2022年
No.9
PubMed Filters applied: from 2022/9/1 - 2022/9/30
1. Cell. 2022 Sep 29;185(20):3807-3822.e12. doi: 10.1016/j.cell.2022.09.015.
A pan-cancer mycobiome analysis reveals fungal involvement in gastrointestinal
and lung tumors.
Dohlman AB(1), Klug J(2), Mesko M(2), Gao IH(2), Lipkin SM(3), Shen X(4), Iliev
ID(5).
Author information:
(1)Department of Biomedical Engineering, Center for Genomics and Computational
Biology, Duke Microbiome Center, Duke University, Durham, NC 27708, USA.
Electronic address: anders.dohlman@duke.edu.
(2)The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill
Cornell Medicine, Cornell University, New York, NY 10021, USA.
(3)Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine,
Cornell University, New York, NY 10021, USA.
(4)Department of Biomedical Engineering, Center for Genomics and Computational
Biology, Duke Microbiome Center, Duke University, Durham, NC 27708, USA;
Terasaki Institute, Los Angeles, CA 90024, USA.
(5)The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill
Cornell Medicine, Cornell University, New York, NY 10021, USA; Joan and Sanford
I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New
York, NY 10021, USA; Department of Microbiology and Immunology, Weill Cornell
Medicine, Cornell University, New York, NY 10065, USA. Electronic address:
iliev@med.cornell.edu.
Fungal microorganisms (mycobiota) comprise a small but immunoreactive component
of the human microbiome, yet little is known about their role in human cancers.
Pan-cancer analysis of multiple body sites revealed tumor-associated mycobiomes
at up to 1 fungal cell per 104 tumor cells. In lung cancer, Blastomyces was
associated with tumor tissues. In stomach cancers, high rates of Candida were
linked to the expression of pro-inflammatory immune pathways, while in colon
cancers Candida was predictive of metastatic disease and attenuated cellular
adhesions. Across multiple GI sites, several Candida species were enriched in
tumor samples and tumor-associated Candida DNA was predictive of decreased
survival. The presence of Candida in human GI tumors was confirmed by external
ITS sequencing of tumor samples and by culture-dependent analysis in an
independent cohort. These data implicate the mycobiota in the pathogenesis of GI
cancers and suggest that tumor-associated fungal DNA may serve as diagnostic or
prognostic biomarkers.
Copyright © 2022 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cell.2022.09.015
PMID: 36179671 [Indexed for MEDLINE]
2. Cell. 2022 Sep 29;185(20):3720-3738.e13. doi: 10.1016/j.cell.2022.08.018. Epub
2022 Sep 13.
mTOR-regulated mitochondrial metabolism limits mycobacterium-induced
cytotoxicity.
Pagán AJ(1), Lee LJ(2), Edwards-Hicks J(3), Moens CB(4), Tobin DM(5),
Busch-Nentwich EM(6), Pearce EL(3), Ramakrishnan L(7).
Author information:
(1)Molecular Immunity Unit, Cambridge Institute of Therapeutic Immunology and
Infectious Diseases, Department of Medicine, University of Cambridge, Cambridge
CB2 0AW, UK; MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK;
Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
Electronic address: apagan@mrc-lmb.cam.ac.uk.
(2)Molecular Immunity Unit, Cambridge Institute of Therapeutic Immunology and
Infectious Diseases, Department of Medicine, University of Cambridge, Cambridge
CB2 0AW, UK; MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.
(3)Max Planck Institute of Immunobiology and Epigenetics, Freiburg im Breisgau,
Germany.
…
Necrosis of macrophages in the granuloma, the hallmark immunological structure
of tuberculosis, is a major pathogenic event that increases host susceptibility.
Through a zebrafish forward genetic screen, we identified the mTOR kinase, a
master regulator of metabolism, as an early host resistance factor in
tuberculosis. We found that mTOR complex 1 protects macrophages from
mycobacterium-induced death by enabling infection-induced increases in
mitochondrial energy metabolism fueled by glycolysis. These metabolic
adaptations are required to prevent mitochondrial damage and death caused by the
secreted mycobacterial virulence determinant ESAT-6. Thus, the host can
effectively counter this early critical mycobacterial virulence mechanism simply
by regulating energy metabolism, thereby allowing pathogen-specific immune
mechanisms time to develop. Our findings may explain why Mycobacterium
tuberculosis, albeit humanity's most lethal pathogen, is successful in only a
minority of infected individuals.
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cell.2022.08.018
PMID: 36103894 [Indexed for MEDLINE]
3. N Engl J Med. 2022 Sep 1;387(9):810-823. doi: 10.1056/NEJMoa2119430.
Bedaquiline-Pretomanid-Linezolid Regimens for Drug-Resistant Tuberculosis.
Conradie F(1), Bagdasaryan TR(1), Borisov S(1), Howell P(1), Mikiashvili L(1),
Ngubane N(1), Samoilova A(1), Skornykova S(1), Tudor E(1), Variava E(1),
Yablonskiy P(1), Everitt D(1), Wills GH(1), Sun E(1), Olugbosi M(1), Egizi E(1),
Li M(1), Holsta A(1), Timm J(1), Bateson A(1), Crook AM(1), Fabiane SM(1), Hunt
R(1), McHugh TD(1), Tweed CD(1), Foraida S(1), Mendel CM(1), Spigelman M(1);
ZeNix Trial Team.
Author information:
(1)From the Clinical HIV Research Unit (F.C., P.H.) and Klerksdorp-Tshepong
Hospital Complex, Department of Internal Medicine (E.V.), Faculty of Health
Sciences, University of the Witwatersrand, Johannesburg, the Clinical HIV
Research Unit, King DinuZulu Hospital, Durban (N.N.), and the TB Alliance,
Pretoria (M.O.) - all in South Africa; the Central TB Research Institute of the
Federal Agency of Scientific Organizations Moscow (T.R.B.), Moscow City Research
and Practice Tuberculosis Treatment Center (S.B.), and National Medical Research
Center of Phthisiopulmonology and Infectious Diseases (A.S.), Moscow, Ural
Research Institute of Phthisiopulmonology, Yekaterinburg (S.S.), and St.
Petersburg Research Institute of Phthisiopulmonology, St. Petersburg (P.Y.) -
all in Russia; the National Center for Tuberculosis and Lung Disease, Tbilisi,
Georgia (L.M.); the Chiril Draganiuc Institute of Phthisiopneumology, Chisinau,
Moldova (E.T.); the TB Alliance, New York (D.E., E.S., E.E., M.L., A.H., J.T.,
S.F., C.M.M., M.S.); and the Medical Research Council Clinical Trials Unit at
University College London (G.H.W., A.M.C., S.M.F., C.D.T.) and the University
College London Centre for Clinical Microbiology (A.B., R.H., T.D.M.), University
College London, London.
Comment in
N Engl J Med. 2022 Sep 1;387(9):842-843.
BACKGROUND: The bedaquiline-pretomanid-linezolid regimen has been reported to
have 90% efficacy against highly drug-resistant tuberculosis, but the incidence
of adverse events with 1200 mg of linezolid daily has been high. The appropriate
dose of linezolid and duration of treatment with this agent to minimize toxic
effects while maintaining efficacy against highly drug-resistant tuberculosis
are unclear.
METHODS: We enrolled participants with extensively drug-resistant (XDR)
tuberculosis (i.e., resistant to rifampin, a fluoroquinolone, and an
aminoglycoside), pre-XDR tuberculosis (i.e., resistant to rifampin and to either
a fluoroquinolone or an aminoglycoside), or rifampin-resistant tuberculosis that
was not responsive to treatment or for which a second-line regimen had been
discontinued because of side effects. We randomly assigned the participants to
receive bedaquiline for 26 weeks (200 mg daily for 8 weeks, then 100 mg daily
for 18 weeks), pretomanid (200 mg daily for 26 weeks), and daily linezolid at a
dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks. The
primary end point in the modified intention-to-treat population was the
incidence of an unfavorable outcome, defined as treatment failure or disease
relapse (clinical or bacteriologic) at 26 weeks after completion of treatment.
Safety was also evaluated.
