secondary causes of lung cancer are

often diminished in perceived importance. To assess the extent of inherited

susceptibility to small cell lung cancer (SCLC), the most lethal type of lung

cancer, we sequenced germline exomes of 87 patients (77 SCLC and 10

extrapulmonary small cell) and considered 607 genes, discovering 42 deleterious

variants in 35 cancer-predisposition genes among 43.7% of patients. These

findings were validated in an independent cohort of 79 patients with SCLC. Loss

of heterozygosity was observed in 3 of 14 (21.4%) tumors. Identification of

variants influenced medical management and family member testing in nine (10.3%)

patients. Unselected patients with SCLC were more likely to carry germline RAD51

paralog D (RAD51D), checkpoint kinase 1 (CHEK1), breast cancer 2 (BRCA2), and

mutY DNA glycosylase (MUTYH) pathogenic variants than healthy controls. Germline

genotype was significantly associated with the likelihood of a first-degree

relative with cancer or lung cancer (odds ratio: 1.82, P = 0.008; and 2.60, P =

0.028), and longer recurrence-free survival after platinum-based chemotherapy (P

= 0.002), independent of known prognostic factors. Treatment of a patient with

relapsed SCLC and germline pathogenic mutation of BRCA1 interacting protein

C-terminal helicase 1 (BRIP1), a homologous recombination-related gene, using

agents synthetically lethal with homologous recombination deficiency, resulted

in a notable disease response. This work demonstrates that SCLC, currently

thought to result almost exclusively from tobacco exposure, may have an

inherited predisposition and lays the groundwork for targeted therapies based on

the genes involved.

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.abc7488

PMID: 33504652

10. Cancer Discov. 2021 Jan 27:candisc.0377.2020. doi: 10.1158/2159-8290. CD-20-0377. Online ahead of print.

An empirical antigen selection method identifies neoantigens that either elicit

broad anti-tumor T cell responses or drive tumor growth.

Lam H(1), McNeil LK(1), Starobinets H(1), DeVault VL(1), Cohen RB(2), Twardowski

P(3), Johnson ML(4), Gillison ML(5), Stein MN(6), Vaishampayan UN(7), DeCillis

AP(1), Foti JJ(1), Vemulapalli V(1), Tjon E(1), Ferber K(1), DeOliveira DB(1),

Broom W(1), Agnihotri P(1), Jaffee EM(8), Wong KK(9), Drake CG(10), Carroll

PM(11), Davis TA(1), Flechtner JB(12).

Author information:

(1)Research, Genocea Biosciences.

(2)Medical Oncology, University of Pennsylvania, Abramson Cancer Center.

(3)John Wayne Cancer Institute.

…

Neoantigens are critical targets of anti-tumor T cell responses. The ATLAS{trade

mark, serif} bioassay was developed to identify neoantigens empirically by

expressing each unique patient-specific tumor mutation individually in E. coli,

pulsing autologous dendritic cells in an ordered array, and testing the

patient's T cells for recognition in an overnight assay. Profiling of T cells

from lung cancer patients revealed both stimulatory and inhibitory responses to

individual neoantigens. In the murine B16F10 melanoma model, therapeutic

immunization with ATLAS-identified stimulatory neoantigens protected animals,

whereas immunization with peptides associated with inhibitory ATLAS responses

resulted in accelerated tumor growth and abolished efficacy of an

otherwise-protective vaccine. A planned interim analysis of a clinical study

testing a poly-ICLC adjuvanted personalized vaccine containing ATLAS-identified

stimulatory neoantigens showed that it is well-tolerated. In an adjuvant

setting, immunized patients generated both CD4+ and CD8+ T cell responses, with

immune responses to 99% of the vaccinated peptide antigens.

Copyright ©2021, American Association for Cancer Research.

DOI: 10.1158/2159-8290.CD-20-0377

PMID: 33504579

11. J Clin Oncol. 2021 Jan 27:JCO2003364. doi: 10.1200/JCO.20.03364. Online ahead of print.

Radiation Therapy for Small-Cell Lung Cancer: ASCO Guideline Endorsement of an

ASTRO Guideline.

Daly ME(1), Ismaila N(2), Decker RH(3), Higgins K(4), Owen D(5), Saxena A(6),

Franklin GE(7), Donaldson D(8), Schneider BJ(9).

Author information:

(1)University of California, Davis, CA.

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

(3)Yale School of Medicine, New Haven, CT.

