2023年
No.9
PubMed
(tuberculosis[Title/Abstract]) OR (lung cancer[Title/Abstract])
Filters applied: from 2023/9/1 - 2023/9/30.
1. Lancet. 2023 Sep 9;402(10405):871-881. doi: 10.1016/S0140-6736(23)01384-3. Epub 2023 Jul 18.
Stereotactic ablative radiotherapy with or without immunotherapy for early-stage
or isolated lung parenchymal recurrent node-negative non-small-cell lung cancer:
an open-label, randomised, phase 2 trial.
Chang JY(1), Lin SH(2), Dong W(3),…
Author information:
(1)Department of Radiation Oncology, The University of Texas MD Anderson Cancer
Center, Houston, TX, USA. Electronic address: jychang@mdanderson.org.
(2)Department of Radiation Oncology, The University of Texas MD Anderson Cancer
Center, Houston, TX, USA.
(3)Department of Biostatistics, The University of Texas MD Anderson Cancer
Center, Houston, TX, USA.
…
Erratum in
Lancet. 2023 Sep 9;402(10405):850.
Comment in
Lancet. 2023 Sep 9;402(10405):829-831.
BACKGROUND: Stereotactic ablative radiotherapy (SABR) is the standard treatment
for medically inoperable early-stage non-small-cell lung cancer (NSCLC), but
regional or distant relapses, or both, are common. Immunotherapy reduces
recurrence and improves survival in people with stage III NSCLC after
chemoradiotherapy, but its utility in stage I and II cases is unclear. We
therefore conducted a randomised phase 2 trial of SABR alone compared with SABR
with immunotherapy (I-SABR) for people with early-stage NSCLC.
METHODS: We did an open-label, randomised, phase 2 trial comparing SABR to
I-SABR, conducted at three different hospitals in TX, USA. People aged 18 years
or older with histologically proven treatment-naive stage IA-IB (tumour size ≤4
cm, N0M0), stage IIA (tumour size ≤5 cm, N0M0), or stage IIB (tumour size >5 cm
and ≤7 cm, N0M0) as per the American Joint Committee on Cancer version 8 staging
system or isolated parenchymal recurrences (tumour size ≤7 cm) NSCLC (TanyNanyM0
before definitive surgery or chemoradiotherapy) were included in this trial.
Participants were randomly assigned (1:1; using the Pocock & Simon method) to
receive SABR with or without four cycles of nivolumab (480 mg, once every 4
weeks, with the first dose on the same day as, or within 36 h after, the first
SABR fraction). This trial was unmasked. The primary endpoint was 4-year
event-free survival (local, regional, or distant recurrence; second primary lung
cancer; or death). Analyses were both intention to treat (ITT) and per protocol.
This trial is registered with ClinicalTrials.gov (NCT03110978) and is closed to
enrolment.
FINDINGS: From June 30, 2017, to March 22, 2022, 156 participants were randomly
assigned, and 141 participants received assigned therapy. At a median 33 months'
follow-up, I-SABR significantly improved 4-year event-free survival from 53%
(95% CI 42-67%) with SABR to 77% (66-91%; per-protocol population, hazard ratio
[HR] 0·38; 95% CI 0·19-0·75; p=0·0056; ITT population, HR 0·42; 95% CI
0·22-0·80; p=0·0080). There were no grade 3 or higher adverse events associated
with SABR. In the I-SABR group, ten participants (15%) had grade 3 immunologial
adverse events related to nivolumab; none had grade 3 pneumonitis or grade 4 or
higher toxicity.
INTERPRETATION: Compared with SABR alone, I-SABR significantly improved
event-free survival at 4 years in people with early-stage treatment-naive or
lung parenchymal recurrent node-negative NSCLC, with tolerable toxicity. I-SABR
could be a treatment option in these participants, but further confirmation from
a number of currently accruing phase 3 trials is required.
FUNDING: Bristol-Myers Squibb and MD Anderson Cancer Center Alliance, National
Cancer Institute at the National Institutes of Health through Cancer Center Core
Support Grant and Clinical and Translational Science Award to The University of
Texas MD Anderson Cancer Center.
Copyright © 2023 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S0140-6736(23)01384-3
PMCID: PMC10529504
PMID: 37478883 [Indexed for MEDLINE]
2. Nat Med. 2023 Oct;29(10):2577-2585. doi: 10.1038/s41591-023-02554-7. Epub 2023
Sep 14.
Amivantamab plus lazertinib in osimertinib-relapsed EGFR-mutant advanced
non-small cell lung cancer: a phase 1 trial.
Cho BC(1), Kim DW(2), Spira AI(3), Gomez JE(4), Haura EB(5), Kim SW(6), Sanborn
RE(7), Cho EK(8), Lee KH(9), Minchom A(10), Lee JS(11), Han JY(12), Nagasaka
M(13), Sabari JK(14), Ou SI(13), Lorenzini P(15), Bauml JM(15), Curtin JC(15),
Roshak A(15), Gao G(15), Xie J(15), Thayu M(15), Knoblauch RE(15), Park
K(16)(17).