RESULTS: A total of 181 participants were enrolled, 88% of whom had XDR or
pre-XDR tuberculosis. Among participants who received
bedaquiline-pretomanid-linezolid with linezolid at a dose of 1200 mg for 26
weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks, 93%, 89%, 91%, and 84%,
respectively, had a favorable outcome; peripheral neuropathy occurred in 38%,
24%, 24%, and 13%, respectively; myelosuppression occurred in 22%, 15%, 2%, and
7%, respectively; and the linezolid dose was modified (i.e., interrupted,
reduced, or discontinued) in 51%, 30%, 13%, and 13%, respectively. Optic
neuropathy developed in 4 participants (9%) who had received linezolid at a dose
of 1200 mg for 26 weeks; all the cases resolved. Six of the seven unfavorable
microbiologic outcomes through 78 weeks of follow-up occurred in participants
assigned to the 9-week linezolid groups.
CONCLUSIONS: A total of 84 to 93% of the participants across all four
bedaquiline-pretomanid-linezolid treatment groups had a favorable outcome. The
overall risk-benefit ratio favored the group that received the three-drug
regimen with linezolid at a dose of 600 mg for 26 weeks, with a lower incidence
of adverse events reported and fewer linezolid dose modifications. (Funded by
the TB Alliance and others; ZeNix ClinicalTrials.gov number, NCT03086486.).
Copyright © 2022 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2119430
PMCID: PMC9490302
PMID: 36053506 [Indexed for MEDLINE]
4. CA Cancer J Clin. 2022 Sep;72(5):409-436. doi: 10.3322/caac.21731. Epub 2022 Jun 23.
Cancer treatment and survivorship statistics, 2022.
Miller KD(1), Nogueira L(2), Devasia T(3), Mariotto AB(4), Yabroff KR(2), Jemal
A(5), Kramer J(6), Siegel RL(1).
Author information:
(1)Surveillance Research, American Cancer Society, Atlanta, Georgia.
(2)Health Services Research, American Cancer Society, Atlanta, Georgia.
(3)Data Analytics Branch, Surveillance Research Program, Division of Cancer
Control and Population Sciences, National Cancer Institute, Bethesda, Maryland.
(4)Surveillance Research Program, Division of Cancer Control and Population
Sciences, National Cancer Institute, Bethesda, Maryland.
(5)Surveillance and Health Equity Science, American Cancer Society, Atlanta,
Georgia.
(6)Department of Hematology and Medical Oncology, Emory University, Atlanta,
Georgia.
The number of cancer survivors continues to increase in the United States due to
the growth and aging of the population as well as advances in early detection
and treatment. To assist the public health community in better serving these
individuals, the American Cancer Society and the National Cancer Institute
collaborate triennially to estimate cancer prevalence in the United States using
incidence and survival data from the Surveillance, Epidemiology, and End Results
cancer registries, vital statistics from the Centers for Disease Control and
Prevention's National Center for Health Statistics, and population projections
from the US Census Bureau. Current treatment patterns based on information in
the National Cancer Database are presented for the most prevalent cancer types
by race, and cancer-related and treatment-related side-effects are also briefly
described. More than 18 million Americans (8.3 million males and 9.7 million
females) with a history of cancer were alive on January 1, 2022. The 3 most
prevalent cancers are prostate (3,523,230), melanoma of the skin (760,640), and
colon and rectum (726,450) among males and breast (4,055,770), uterine corpus
(891,560), and thyroid (823,800) among females. More than one-half (53%) of
survivors were diagnosed within the past 10 years, and two-thirds (67%) were
aged 65 years or older. One of the largest racial disparities in treatment is
for rectal cancer, for which 41% of Black patients with stage I disease receive
proctectomy or proctocolectomy compared to 66% of White patients. Surgical
receipt is also substantially lower among Black patients with non-small cell
lung cancer, 49% for stages I-II and 16% for stage III versus 55% and 22% for
White patients, respectively. These treatment disparities are exacerbated by the
fact that Black patients continue to be less likely to be diagnosed with stage I
disease than White patients for most cancers, with some of the largest
disparities for female breast (53% vs 68%) and endometrial (59% vs 73%).
Although there are a growing number of tools that can assist patients,
caregivers, and clinicians in navigating the various phases of cancer
survivorship, further evidence-based strategies and equitable access to
available resources are needed to mitigate disparities for communities of color
and optimize care for people with a history of cancer. CA Cancer J Clin.
2022;72:409-436.
© 2022 The Authors. CA: A Cancer Journal for Clinicians published by Wiley
Periodicals LLC on behalf of American Cancer Society.
DOI: 10.3322/caac.21731
PMID: 35736631 [Indexed for MEDLINE]
5. JAMA. 2022 Sep 27;328(12):1223-1232. doi: 10.1001/jama.2022.16464.
Effect of First-Line Serplulimab vs Placebo Added to Chemotherapy on Survival in
Patients With Extensive-Stage Small Cell Lung Cancer: The ASTRUM-005 Randomized
Clinical Trial.
Cheng Y(1), Han L(2), Wu L(3), Chen J(4), Sun H(5), Wen G(6), Ji Y(7), Dvorkin
M(8), Shi J(9), Pan Z(10), Shi J(11), Wang X(12), Bai Y(13), Melkadze T(14), Pan
Y(15), Min X(16), Viguro M(17), Li X(18), Zhao Y(19), Yang J(20), Makharadze
T(21), Arkania E(22), Kang W(23), Wang Q(23), Zhu J(23); ASTRUM-005 Study Group.
Author information:
(1)Department of Oncology, Jilin Cancer Hospital, Changchun, China.
(2)Department of Oncology, Xuzhou Central Hospital, Xuzhou, China.
(3)Department of Thoracic Medical Oncology, Hunan Cancer Hospital, the
Affiliated Cancer Hospital of Xiangya School of Medicine, Central South
University, Changsha, China.
Comment in
JAMA. 2022 Sep 27;328(12):1205-1207.
IMPORTANCE: Programmed cell death ligand 1 inhibitors combined with chemotherapy
has changed the approach to first-line treatment in patients with
extensive-stage small cell lung cancer (SCLC). It remained unknown whether
adding a programmed cell death 1 (PD-1) inhibitor to chemotherapy provided
similar or better benefits in patients with extensive-stage SCLC, which would
add evidence on the efficacy of checkpoint inhibitors in the treatment of
extensive-stage SCLC.
OBJECTIVE: To evaluate the efficacy and adverse event profile of the PD-1
inhibitor serplulimab plus chemotherapy compared with placebo plus chemotherapy
as first-line treatment in patients with extensive-stage SCLC.
DESIGN, SETTING, AND PARTICIPANTS: This international, double-blind, phase 3
randomized clinical trial (ASTRUM-005) enrolled patients at 114 hospital sites
in 6 countries between September 12, 2019, and April 27, 2021. Of 894 patients
who were screened, 585 with extensive-stage SCLC who had not previously received
systemic therapy were randomized. Patients were followed up through October 22,
2021.
INTERVENTIONS: Patients were randomized 2:1 to receive either 4.5 mg/kg of
serplulimab (n = 389) or placebo (n = 196) intravenously every 3 weeks. All
patients received intravenous carboplatin and etoposide every 3 weeks for up to
12 weeks.
MAIN OUTCOMES AND MEASURES: The primary outcome was overall survival
(prespecified significance threshold at the interim analysis, 2-sided P < .012).
There were 13 secondary outcomes, including progression-free survival and
adverse events.
RESULTS: Among the 585 patients who were randomized (mean age, 61.1 [SD, 8.67]
years; 104 [17.8%] women), 246 (42.1%) completed the trial and 465 (79.5%)
discontinued study treatment. All patients received study treatment and were
included in the primary analyses. As of the data cutoff (October 22, 2021) for
this interim analysis, the median duration of follow-up was 12.3 months (range,
0.2-24.8 months). The median overall survival was significantly longer in the
serplulimab group (15.4 months [95% CI, 13.3 months-not evaluable]) than in the
placebo group (10.9 months [95% CI, 10.0-14.3 months]) (hazard ratio, 0.63 [95%
CI, 0.49-0.82]; P < .001). The median progression-free survival (assessed by an
independent radiology review committee) also was longer in the serplulimab group
(5.7 months [95% CI, 5.5-6.9 months]) than in the placebo group (4.3 months [95%
CI, 4.2-4.5 months]) (hazard ratio, 0.48 [95% CI, 0.38-0.59]). Treatment-related
adverse events that were grade 3 or higher occurred in 129 patients (33.2%) in
the serplulimab group and in 54 patients (27.6%) in the placebo group.