…

PURPOSE: The American Society for Radiation Oncology (ASTRO) produced an

evidence-based guideline on radiation therapy (RT) for small-cell lung cancer

(SCLC). Because of the relevance of this topic to ASCO membership, ASCO reviewed

the guideline, applying a set of procedures and policies used to critically

examine guidelines developed by other organizations.

METHODS: The ASTRO guideline on RT for SCLC was reviewed for developmental rigor

by methodologists. Then, an ASCO Expert Panel reviewed the content and the

recommendations.

RESULTS: The ASCO Expert Panel determined that the recommendations from ASTRO

guideline on RT for SCLC, published in June 2020, are clear, thorough, and based

upon the most relevant scientific evidence. ASCO endorsed ASTRO guideline on RT

for SCLC with a few discussion points.

RECOMMENDATIONS: Recommendations addressed thoracic radiotherapy for

limited-stage SCLC, role of stereotactic body radiotherapy in stage I or II

node-negative SCLC, prophylactic cranial radiotherapy, and thoracic

consolidation for extensive-stage SCLC.Additional information is available at

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

DOI: 10.1200/JCO.20.03364

PMID: 33502911

12. Nat Commun. 2021 Jan 18;12(1):424. doi: 10.1038/s41467-020-20731-x.

Modelling the global burden of drug-resistant tuberculosis avertable by a

post-exposure vaccine.

Fu H(1), Lewnard JA(2), Frost I(3)(4), Laxminarayan R(3)(5), Arinaminpathy N(6).

Author information:

(1)MRC Centre for Global Infectious Disease Analysis; and the Abdul Latif Jameel

Institute for Disease and Emergency Analytics (J-IDEA), School of Public Health,

Imperial College London, London, W2 1PG, UK. h.fu15@imperial.ac.uk.

(2)Division of Epidemiology, School of Public Health, University of California,

Berkeley, Berkeley, CA, 94720, USA.

(3)Center for Disease Dynamics, Economics & Policy, New Delhi, India.

…

There have been notable advances in the development of vaccines against active

tuberculosis (TB) disease for adults and adolescents. Using mathematical models,

we seek to estimate the potential impact of a post-exposure TB vaccine, having

50% efficacy in reducing active disease, on global rifampicin-resistant (RR-) TB

burden. In 30 countries that together accounted for 90% of global RR-TB

incidence in 2018, a future TB vaccine could avert 10% (95% credible interval:

9.7-11%) of RR-TB cases and 7.3% (6.6-8.1%) of deaths over 2020-2035, with

India, China, Indonesia, Pakistan, and the Russian Federation having the

greatest contribution. This impact would increase to 14% (12-16%) and 31%

(29-33%) respectively, when combined with improvements in RR-TB diagnosis and

treatment relative to a scenario of no vaccine and no such improvements. A

future TB vaccine could have important implications for the global control of

RR-TB, especially if implemented alongside enhancements in management of drug

resistance.

DOI: 10.1038/s41467-020-20731-x

PMCID: PMC7814030

PMID: 33462224 [Indexed for MEDLINE]

13. Nat Commun. 2021 Jan 15;12(1):394. doi: 10.1038/s41467-020-20533-1.

Pore-forming Esx proteins mediate toxin secretion by Mycobacterium tuberculosis.

Tak U(1), Dokland T(1), Niederweis M(2).

Author information:

(1)Department of Microbiology, University of Alabama at Birmingham, 845 19th

Street South, Birmingham, AL, 35294, USA.

(2)Department of Microbiology, University of Alabama at Birmingham, 845 19th

Street South, Birmingham, AL, 35294, USA. mnieder@uab.edu.

Mycobacterium tuberculosis secretes the tuberculosis necrotizing toxin (TNT) to

kill host cells. Here, we show that the WXG100 proteins EsxE and EsxF are

essential for TNT secretion. EsxE and EsxF form a water-soluble heterodimer

(EsxEF) that assembles into oligomers and long filaments, binds to membranes,

and forms stable membrane-spanning channels. Electron microscopy of EsxEF

reveals mainly pentameric structures with a central pore. Mutations of both WXG

motifs and of a GXW motif do not affect dimerization, but abolish pore

formation, membrane deformation and TNT secretion. The WXG/GXW mutants are

locked in conformations with altered thermostability and solvent exposure,

indicating that the WXG/GXW motifs are molecular switches controlling membrane

interaction and pore formation. EsxF is accessible on the bacterial cell

surface, suggesting that EsxEF form an outer membrane channel for toxin export.