Author information:
(1)Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College
of Medicine, Seoul, Republic of Korea. CBC1971@yuhs.ac.
(2)Seoul National University College of Medicine and Seoul National University
Hospital, Seoul, Republic of Korea.
(3)Virginia Cancer Specialists Research Institute, US Oncology Research,
Fairfax, VA, USA.
…
Patients with epidermal growth factor receptor (EGFR)-mutated non-small cell
lung cancer (NSCLC) often develop resistance to current standard
third-generation EGFR tyrosine kinase inhibitors (TKIs); no targeted treatments
are approved in the osimertinib-relapsed setting. In this open-label,
dose-escalation and dose-expansion phase 1 trial, the potential for improved
anti-tumor activity by combining amivantamab, an EGFR-MET bispecific antibody,
with lazertinib, a third-generation EGFR TKI, was evaluated in patients with
EGFR-mutant NSCLC whose disease progressed on third-generation TKI monotherapy
but were chemotherapy naive (CHRYSALIS cohort E). In the dose-escalation phase,
the recommended phase 2 combination dose was established; in the dose-expansion
phase, the primary endpoints were safety and overall response rate, and key
secondary endpoints included progression-free survival and overall survival. The
safety profile of amivantamab and lazertinib was generally consistent with
previous experience of each agent alone, with 4% experiencing grade ≥3 events;
no new safety signals were identified. In an exploratory cohort of 45 patients
who were enrolled without biomarker selection, the primary endpoint of
investigator-assessed overall response rate was 36% (95% confidence interval,
22-51). The median duration of response was 9.6 months, and the median
progression-free survival was 4.9 months. Next-generation sequencing and
immunohistochemistry analyses identified high EGFR and/or MET expression as
potential predictive biomarkers of response, which will need to be validated
with prospective assessment. ClinicalTrials.gov identifier: NCT02609776 .
© 2023. The Author(s).
DOI: 10.1038/s41591-023-02554-7
PMCID: PMC10579096
PMID: 37710001 [Indexed for MEDLINE]
3. Cancer Cell. 2023 Oct 9;41(10):1749-1762.e6. doi: 10.1016/j.ccell.2023.08.010.
Epub 2023 Sep 7.
Individualized tumor-informed circulating tumor DNA analysis for postoperative
monitoring of non-small cell lung cancer.
Chen K(1), Yang F(2), Shen H(3), Wang C(4), Li X(4), Chervova O(5), Wu S(4), Qiu
F(4), Peng D(4), Zhu X(4), Chuai S(4), Beck S(5), Kanu N(5), Carbone D(6), Zhang
Z(7), Wang J(8).
Author information:
(1)Thoracic Oncology Institute, Peking University People's Hospital, Beijing
100044, China; Department of Thoracic Surgery, Peking University People's
Hospital, Beijing 100044, China. Electronic address: chenkezhong@pkuph.edu.cn.
(2)Thoracic Oncology Institute, Peking University People's Hospital, Beijing
100044, China; Department of Thoracic Surgery, Peking University People's
Hospital, Beijing 100044, China.
(3)Department of Thoracic Surgery, Peking University People's Hospital, Beijing
100044, China.
…
Comment in
Cancer Cell. 2023 Oct 9;41(10):1699-1701.
We report a personalized tumor-informed technology, Patient-specific pROgnostic
and Potential tHErapeutic marker Tracking (PROPHET) using deep sequencing of 50
patient-specific variants to detect molecular residual disease (MRD) with a
limit of detection of 0.004%. PROPHET and state-of-the-art fixed-panel assays
were applied to 760 plasma samples from 181 prospectively enrolled early stage
non-small cell lung cancer patients. PROPHET shows higher sensitivity of 45% at
baseline with circulating tumor DNA (ctDNA). It outperforms fixed-panel assays
in prognostic analysis and demonstrates a median lead-time of 299 days to
radiologically confirmed recurrence. Personalized non-canonical variants account
for 98.2% with prognostic effects similar to canonical variants. The proposed
tumor-node-metastasis-blood (TNMB) classification surpasses TNM staging for
prognostic prediction at the decision point of adjuvant treatment. PROPHET shows
potential to evaluate the effect of adjuvant therapy and serve as an arbiter of
the equivocal radiological diagnosis. These findings highlight the potential
advantages of personalized cancer techniques in MRD detection.
Copyright © 2023 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ccell.2023.08.010
PMID: 37683638 [Indexed for MEDLINE]
4. Lancet Oncol. 2023 Sep;24(9):1002-1017. doi: 10.1016/S1470-2045(23)00344-3.
Tumor Treating Fields therapy with standard systemic therapy versus standard
systemic therapy alone in metastatic non-small-cell lung cancer following
progression on or after platinum-based therapy (LUNAR): a randomised,
open-label, pivotal phase 3 study.