CONCLUSIONS AND RELEVANCE: Among patients with previously untreated
extensive-stage SCLC, serplulimab plus chemotherapy significantly improved
overall survival compared with chemotherapy alone, supporting the use of
serplulimab plus chemotherapy as the first-line treatment for this patient
population.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04063163.
DOI: 10.1001/jama.2022.16464
PMID: 36166026 [Indexed for MEDLINE]
6. Lancet Oncol. 2022 Oct;23(10):1274-1286. doi: 10.1016/S1470-2045(22)00518-6.
Epub 2022 Sep 12.
Pembrolizumab versus placebo as adjuvant therapy for completely resected stage
IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of
a randomised, triple-blind, phase 3 trial.
O'Brien M(1), Paz-Ares L(2), Marreaud S(3), Dafni U(4), Oselin K(5), Havel L(6),
Esteban E(7), Isla D(8), Martinez-Marti A(9), Faehling M(10), Tsuboi M(11), Lee
JS(12), Nakagawa K(13), Yang J(14), Samkari A(14), Keller SM(14), Mauer M(3),
Jha N(3), Stahel R(15), Besse B(16), Peters S(17); EORTC-1416-LCG/ETOP 8-15 –
PEARLS/KEYNOTE-091 Investigators.
Author information:
(1)Lung Unit, Royal Marsden Hospital, London, UK. Electronic address:
mary.obrien@rmh.nhs.uk.
(2)Hospital Universitario 12 de Octubre, CNIO, Ciberonc & Universidad
Complutense, Madrid, Spain.
(3)European Organisation for Research and Treatment of Cancer, Brussels,
Belgium.
…
BACKGROUND: Pembrolizumab is a standard-of-care for advanced non-small-cell lung
cancer (NSCLC). We assessed pembrolizumab as adjuvant therapy for completely
resected stage IB-IIIA NSCLC.
METHODS: In this randomised, triple-blind, phase 3 trial (PEARLS/KEYNOTE-091),
patients were recruited from 196 medical centres in 29 countries. Eligible
patients were aged 18 years or older, with completely resected, pathologically
confirmed stage IB (tumours of ≥4 cm in diameter), II, or IIIA NSCLC per the
American Joint Committee on Cancer staging system (7th edition) of any histology
or PD-L1 expression level, and an Eastern Cooperative Oncology Group performance
status of 0 or 1; adjuvant chemotherapy was to be considered for stage IB
disease and was strongly recommended for stage II and IIIA disease, according to
national and local guidelines. Using a central interactive voice-response
system, eligible participants were randomly assigned (1:1), using a minimisation
technique and stratified by disease stage, previous adjuvant chemotherapy, PD-L1
expression, and geographical region, to pembrolizumab 200 mg or placebo, both
administered intravenously every 3 weeks for up to 18 cycles. Participants,
investigators, and analysts were masked to treatment assignment. Dual primary
endpoints were disease-free survival in the overall population and in the
population with PD-L1 tumour proportion score (TPS) of 50% or greater. Efficacy
was assessed in the intention-to-treat (ITT) population (ie, all participants
randomly assigned to a treatment group). Safety was assessed in all participants
randomly assigned to treatment who received at least one dose of study
treatment. Here we report results of the second interim analysis, prespecified
to occur when approximately 118 disease-free survival events had occurred in the
PD-L1 TPS of 50% or greater population. This study is registered with
ClinicalTrials.gov, NCT02504372, and is active but not recruiting.
FINDINGS: Between Jan 20, 2016, and May 6, 2020, 1177 (60%) of 1955 screened
participants were randomly assigned to pembrolizumab (n=590, including n=168
with PD-L1 TPS of ≥50%) or placebo (n=587; including n=165 with PD-L1 TPS of
≥50%) and included in the ITT population. Median follow-up as of data cutoff
(Sept 20, 2021) for this interim analysis was 35·6 months (IQR 27·1-45·5). In
the overall population, median disease-free survival was 53·6 months (95% CI
39·2 to not reached) in the pembrolizumab group versus 42·0 months (31·3 to not
reached) in the placebo group (HR 0·76 [95% CI 0·63-0·91], p=0·0014). In the PD-L1
TPS of 50% or greater population, median disease-free survival was not
reached in either the pembrolizumab group (95% CI 44·3 to not reached) or the
placebo group (95% CI 35·8 to not reached; HR 0·82 [95% CI 0·57-1·18]; p=0·14).
Grade 3 or worse adverse events occurred in 198 (34%) of 580 participants who
received pembrolizumab and 150 (26%) of 581 participants who received placebo.
Grade 3 or worse events that occurred in at least ten participants in either
treatment group were hypertension (35 [6%]) and pneumonia (12 [2%]) with
pembrolizumab and hypertension (32 [6%]) with placebo. Serious adverse events
occurred in 142 (24%) participants in the pembrolizumab group and 90 (15%) in
the placebo group; serious adverse events that occurred in more than 1% of
participants were pneumonia (13 [2%]), pneumonitis (12 [2%]), and diarrhoea
(seven [1%]) with pembrolizumab and pneumonia (nine [2%]) with placebo.
Treatment-related adverse events led to death in four (1%) participants treated
with pembrolizumab (one due to both cardiogenic shock and myocarditis, one due
to both septic shock and myocarditis, one due to pneumonia, and one due to
sudden death) and in no participants treated with placebo.
INTERPRETATION: Pembrolizumab significantly improved disease-free survival
compared with placebo and was not associated with new safety signals in
completely resected, PD-L1-unselected, stage IB-IIIA NSCLC. Pembrolizumab is
potentially a new treatment option for stage IB-IIIA NSCLC after complete
resection and, when recommended, adjuvant chemotherapy, regardless of PD-L1
expression.
FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.
Copyright © 2022 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1470-2045(22)00518-6
PMID: 36108662 [Indexed for MEDLINE]
7. Nat Med. 2022 Sep 12. doi: 10.1038/s41591-022-01962-5. Online ahead of print.
Neoadjuvant atezolizumab for resectable non-small cell lung cancer: an
open-label, single-arm phase II trial.
Chaft JE(#)(1)(2), Oezkan F(#)(3)(4)(5)(6), Kris MG(1)(2), Bunn PA(7), Wistuba
II(8), Kwiatkowski DJ(9)(10), Owen DH(3)(11), Tang Y(10), Johnson BE(9)(10), Lee
JM(12), Lozanski G(11), Pietrzak M(11), Seweryn M(11)(13)(14), Byun WY(11),
Schulze K(15), Nicholas A(15), Johnson A(15), Grindheim J(15), Hilz S(15),
Shames DS(15), Rivard C(7), Toloza E(16), Haura EB(16), McNamee CJ(9)(10),
Patterson GA(17), Waqar SN(17), Rusch VW(1), Carbone DP(18)(19); LCMC study
investigators.
Collaborators: Waqar SN, Shum E, Nagasaka M, Koczywas M, Garon EB, Finley DJ,
Camidge DR, Carlisle JW, Blasberg JD.
Author information:
(1)Memorial Sloan Kettering Cancer Center, New York, NY, USA.
(2)Weill Cornell Medical College, New York, NY, USA.
(3)The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
…
In an ongoing, open-label, single-arm phase II study ( NCT02927301 ), 181
patients with untreated, resectable, stage IB-IIIB non-small cell lung cancer
received two doses of neoadjuvant atezolizumab monotherapy. The primary end
point was major pathological response (MPR; ≤10% viable malignant cells) in
resected tumors without EGFR or ALK alterations. Of the 143 patients in the
primary end point analysis, the MPR was 20% (95% confidence interval, 14-28%).
With a minimum duration of follow-up of 3 years, the 3-year survival rate of 80%
was encouraging. The most common adverse events during the neoadjuvant phase
were fatigue (39%, 71 of 181) and procedural pain (29%, 53 of 181), along with
expected immune-related toxicities; there were no unexpected safety signals. In
exploratory analyses, MPR was predicted using the pre-treatment peripheral blood
immunophenotype based on 14 immune cell subsets. Immune cell subsets predictive
of MPR in the peripheral blood were also identified in the tumor
microenvironment and were associated with MPR. This study of neoadjuvant
atezolizumab in a large cohort of patients with resectable non-small cell lung
cancer was safe and met its primary end point of MPR ≥ 15%. Data from this
single-arm, non-randomized trial suggest that profiles of innate immune cells in
pre-treatment peripheral blood may predict pathological response after
neoadjuvant atezolizumab, but additional studies are needed to determine whether
these profiles can inform patient selection and new therapeutic approaches.