Thus, our study reveals a protein secretion mechanism in bacteria that relies on

pore formation by small WXG proteins.

DOI: 10.1038/s41467-020-20533-1

PMCID: PMC7810871

PMID: 33452244 [Indexed for MEDLINE]

14. J Clin Oncol. 2021 Jan 15:JCO2001605. doi: 10.1200/JCO.20.01605. Online ahead of print.

Five-Year Outcomes From the Randomized, Phase III Trials CheckMate 017 and 057:

Nivolumab Versus Docetaxel in Previously Treated Non-Small-Cell Lung Cancer.

Borghaei H(1), Gettinger S(2), Vokes EE(3), Chow LQM(4), Burgio MA(5), …

Author information:

(1)Fox Chase Cancer Center, Philadelphia, PA.

(2)Yale Comprehensive Cancer Center, New Haven, CT.

(3)Univeristy of Chicago Medicine and Biologic Sciences Division, Chicago, IL.

…

PURPOSE: Immunotherapy has revolutionized the treatment of advanced

non-small-cell lung cancer (NSCLC). In two phase III trials (CheckMate 017 and

CheckMate 057), nivolumab showed an improvement in overall survival (OS) and

favorable safety versus docetaxel in patients with previously treated, advanced

squamous and nonsquamous NSCLC, respectively. We report 5-year pooled efficacy

and safety from these trials.

METHODS: Patients (N = 854; CheckMate 017/057 pooled) with advanced NSCLC, ECOG

PS ≤ 1, and progression during or after first-line platinum-based chemotherapy

were randomly assigned 1:1 to nivolumab (3 mg/kg once every 2 weeks) or

docetaxel (75 mg/m2 once every 3 weeks) until progression or unacceptable

toxicity. The primary end point for both trials was OS; secondary end points

included progression-free survival (PFS) and safety. Exploratory landmark

analyses were investigated.

RESULTS: After the minimum follow-up of 64.2 and 64.5 months for CheckMate 017

and 057, respectively, 50 nivolumab-treated patients and nine docetaxel-treated

patients were alive. Five-year pooled OS rates were 13.4% versus 2.6%,

respectively; 5-year PFS rates were 8.0% versus 0%, respectively.

Nivolumab-treated patients without disease progression at 2 and 3 years had an

82.0% and 93.0% chance of survival, respectively, and a 59.6% and 78.3% chance

of remaining progression-free at 5 years, respectively. Treatment-related

adverse events (TRAEs) were reported in 8 of 31 (25.8%) nivolumab-treated

patients between 3-5 years of follow-up, seven of whom experienced new events;

one (3.2%) TRAE was grade 3, and there were no grade 4 TRAEs.

CONCLUSION: At 5 years, nivolumab continued to demonstrate a survival benefit

versus docetaxel, exhibiting a five-fold increase in OS rate, with no new safety

signals. These data represent the first report of 5-year outcomes from

randomized phase III trials of a programmed death-1 inhibitor in previously

treated, advanced NSCLC.

DOI: 10.1200/JCO.20.01605

PMID: 33449799

15. J Clin Oncol. 2021 Jan 13:JCO2001055. doi: 10.1200/JCO.20.01055. Online ahead of print.

Updated Overall Survival and PD-L1 Subgroup Analysis of Patients With

Extensive-Stage Small-Cell Lung Cancer Treated With Atezolizumab, Carboplatin,

and Etoposide (IMpower133).

Liu SV(1), Reck M(2), Mansfield AS(3), Mok T(4), Scherpereel A(5), Reinmuth

N(6), Garassino MC(7), De Castro Carpeno J(8), Califano R(9), Nishio M(10),

Orlandi F(11), Alatorre-Alexander J(12), Leal T(13), Cheng Y(14), Lee JS(15),

Lam S(16), McCleland M(16), Deng Y(16), Phan S(16), Horn L(17).

Author information:

(1)Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.

(2)Lung Clinic Grosshansdorf, Airway Research Center North, German Center of

Lung Research, Grosshansdorf, Germany.

(3)Division of Medical Oncology, Mayo Clinic, Rochester, MN.