© 2022. The Author(s).
DOI: 10.1038/s41591-022-01962-5
PMID: 36097216
8. Cancer Cell. 2022 Sep 12;40(9):1010-1026.e11. doi: 10.1016/j.ccell.2022.08.003.
Epub 2022 Aug 25.
Personalized neoantigen vaccine NEO-PV-01 with chemotherapy and anti-PD-1 as
first-line treatment for non-squamous non-small cell lung cancer.
Awad MM(1), Govindan R(2), Balogh KN(3), Spigel DR(4), Garon EB(5), Bushway
ME(3), Poran A(3), Sheen JH(3), Kohler V(3), Esaulova E(3), Srouji J(3), Ramesh
S(3), Vyasamneni R(3), Karki B(5), Sciuto TE(3), Sethi H(6), Dong JZ(3), Moles
MA(3), Manson K(3), Rooney MS(3), Khondker ZS(3), DeMario M(3), Gaynor RB(7),
Srinivasan L(8).
Author information:
(1)Dana Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical
School, Boston, MA, USA.
(2)Washington University School of Medicine, St. Louis, MO, USA.
(3)BioNTech US, Cambridge, MA, USA.
…
Comment in
Cancer Cell. 2022 Sep 12;40(9):903-905.
Neoantigens arising from mutations in tumor DNA provide targets for immune-based
therapy. Here, we report the clinical and immune data from a Phase Ib clinical
trial of a personalized neoantigen-vaccine NEO-PV-01 in combination with
pemetrexed, carboplatin, and pembrolizumab as first-line therapy for advanced
non-squamous non-small cell lung cancer (NSCLC). This analysis of 38 patients
treated with the regimen demonstrated no treatment-related serious adverse
events. Multiple parameters including baseline tumor immune infiltration and
on-treatment circulating tumor DNA levels were highly correlated with clinical
response. De novo neoantigen-specific CD4+ and CD8+ T cell responses were
observed post-vaccination. Epitope spread to non-vaccinating neoantigens,
including responses to KRAS G12C and G12V mutations, were detected
post-vaccination. Neoantigen-specific CD4+ T cells generated post-vaccination
revealed effector and cytotoxic phenotypes with increased CD4+ T cell
infiltration in the post-vaccine tumor biopsy. Collectively, these data support
the safety and immunogenicity of this regimen in advanced non-squamous NSCLC.
Copyright © 2022 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ccell.2022.08.003
PMID: 36027916 [Indexed for MEDLINE]
9. Lancet Oncol. 2022 Sep;23(9):1180-1188. doi: 10.1016/S1470-2045(22)00451-X. Epub 2022 Aug 11.
Chest CT scan plus x-ray versus chest x-ray for the follow-up of completely
resected non-small-cell lung cancer (IFCT-0302): a multicentre, open-label,
randomised, phase 3 trial.
Westeel V(1), Foucher P(2), Scherpereel A(3), Domas J(4), Girard P(5), Trédaniel
J(6), Wislez M(7), Dumont P(8), Quoix E(9), Raffy O(10), Braun D(11), Derollez
M(12), Goupil F(13), Hermann J(14), Devin E(15), Barbieux H(16), Pichon E(17),
Debieuvre D(18), Ozenne G(19), Muir JF(19), Dehette S(20), Virally J(21),
Grivaux M(22), Lebargy F(23), Souquet PJ(24), Freijat FA(25), Girard N(26),
Courau E(27), Azarian R(28), Farny M(29), Duhamel JP(30), Langlais A(31), Morin
F(31), Milleron B(7), Zalcman G(32), Barlesi F(33).
Author information:
(1)Department of Pneumology, University Hospital of Besançon, INSERM UMR1098,
Université de Bourgogne-Franche-Comté, Besançon, France. Electronic address:
virginie.westeel@univ-fcomte.fr.
(2)Department of Pneumology, University Hospital Bocage, Dijon, France.
(3)University of Lille, CHU Lille, Thoracic Oncology Department, CNRS, Inserm,
Institut Pasteur de Lille, UMR9020-UMR-S 1277-Canther, Lille, France.
…
Comment in
Lancet Oncol. 2022 Sep;23(9):1115-1116.
BACKGROUND: Even after resection of early-stage non-small-cell lung cancer
(NSCLC), patients have a high risk of developing recurrence and second primary
lung cancer. We aimed to assess efficacy of a follow-up approach including
clinic visits, chest x-rays, chest CT scans, and fibre-optic bronchoscopy versus
clinical visits and chest x-rays after surgery for resectable NSCLC.
METHODS: In this multicentre, open-label, randomised, phase 3 trial (IFCT-0302),
patients aged 18 years or older and after complete resection of pathological
stage I-IIIA NSCLC according to the sixth edition of the TNM classification were
enrolled within 8 weeks of resection from 122 hospitals and tertiary centres in
France. Patients were randomly assigned (1:1) to CT-based follow-up (clinic
visits, chest x-rays, thoraco-abdominal CT scans, and fibre-optic bronchoscopy
for non-adenocarcinoma histology) or minimal follow-up (visits and chest x-rays)
after surgery for NSCLC, by means of a computer-generated sequence using the
minimisation method. Procedures were repeated every 6 months for the first 2
years and yearly until 5 years. The primary endpoint was overall survival
analysed in the intention-to-treat population. Secondary endpoints, also
analysed in the intention-to-treat population, included disease-free survival.
This trial is registered with ClinicalTrials.gov, NCT00198341, and is active,
but not enrolling.
FINDINGS: Between Jan 3, 2005, and Nov 30, 2012, 1775 patients were enrolled and
randomly assigned to a follow-up group (888 patients to the minimal follow-up
group; 887 patients to the CT-based follow-up group). Median overall survival
was not significantly different between follow-up groups (8·5 years [95% CI
7·4-9·6] in the minimal follow-up group vs 10·3 years [8·1-not reached] in the CT-based
follow-up group; adjusted hazard ratio [HR] 0·95, 95% CI 0·83-1·10; log-rank p=0·49).
Disease-free survival was not significantly different between follow-up groups (median
not reached [95% CI not estimable-not estimable] in the minimal follow-up group
vs 4·9 [4·3-not reached] in the CT-based follow-up group; adjusted HR 1·14, 95% CI 0·99-1·30; log-rank p=0·063).
Recurrence was detected in 246 (27·7%) of 888 patients in the minimal follow-up group and in 289 (32·6%)
patients of 887 in the CT-based follow-up group. Second primary lung cancer was diagnosed in 27 (3·0%) patients
in the minimal follow-up group and 40 patients (4·5%) in the CT-based follow-up group. No serious adverse events
related to the trial procedures were reported.
INTERPRETATION: The addition of thoracic CT scans during follow-up, which
included clinic visits and chest x-rays after surgery, did not result in longer
survival among patients with NSCLC. However, it did enable the detection of more
cases of early recurrence and second primary lung cancer, which are more
amenable to curative-intent treatment, supporting the use of CT-based follow-up,
especially in countries where lung cancer screening is already implemented,
alongside with other supportive measures.
FUNDING: French Health Ministry, French National Cancer Institute,
Weisbrem-Benenson Foundation, La Ligue Nationale Contre Le Cancer, and Lilly
Oncology.
TRANSLATION: For the French translation of the abstract see Supplementary
Materials section.
Copyright © 2022 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1470-2045(22)00451-X
PMID: 35964621 [Indexed for MEDLINE]
10. Lancet Oncol. 2022 Sep;23(9):1167-1179. doi: 10.1016/S1470-2045(22)00382-5. Epub 2022 Jul 28.
Sintilimab plus bevacizumab biosimilar IBI305 and chemotherapy for patients with
EGFR-mutated non-squamous non-small-cell lung cancer who progressed on EGFR
tyrosine-kinase inhibitor therapy (ORIENT-31): first interim results from a
randomised, double-blind, multicentre, phase 3 trial.
Lu S(1), Wu L(2), Jian H(3), Chen Y(4), Wang Q(5), Fang J(6), Wang Z(6), Hu
Y(7), Sun M(8), Han L(9), Miao L(10), Ding C(11), Cui J(12), Li B(13), Pan
Y(14), Li X(15), Ye F(16), Liu A(17), Wang K(18), Cang S(19), Zhou H(20), Sun
X(21), Ferry D(22), Lin Y(23), Wang S(20), Zhang W(21), Zhang C(20).
Author information:
(1)Department of Medical Oncology, Shanghai Chest Hospital, School of Medicine,
Shanghai Jiao Tong University, Shanghai, China. Electronic address:
shunlu@sjtu.edu.cn.
(2)Department of Thoracic Medical Oncology, Hunan Cancer Hospital and the
Affiliated Cancer Hospital of Xiangya School of Medicine, Central South
University, Changsha, China.
(3)Department of Medical Oncology, Shanghai Chest Hospital, School of Medicine,
Shanghai Jiao Tong University, Shanghai, China.
…
Erratum in
Lancet Oncol. 2022 Sep;23(9):e404.
Comment in
Lancet Oncol. 2022 Sep;23(9):1113-1114.
BACKGROUND: VEGF inhibitors can enhance the efficacy of immunotherapy. However,
despite high initial response rates, almost all patients eventually develop
treatment resistance to EGFR tyrosine-kinase inhibitors. We aimed to evaluate
the efficacy and safety of sintilimab with or without IBI305 plus pemetrexed and
cisplatin, compared with pemetrexed and cisplatin alone, for the treatment of
patients with locally advanced or metastatic EGFR-mutated non-small-cell lung
cancer (NSCLC) who had disease progression after receiving EGFR tyrosine-kinase
inhibitor therapy.
METHODS: This randomised, double-blind, multicentre, phase 3 trial was conducted
at 52 hospitals in China. Eligible participants were adults aged 18-75 years
with locally advanced or metastatic NSCLC and EGFRmut who progressed after
receiving a EGFR tyrosine-kinase inhibitor, had an Eastern Cooperative Oncology
Group performance status of 0 or 1 with at least one measurable lesion, and an
estimated life expectancy of at least 3 months. Participants were randomly
assigned (1:1:1) to receive sintilimab (200 mg) plus IBI305 (15 mg/kg) plus
pemetrexed (500 mg/m2) and cisplatin (75 mg/m2), sintilimab plus pemetrexed and
cisplatin, or pemetrexed and cisplatin (chemotherapy alone) using block
randomisation with stratification according to sex and presence or absence of
brain metastases. All study drugs were administered intravenously on day 1 of
each cycle, once every 3 weeks. Except for cisplatin, which was only given in
the first four cycles, treatment was given for 24 months or until disease
progression, intolerable toxic effects, withdrawal of consent, death, or other
protocol-specified conditions, whichever occurred first. The primary endpoint
was progression-free survival in the intention-to-treat population. We herein
report the first planned interim analysis, with progression-free survival
results for the comparison between sintilimab plus IBI305 plus chemotherapy
versus chemotherapy alone. The progression-free survival results for the
sintilimab plus pemetrexed and cisplatin group are immature and not reported
here. This study is registered with ClinicalTrials.gov, NCT03802240
(recruiting).
FINDINGS: Between July 11, 2019, and July 31, 2021, 936 patients were screened
and 444 were randomly assigned (148 to the sintilimab plus IBI305 plus
chemotherapy group, 145 to the sintilimab plus chemotherapy group, and 151 to
the chemotherapy alone group). Data cutoff for this interim analysis was July
31, 2021. After a median follow-up of 9·8 months (IQR 4·4-13·3),
progression-free survival was significantly longer in the sintilimab plus IBI305
plus chemotherapy group versus the chemotherapy alone group (median 6·9 months
[95% CI 6·0-9.3] vs 4·3 months [4·1-5·4]; hazard ratio 0·46 [0·34-0·64];
p<0·0001). The most common grade 3 or 4 treatment-related adverse events were
decreased neutrophil count (30 [20%] in the sintilimab plus IBI305 plus
chemotherapy group vs 26 [18%] in the sintilimab plus chemotherapy group vs 27
[18%] in the chemotherapy alone group), decreased white blood cell count (17
[11%] vs 12 [8%] vs 13 [9%]), and anaemia (18 [12%] vs ten [7%] vs 15 [10%]).
Potentially treatment-related deaths occurred in six patients (intestinal
obstruction, gastrointestinal haemorrhage, and myelosuppression in one patient
each, and three deaths of unknown cause) in the sintilimab plus IBI305 plus
chemotherapy group, and in one patient in the chemotherapy alone group (unknown
cause).
INTERPRETATION: In this interim analysis, sintilimab plus IBI305 plus cisplatin
and pemetrexed was generally efficacious and well tolerated in patients with
EGFR-mutated NSCLC who progressed after receiving EGFR tyrosine-kinase inhibitor
therapy.
FUNDING: Innovent Biologics and the National Natural Science Foundation of
China.
TRANSLATION: For the Chinese translation of the abstract see Supplementary
Materials section.
Copyright © 2022 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1470-2045(22)00382-5
PMID: 35908558 [Indexed for MEDLINE]
11. J Clin Oncol. 2022 Sep 19:JCO2200393. doi: 10.1200/JCO.22.00393. Online ahead of print.
Selpercatinib in Patients With RET Fusion-Positive Non-Small-Cell Lung Cancer:
Updated Safety and Efficacy From the Registrational LIBRETTO-001 Phase I/II
Trial.
Drilon A(1), Subbiah V(2), Gautschi O(3), Tomasini P(4), de Braud F(5), Solomon
BJ(6), Shao-Weng Tan D(7), Alonso G(8), Wolf J(9), Park K(10), Goto K(11),
Soldatenkova V(12), Szymczak S(13), Barker SS(12), Puri T(12), Bence Lin A(12),
Loong H(14), Besse B(15).
Author information:
(1)Memorial Sloan Kettering Cancer Center and Weill Cornell Medical Center, New
York, NY.
(2)The University of Texas MD Anderson Cancer Center, Houston, TX.
(3)University of Berne and Cantonal Hospital of Lucerne, Lucerne, Switzerland.
…
PURPOSE: Selpercatinib, a first-in-class, highly selective, and potent
CNS-active RET kinase inhibitor, is currently approved for the treatment of
patients with RET fusion-positive non-small-cell lung cancer (NSCLC). We provide
a registrational data set update in more than double (n = 316) of the original
reported population (n = 144) and better characterization of long-term efficacy
and safety.
METHODS: Patients were enrolled to LIBRETTO-001, a phase I/II, single-arm,
open-label study of selpercatinib in patients with RET-altered cancers. An
analysis of patients with RET fusion-positive NSCLC, including 69
treatment-naive and 247 with prior platinum-based chemotherapy, was performed.
The primary end point was objective response rate (ORR; RECIST v1.1, independent
review committee). Secondary end points included duration of response (DoR),
progression-free survival (PFS), overall survival, and safety.
RESULTS: In treatment-naive patients, the ORR was 84% (95% CI, 73 to 92); 6%
achieved complete responses (CRs). The median DoR was 20.2 months (95% CI, 13.0
to could not be evaluated); 40% of responses were ongoing at the data cutoff
(median follow-up of 20.3 months). The median PFS was 22.0 months; 35% of
patients were alive and progression-free at the data cutoff (median follow-up of
21.9 months). In platinum-based chemotherapy pretreated patients, the ORR was
61% (95% CI, 55 to 67); 7% achieved CRs. The median DoR was 28.6 months (95% CI,
20.4 to could not be evaluated); 49% of responses were ongoing (median follow-up
of 21.2 months). The median PFS was 24.9 months; 38% of patients were alive and
progression-free (median follow-up of 24.7 months). Of 26 patients with
measurable baseline CNS metastasis by the independent review committee, the
intracranial ORR was 85% (95% CI, 65 to 96); 27% were CRs. In the full safety
population (n = 796), the median treatment duration was 36.1 months. The safety
profile of selpercatinib was consistent with previous reports.
CONCLUSION: In a large cohort with extended follow-up, selpercatinib continued
to demonstrate durable and robust responses, including intracranial activity, in
previously treated and treatment-naive patients with RET fusion-positive NSCLC.
DOI: 10.1200/JCO.22.00393
PMID: 36122315
12. J Clin Invest. 2022 Sep 15;132(18):e162688. doi: 10.1172/JCI162688.
A world without tuberculosis: moving from imagination to reality.
Jacobs WR Jr.