…

PURPOSE: IMpower133 (ClinicalTrials.gov identifier: NCT02763579), a randomized,

double-blind, phase I/III study, demonstrated that adding atezolizumab

(anti-programmed death-ligand 1 [PD-L1]) to carboplatin plus etoposide (CP/ET)

for first-line (1L) treatment of extensive-stage small-cell lung cancer

(ES-SCLC) resulted in significant improvement in overall survival (OS) and

progression-free survival (PFS) versus placebo plus CP/ET. Updated OS, disease

progression patterns, safety, and exploratory biomarkers (PD-L1, blood-based

tumor mutational burden [bTMB]) are reported.

PATIENTS AND METHODS: Patients with untreated ES-SCLC were randomly assigned 1:1

to receive four 21-day cycles of CP (area under the curve 5 mg per mL/min

intravenously [IV], day 1) plus ET (100 mg/m2 IV, days 1-3) with atezolizumab

(1,200 mg IV, day 1) or placebo, and then maintenance atezolizumab or placebo

until unacceptable toxicity, disease progression, or loss of clinical benefit.

Tumor specimens were collected; PD-L1 testing was not required for enrollment.

The two primary end points, investigator-assessed PFS and OS, were statistically

significant at the interim analysis. Updated OS and PFS and exploratory

biomarker analyses were conducted.

RESULTS: Patients received atezolizumab plus CP/ET (n = 201) or placebo plus

CP/ET (n = 202). At the updated analysis, median follow-up for OS was 22.9

months; 302 deaths had occurred. Median OS was 12.3 and 10.3 months with

atezolizumab plus CP/ET and placebo plus CP/ET, respectively (hazard ratio,

0.76; 95% CI, 0.60 to 0.95; descriptive P = .0154). At 18 months, 34.0% and

21.0% of patients were alive in atezolizumab plus CP/ET and placebo plus CP/ET

arms, respectively. Patients derived benefit from the addition of atezolizumab,

regardless of PD-L1 immunohistochemistry or bTMB status.

CONCLUSION: Adding atezolizumab to CP/ET as 1L treatment for ES-SCLC continued

to demonstrate improved OS and a tolerable safety profile at the updated

analysis, confirming the regimen as a new standard of care. Exploratory analyses

demonstrated treatment benefit independent of biomarker status.

DOI: 10.1200/JCO.20.01055

PMID: 33439693

16. Cell Host Microbe. 2021 Jan 13;29(1):68-82.e5. doi: 10.1016/j.chom.2020.10.003.

Epub 2020 Nov 2.

Ultra-low Dose Aerosol Infection of Mice with Mycobacterium tuberculosis More

Closely Models Human Tuberculosis.

Plumlee CR(1), Duffy FJ(1), Gern BH(2), Delahaye JL(3), Cohen SB(1), Stoltzfus

CR(4), Rustad TR(1), Hansen SG(5), Axthelm MK(5), Picker LJ(5), Aitchison JD(1),

Sherman DR(6), Ganusov VV(7), Gerner MY(4), Zak DE(8), Urdahl KB(9).

Author information:

(1)Center for Global Infectious Disease Research, Seattle Children's Research

Institute, Seattle, WA 98109, USA.

(2)Center for Global Infectious Disease Research, Seattle Children's Research

Institute, Seattle, WA 98109, USA; Department of Pediatrics, University of

Washington, Seattle, WA 98109, USA.

(3)Center for Global Infectious Disease Research, Seattle Children's Research

Institute, Seattle, WA 98109, USA; Department of Immunology, University of

Washington, Seattle, WA 98109, USA.

…

Tuberculosis (TB) is a heterogeneous disease manifesting in a subset of

individuals infected with aerosolized Mycobacterium tuberculosis (Mtb). Unlike

human TB, murine infection results in uniformly high lung bacterial burdens and

poorly organized granulomas. To develop a TB model that more closely resembles

human disease, we infected mice with an ultra-low dose (ULD) of between 1-3

founding bacteria, reflecting a physiologic inoculum. ULD-infected mice

exhibited highly heterogeneous bacterial burdens, well-circumscribed granulomas

that shared features with human granulomas, and prolonged Mtb containment with

unilateral pulmonary infection in some mice. We identified blood RNA signatures

in mice infected with an ULD or a conventional Mtb dose (50-100 CFU) that

correlated with lung bacterial burdens and predicted Mtb infection outcomes

across species, including risk of progression to active TB in humans. Overall,

these findings highlight the potential of the murine TB model and show that ULD

infection recapitulates key features of human TB.

Copyright © 2020 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.chom.2020.10.003

PMID: 33142108