Comment on
J Clin Invest. 2022 Sep 15;132(18):
Tuberculosis (TB), caused by Mycobacterium tuberculosis infection, remains a
leading cause of death from an infectious agent, resulting in more than a
million deaths per year. Despite vaccines and chemotherapies, patients often
harbor persister M. tuberculosis cells that resist immune assault and
chemotherapeutic treatments, resulting in a latent TB infection (LTBI). In this
issue of the JCI, Sharan et al. used an aerosol-based macaque model to show that
weekly treatments with isoniazid and rifapentine for 3 months reduced active M.
tuberculosis infection and LTBI. Lung tissue from treated animals showed fewer
granulomas when compared with the untreated control animals. These findings
suggest that it is possible to eliminate persister M. tuberculosis cells,
thereby eliminating LTBI. If similar elimination routinely occurs in patients
undergoing the isoniazid and rifapentine treatment, the hidden reservoir of M.
tuberculosis associated with LTBI would be greatly reduced, allowing us to
imagine, and eventually achieve, a world without TB.
DOI: 10.1172/JCI162688
PMCID: PMC9479609
PMID: 36106635 [Indexed for MEDLINE]
13. Am J Respir Crit Care Med. 2022 Sep 14. doi: 10.1164/rccm.202203-0457OC. Online ahead of print.
Tuberculosis Diagnoses Following Wildfire Smoke Exposure in California.
Linde LR(1), Readhead A(2), Barry PM(2), Balmes JR(3)(4), Lewnard JA(5).
Author information:
(1)University of California, Berkeley, School of Public Health, Berkeley,
California, United States.
(2)California Department of Public Health, Richmond, United States.
(3)University of California, Berkeley, Environmental Health Sciences, School of
Public Health, Berkeley, California, United States.
(4)University of California, San Francisco, Department of Medicine, San
Francisco, California, United States.
(5)UC Berkeley, Berkeley, United States; jlewnard@berkeley.edu.
RATIONALE: Wildfires are a significant cause of exposure to ambient air
pollution in the United States and other settings. While indoor air pollution is
a known contributor to tuberculosis reactivation and progression, it is unclear
whether ambient pollution exposures, including wildfire smoke, similarly
increase risk.
OBJECTIVES: To determine whether tuberculosis diagnosis was associated with
recent exposure to acute outdoor air pollution events, including those caused by
wildfire smoke.
METHODS: We conducted a case-crossover analysis of 6,238 patients aged ≥15 years
diagnosed with active tuberculosis disease over the years 2014-2019 in 8
California counties. Using geocoded address data, we characterized individuals'
daily exposure to<2.5µm-diameter particulate matter (PM2.5) during
counterfactual risk periods 3-6 months before tuberculosis diagnosis (hazard
period), and the same time one year previously (control period). We compared the
frequency of residential PM2.5 exposures exceeding 35µg/m3 (PM2.5 events),
overall and for wildfire-associated and non-wildfire events, during individuals'
hazard and control periods.
MEASUREMENTS AND MAIN RESULTS: In total, 3,139 patients experienced ≥1 PM2.5
event during the hazard period, including 671 experiencing ≥1
wildfire-associated event. Adjusted odds of tuberculosis diagnosis increased by
5% (95% confidence interval: 3-6%) with each PM2.5 event experienced over the
6-month observation periods. Each wildfire-associated PM2.5 event was associated
with 23% (19-28%) higher odds of tuberculosis diagnosis in this time window,
whereas no association was apparent for non-wildfire-associated events.
CONCLUSIONS: Residential exposure to wildfire-associated ambient air pollution
is associated with increased risk of active tuberculosis diagnosis.
DOI: 10.1164/rccm.202203-0457OC
PMID: 36103611
14. PLoS Biol. 2022 Sep 12;20(9):e3001765. doi: 10.1371/journal.pbio.3001765.
eCollection 2022 Sep.
Plasma metabolome predicts trained immunity responses after antituberculosis BCG
vaccination.
Koeken VACM(1)(2)(3), Qi C(2)(3), Mourits VP(1), de Bree LCJ(1), Moorlag
SJCFM(1), Sonawane V(1), Lemmers H(1), Dijkstra H(1), Joosten LAB(1)(4), van
Laarhoven A(1), Xu CJ(1)(2)(3), van Crevel R(1), Netea MG(1)(4)(5), Li
Y(1)(2)(3).
Author information:
(1)Department of Internal Medicine and Radboud Center for Infectious Diseases
(RCI), Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University
Medical Center, Nijmegen, the Netherlands.
(2)Department of Computational Biology for Individualised Infection Medicine,
Centre for Individualised Infection Medicine (CiiM), a joint venture between the
Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School
(MHH), Hannover, Germany.
(3)TWINCORE, a joint venture between the Helmholtz-Centre for Infection Research
(HZI) and the Hannover Medical School (MHH), Hannover, Germany.
…
The antituberculosis vaccine Bacillus Calmette-Guérin (BCG) induces nonspecific
protection against heterologous infections, at least partly through induction of
innate immune memory (trained immunity). The amplitude of the response to BCG is
variable, but the factors that influence this response are poorly understood.
Metabolites, either released by cells or absorbed from the gut, are known to
influence immune responses, but whether they impact BCG responses is not known.
We vaccinated 325 healthy individuals with BCG, and collected blood before, 2
weeks and 3 months after vaccination, to assess the influence of circulating
metabolites on the immune responses induced by BCG. Circulating metabolite
concentrations after BCG vaccination were found to have a more pronounced impact
on trained immunity responses, such as the increase in IL-1β and TNF-α
production upon Staphylococcus aureus stimulation, than on specific adaptive
immune memory, assessed as IFN-γ production in response to Mycobacterium
tuberculosis. Circulating metabolites at baseline were able to predict trained
immunity responses at 3 months after vaccination and enrichment analysis based
on the metabolites positively associated with trained immunity revealed
enrichment of the tricarboxylic acid (TCA) cycle and glutamine metabolism, both
of which were previously found to be important for trained immunity. Several new
metabolic pathways that influence trained immunity were identified, among which
taurine metabolism associated with BCG-induced trained immunity, a finding
validated in functional experiments. In conclusion, circulating metabolites are
important factors influencing BCG-induced trained immunity in humans. Modulation
of metabolic pathways may be a novel strategy to improve vaccine and trained
immunity responses.
DOI: 10.1371/journal.pbio.3001765
PMCID: PMC9499240
PMID: 36094960 [Indexed for MEDLINE]
15. J Exp Med. 2022 Nov 7;219(11):e20220504. doi: 10.1084/jem.20220504. Epub 2022
Sep 7.
GPX4 regulates cellular necrosis and host resistance in Mycobacterium
tuberculosis infection.
Amaral EP(1), Foreman TW(2), Namasivayam S(1), Hilligan KL(1), Kauffman KD(2),
Barbosa Bomfim CC(1), Costa DL(3), Barreto-Duarte B(4)(5)(6), Gurgel-Rocha
C(7)(8), Santana MF(9)(10)(11), Cordeiro-Santos M(10)(11)(12), Du Bruyn E(13),
Riou C(13), Aberman K(1), Wilkinson RJ(13)(14)(15), Barber DL(2), Mayer-Barber
KD(16), Andrade BB(4)(5)(6)(17)(18)(19)(20), Sher A(1).
Author information:
(1)Immunobiology Section, Laboratory of Parasitic Diseases, National Institute
of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD.
(2)T Lymphocyte Biology Section, Laboratory of Parasitic Diseases, National
Institute of Allergy and Infectious Disease, National Institutes of Health,
Bethesda, MD.
(3)Departmento de Bioquímica e Imunologia, Programa de Pós-Graduação em
Imunologia Básica e Aplicada, Faculdade de Medicina de Ribeirão Preto,
Universidade de São Paulo, Ribeirão Preto, Brazil.
…
Cellular necrosis during Mycobacterium tuberculosis (Mtb) infection promotes
both immunopathology and bacterial dissemination. Glutathione peroxidase-4
(Gpx4) is an enzyme that plays a critical role in preventing iron-dependent
lipid peroxidation-mediated cell death (ferroptosis), a process previously
implicated in the necrotic pathology seen in Mtb-infected mice. Here, we
document altered GPX4 expression, glutathione levels, and lipid peroxidation in
patients with active tuberculosis and assess the role of this pathway in mice
genetically deficient in or overexpressing Gpx4. We found that Gpx4-deficient
mice infected with Mtb display substantially increased lung necrosis and
bacterial burdens, while transgenic mice overexpressing the enzyme show
decreased bacterial loads and necrosis. Moreover, Gpx4-deficient macrophages
exhibited enhanced necrosis upon Mtb infection in vitro, an outcome suppressed
by the lipid peroxidation inhibitor, ferrostatin-1. These findings provide
support for the role of ferroptosis in Mtb-induced necrosis and implicate the
Gpx4/GSH axis as a target for host-directed therapy of tuberculosis.
© 2022 Amaral et al.
DOI: 10.1084/jem.20220504
PMCID: PMC9458471
PMID: 36069923 [Indexed for MEDLINE]
16. Nat Commun. 2022 Sep 5;13(1):5093. doi: 10.1038/s41467-022-32639-9.
HIF-1 stabilization in T cells hampers the control of Mycobacterium tuberculosis
infection.
Liu R(1), Muliadi V(1), Mou W(1)(2), Li H(1), Yuan J(3), Holmberg J(3), Chambers
BJ(4), Ullah N(1), Wurth J(1)(5), Alzrigat M(1), Schlisio S(1), Carow B(1)(6),
Larsson LG(1), Rottenberg ME(7).
Author information:
(1)Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet,
Stockholm, Sweden.
(2)Capital Children's Hospital, Beijing, China.
(3)Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm,
Sweden.
…
The hypoxia-inducible factors (HIFs) regulate the main transcriptional pathway
of response to hypoxia in T cells and are negatively regulated by von
Hippel-Lindau factor (VHL). But the role of HIFs in the regulation of CD4 T cell
responses during infection with M. tuberculosis isn't well understood. Here we
show that mice lacking VHL in T cells (Vhl cKO) are highly susceptible to
infection with M. tuberculosis, which is associated with a low accumulation of
mycobacteria-specific T cells in the lungs that display reduced proliferation,
altered differentiation and enhanced expression of inhibitory receptors. In
contrast, HIF-1 deficiency in T cells is redundant for M. tuberculosis control.
Vhl cKO mice also show reduced responses to vaccination. Further, VHL promotes
proper MYC-activation, cell-growth responses, DNA synthesis, proliferation and
survival of CD4 T cells after TCR activation. The VHL-deficient T cell responses
are rescued by the loss of HIF-1α, indicating that the increased susceptibility
to M. tuberculosis infection and the impaired responses of Vhl-deficient T cells
are HIF-1-dependent.
© 2022. The Author(s).
DOI: 10.1038/s41467-022-32639-9
PMCID: PMC9445005
PMID: 36064840 [Indexed for MEDLINE]
17. J Clin Invest. 2022 Sep 1:e160152. doi: 10.1172/JCI160152. Online ahead of
print.
Targeting acetylcholine signaling modulates persistent drug tolerance in
EGFR-mutant lung cancer and impedes tumor relapse.
Nie M(1), Chen N(1), Pang H(1), Jiang T(2), Jiang W(3), Tian P(4), Yao L(1),
Chen Y(1), DeBerardinis RJ(5), Li W(4), Yu Q(3), Zhou C(2), Hu Z(1).
Author information:
(1)School of Pharmaceutical Sciences, Tsinghua University, Beijing, China.
(2)Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji
University Medical School Cancer Institute, Shanghai, China.
(3)Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China.
(4)Department of Respiratory and Critical Care Medicine, West China Hospital,
Sichuan University, Chengdu, China.
(5)Children's Medical Center Research Institute, UT Southwestern, Dallas, United
States of America.
Although first-line epidermal growth factor receptor (EGFR) tyrosine kinase
inhibitor (TKI) therapy is effective for treating EGFR-mutant non-small cell
lung cancer (NSCLC), it is now understood that drug-tolerant persister (DTP)
cells escaping from initial treatment eventually drives drug resistance. Here,
through integration of metabolomics and transcriptomics, we found that the
neurotransmitter acetylcholine (ACh) was specifically accumulated in DTP cells,
and illustrated that treatment with EGFR-TKI heightens the expression of the
rate-limiting enzyme choline acetyltransferase (ChAT) in ACh biosynthesis via
YAP mediation. Genetic and pharmacological manipulation of ACh biosynthesis or
ACh signaling could predictably regulate the extent of DTP formation in vitro
and in vivo. Strikingly, pharmacologically targeting ACh/M3R signaling with an
FDA-approved drug, Darifenacin, retarded tumor relapse in vivo. Mechanistically,
upregulated ACh metabolism mediated drug tolerance in part through activating
WNT signaling via ACh muscarinic receptor-3 (M3R). Importantly, aberrant ACh
metabolism in NSCLC patients represented a potential role in predicting EGFR-TKI
response rate and progression-free survival. Our study therefore defines a new
therapeutic strategy-targeting ACh-M3R-WNT axis-for manipulating EGFR TKI drug
tolerance in the treatment of NSCLC.
DOI: 10.1172/JCI160152
PMID: 36048538
18. Mol Cell. 2022 Sep 1;82(17):3151-3165.e9. doi: 10.1016/j.molcel.2022.06.019.
Epub 2022 Jul 30.
HelR is a helicase-like protein that protects RNA polymerase from rifamycin
antibiotics.
Surette MD(1), Waglechner N(2), Koteva K(1), Wright GD(3).
Author information:
(1)David Braley Center for Antibiotic Discovery, M.G. DeGroote Institute for
Infectious Disease Research, Department of Biochemistry and Biomedical Sciences,
McMaster University, Hamilton, ON L8S 4L8, Canada.
(2)Toronto Invasive Bacterial Diseases Network, Mount Sinai Hospital, Toronto,
ON M5G 1X5, Canada.
(3)David Braley Center for Antibiotic Discovery, M.G. DeGroote Institute for
Infectious Disease Research, Department of Biochemistry and Biomedical Sciences,
McMaster University, Hamilton, ON L8S 4L8, Canada. Electronic address:
wrightge@mcmaster.ca.
Rifamycin antibiotics such as rifampin are potent inhibitors of prokaryotic RNA
polymerase (RNAP) used to treat tuberculosis and other bacterial infections.
Although resistance arises in the clinic principally through mutations in RNAP,
many bacteria possess highly specific enzyme-mediated resistance mechanisms that
modify and inactivate rifamycins. The expression of these enzymes is controlled
by a 19-bp cis-acting rifamycin-associated element (RAE). Guided by the presence
of RAE sequences, we identify a helicase-like protein, HelR, in Streptomyces
venezuelae that confers broad-spectrum rifamycin resistance. We show that HelR
also promotes tolerance to rifamycins, enabling bacterial evasion of the toxic
properties of these antibiotics. HelR forms a complex with RNAP and rescues
transcription inhibition by displacing rifamycins from RNAP, thereby providing
resistance by target protection . Furthermore, HelRs are broadly distributed in
Actinobacteria, including several opportunistic Mycobacterial pathogens,
offering yet another challenge for developing new rifamycin antibiotics.
Copyright © 2022 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.molcel.2022.06.019
PMID: 35907401 [Indexed for MEDLINE]
19. Mol Cell. 2022 Sep 1;82(17):3166-3177.e5. doi: 10.1016/j.molcel.2022.06.034.
Epub 2022 Jul 28.
Mycobacterium abscessus HelR interacts with RNA polymerase to confer intrinsic
rifamycin resistance.
Hurst-Hess KR(1), Saxena A(2), Rudra P(1), Yang Y(1), Ghosh P(3).
Author information:
(1)Division of Genetics, Wadsworth Center, New York State Department of Health,
Albany, NY 12208, USA.
(2)School of Public Health, University at Albany, Albany, NY 12208, USA.
(3)Division of Genetics, Wadsworth Center, New York State Department of Health,
Albany, NY 12208, USA; School of Public Health, University at Albany, Albany, NY
12208, USA. Electronic address: pallavi.ghosh@health.ny.gov.
Rifampicin (RIF), the frontline drug against M. tuberculosis, is completely
ineffective against M. abscessus, partially due to the presence of an
ADP-ribosyltransferase (Arr) that inactivates RIF. Using RNA-seq, we show that
exposure of M. abscessus to sublethal doses of RIF and Rifabutin (RBT), a close
analog of RIF, results in an ∼25-fold upregulation of Mab_helR in laboratory and
clinical isolates. An isogenic deletion in Mab_helR results in RIF/RBT
hypersensitivity, and overexpression of Mab_helR confers RIF tolerance in
M. tuberculosis. We demonstrate an increased HelR-RNAP association in
RIF-exposed bacteria and a MabHelR-mediated dissociation of RNAP from stalled
initiation complexes in vitro. Finally, we show that the tip of the PCh-loop of
Mab_helR, present in proximity to RIF, is critical for conferring RIF resistance
but dispensable for dissociation of stalled RNAP complexes, suggesting that
HelR-mediated RIF resistance requires a step in addition to displacement of
RIF-stalled RNAP.
Copyright © 2022 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.molcel.2022.06.034
PMCID: PMC9444957
PMID: 35905736 [Indexed for MEDLINE]
20. J Clin Invest. 2022 Sep 15;132(18):e161564. doi: 10.1172/JCI161564.
Isoniazid and rifapentine treatment effectively reduces persistent M.
tuberculosis infection in macaque lungs.
Sharan R(1), Ganatra SR(1), Singh DK(1), Cole J(1), Foreman TW(2), Thippeshappa
R(1), Peloquin CA(3), Shivanna V(1), Gonzalez O(1), Day CL(4), Gandhi
NR(4)(5)(6), Dick EJ Jr(1), Hall-Ursone S(1), Mehra S(1), Schlesinger LS(1),
Rengarajan J(4)(5)(6), Kaushal D(1).
Author information:
(1)Southwest National Primate Research Center, Texas Biomedical Research
Institute, San Antonio, Texas, USA.
(2)National Institute of Allergy and Infectious Diseases, Bethesda, Maryland,
USA.
(3)University of Florida College of Pharmacy, Gainesville, Florida, USA.
(4)Emory Tuberculosis Center and.
(5)Emory Vaccine Center, Emory National Primate Research Center, Emory
University, Atlanta, Georgia, USA.
(6)Department of Medicine, Division of Infectious Diseases, Emory University
School of Medicine, Atlanta, Georgia, USA.
Comment in
J Clin Invest. 2022 Sep 15;132(18):
A once-weekly oral dose of isoniazid and rifapentine for 3 months (3HP) is
recommended by the CDC for treatment of latent tuberculosis infection (LTBI).
The aim of this study is to assess 3HP-mediated clearance of M. tuberculosis
bacteria in macaques with asymptomatic LTBI. Twelve Indian-origin rhesus
macaques were infected with a low dose (~10 CFU) of M. tuberculosis CDC1551 via
aerosol. Six animals were treated with 3HP and 6 were left untreated. The
animals were imaged via PET/CT at frequent intervals. Upon treatment completion,
all animals except 1 were coinfected with SIV to assess reactivation of LTBI to
active tuberculosis (ATB). Four of 6 treated macaques showed no evidence of
persistent bacilli or extrapulmonary spread until the study end point. PET/CT
demonstrated the presence of significantly more granulomas in untreated animals
relative to the treated group. The untreated animals harbored persistent bacilli
and demonstrated tuberculosis (TB) reactivation following SIV coinfection, while
none of the treated animals reactivated to ATB. 3HP treatment effectively
reduced persistent infection with M. tuberculosis and prevented reactivation of
TB in latently infected macaques.
DOI: 10.1172/JCI161564
PMCID: PMC9479578
PMID: 35862216 [Indexed for MEDLINE]
21. Annu Rev Microbiol. 2022 Sep 8;76:661-680. doi:
10.1146/annurev-micro-121321-093031. Epub 2022 Jun 16.
Evolution of Tuberculosis Pathogenesis.
Pepperell CS(1).
Author information:
(1)Division of Infectious Diseases, Department of Medicine, and Department of
Medical Microbiology and Immunology, School of Medicine and Public Health,
University of Wisconsin-Madison, Madison, Wisconsin, USA; email:
pepperell@wisc.edu.
Mycobacterium tuberculosis is a globally distributed, lethal pathogen of humans.
The virulence armamentarium of M. tuberculosis appears to have been developed on
a scaffold of antiphagocytic defenses found among diverse, mostly free-living
species of Mycobacterium. Pathoadaptation was further aided by the modularity,
flexibility, and interactivity characterizing mycobacterial effectors and their
regulators. During emergence of M. tuberculosis, novel genetic material was
acquired, created, and integrated with existing tools. The major mutational
mechanisms underlying these adaptations are discussed in this review, with
examples. During its evolution, M. tuberculosis lost the ability and/or
opportunity to engage in lateral gene transfer, but despite this it has retained
the adaptability that characterizes mycobacteria. M. tuberculosis exemplifies
the evolutionary genomic mechanisms underlying adoption of the pathogenic niche,
and studies of its evolution have uncovered a rich array of discoveries about
how new pathogens are made.
DOI: 10.1146/annurev-micro-121321-093031
PMID: 35709500 [Indexed for MEDLINE]
22. Lancet Infect Dis. 2022 Sep;22(9):e271-e278. doi: 10.1016/S1473-3099(22)00153-0. Epub 2022 May 5.
Are we underestimating the annual risk of infection with Mycobacterium
tuberculosis in high-burden settings?
Dowdy DW(1), Behr MA(2).
Author information:
(1)Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health,
Baltimore, MD, USA. Electronic address: ddowdy1@jhmi.edu.
(2)McGill International Tuberculosis Centre and Department of Medicine, McGill
University, Montreal, QC, Canada.
Comment in
Lancet Infect Dis. 2022 Sep;22(9):1275-1276.
Lancet Infect Dis. 2022 Sep;22(9):1276-1277.
Lancet Infect Dis. 2022 Sep;22(9):1277-1278.
The annual risk of infection with Mycobacterium tuberculosis determines a
population's exposure level and thus the fraction of incident tuberculosis
resulting from recent infection (often considered as having occurred within the
past 2 years). Contemporary annual risk of infection estimates centre around 1%
in most high-burden countries. We present three arguments why these
estimates-primarily derived from cross-sectional tuberculin surveys in young
school children (aged 5-12 years)-might underrepresent the true annual risk of
infection. First, young children are expected to have lower risk of infection
than older adolescents and adults (ie, those aged 15 years and older). Second,
exposure might not lead to a positive test result in some individuals. Third,
cross-sectional surveys might overlook transient immune responses. Accounting
for these biases, the true annual risk of infection among adults in high-burden
settings is probably closer to 5-10%. Consequently, most tuberculosis in those
settings should reflect infection within the past 2 years rather than remote
infection occurring many years ago. Under this reframing, major reductions in
tuberculosis incidence could be achievable by focusing on the minority of people
who have been recently infected.
Copyright © 2022 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1473-3099(22)00153-0
PMID: 35526558 [Indexed for MEDLINE]
23. Clin Microbiol Rev. 2022 Sep 21;35(3):e0022721. doi: 10.1128/cmr.00227-21. Epub 2022 Mar 21.
Tuberculosis Treatment Monitoring and Outcome Measures: New Interest and New
Strategies.
Heyckendorf J(#)(1)(2)(3)(4), Georghiou SB(#)(5), Frahm N(6), Heinrich N(7),
Kontsevaya I(2)(3)(4), Reimann M(2)(3)(4), Holtzman D(5), Imperial M(8), Cirillo
DM(9), Gillespie SH(10), Ruhwald M(5); UNITE4TB Consortium.
Author information:
(1)Department of Medicine I, University Hospital Schleswig-Holstein, Kiel,
Germany.
(2)Division of Clinical Infectious Diseases, Research Center Borstel, Borstel,
Germany.
(3)German Center for Infection Research (DZIF), Braunschweig, Germany.
…
Despite the advent of new diagnostics, drugs and regimens, tuberculosis (TB)
remains a global public health threat. A significant challenge for TB control
efforts has been the monitoring of TB therapy and determination of TB treatment
success. Current recommendations for TB treatment monitoring rely on sputum and
culture conversion, which have low sensitivity and long turnaround times,
present biohazard risk, and are prone to contamination, undermining their
usefulness as clinical treatment monitoring tools and for drug development. We
review the pipeline of molecular technologies and assays that serve as suitable
substitutes for current culture-based readouts for treatment response and
outcome with the potential to change TB therapy monitoring and accelerate drug
development.
DOI: 10.1128/cmr.00227-21
PMCID: PMC9491169
PMID: 35311552 [Indexed for MEDLINE]