Leal T(1), Kotecha R(2), Ramlau R(3), …
Author information:
(1)Winship Cancer Institute at Emory University, Atlanta, GA, USA. Electronic
address: ticiana.a.leal@emory.edu.
(2)Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA.
(3)Poznan University of Medical Sciences, Poznan, Poland.
…
Comment in
Lancet Oncol. 2023 Sep;24(9):946-947.
BACKGROUND: Tumor Treating Fields (TTFields) are electric fields that disrupt
processes critical for cancer cell survival, leading to immunogenic cell death
and enhanced antitumour immune response. In preclinical models of non-small-cell
lung cancer, TTFields amplified the effects of chemotherapy and immune
checkpoint inhibitors. We report primary results from a pivotal study of
TTFields therapy in metastatic non-small-cell lung cancer.
METHODS: This randomised, open-label, pivotal phase 3 study recruited patients
at 130 sites in 19 countries. Participants were aged 22 years or older with
metastatic non-small-cell lung cancer progressing on or after platinum-based
therapy, with squamous or non-squamous histology and ECOG performance status of
2 or less. Previous platinum-based therapy was required, but no restriction was
placed on the number or type of previous lines of systemic therapy. Participants
were randomly assigned (1:1) to TTFields therapy and standard systemic therapy
(investigator's choice of immune checkpoint inhibitor [nivolumab, pembrolizumab,
or atezolizumab] or docetaxel) or standard therapy alone. Randomisation was
performed centrally using variable blocked randomisation and an interactive
voice-web response system, and was stratified by tumour histology, treatment,
and region. Systemic therapies were dosed according to local practice
guidelines. TTFields therapy (150 kHz) was delivered continuously to the
thoracic region with the recommendation to achieve an average of at least 18
h/day device usage. The primary endpoint was overall survival in the
intention-to-treat population. The safety population included all patients who
received any study therapy and were analysed according to the actual treatment
received. The study is registered with ClinicalTrials.gov, NCT02973789.
FINDINGS: Between Feb 13, 2017, and Nov 19, 2021, 276 patients were enrolled and
randomly assigned to receive TTFields therapy with standard therapy (n=137) or
standard therapy alone (n=139). The median age was 64 years (IQR 59-70), 178
(64%) were male and 98 (36%) were female, 156 (57%) had non-squamous
non-small-cell lung cancer, and 87 (32%) had received a previous immune
checkpoint inhibitor. Median follow-up was 10·6 months (IQR 6·1-33·7) for
patients receiving TTFields therapy with standard therapy, and 9·5 months
(0·1-32·1) for patients receiving standard therapy. Overall survival was
significantly longer with TTFields therapy and standard therapy than with
standard therapy alone (median 13·2 months [95% CI 10·3-15·5] vs 9·9 months
[8·1-11·5]; hazard ratio [HR] 0·74 [95% CI 0·56-0·98]; p=0·035). In the safety population (n=267),
serious adverse events of any cause were reported in 70 (53%) of 133 patients receiving
TTFields therapy plus standard therapy and 51 (38%) of 134 patients receiving standard therapy alone.
The most frequent grade 3-4 adverse events were leukopenia (37 [14%] of 267), pneumonia (28 [10%]), and
anaemia (21 [8%]). TTFields therapy-related adverse events were reported in 95
(71%) of 133 patients; these were mostly (81 [85%]) grade 1-2 skin and
subcutaneous tissue disorders. There were three deaths related to standard
therapy (two due to infections and one due to pulmonary haemorrhage) and no
deaths related to TTFields therapy.
INTERPRETATION: TTFields therapy added to standard therapy significantly
improved overall survival compared with standard therapy alone in metastatic
non-small-cell lung cancer after progression on platinum-based therapy without
exacerbating systemic toxicities. These data suggest that TTFields therapy is
efficacious in metastatic non-small-cell lung cancer and should be considered as
a treatment option to manage the disease in this setting.
FUNDING: Novocure.
Copyright © 2023 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1470-2045(23)00344-3
PMID: 37657460 [Indexed for MEDLINE]
5. Nat Commun. 2023 Sep 22;14(1):5916. doi: 10.1038/s41467-023-41585-z.
YAP silencing by RB1 mutation is essential for small-cell lung cancer
metastasis.
Wu Z(1), Su J(2), Li FL(3), Chen T(4), Mayner J(5), Engler A(5), Ma S(6), Li
Q(7), Guan KL(8)(9).
Author information:
(1)Department of Pharmacology and Moores Cancer Center, University of
California, San Diego, La Jolla, CA, 92093, USA.
(2)Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai,
201203, China.
(3)College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058,
China.
…
Small cell lung cancer (SCLC) is highly lethal due to its prevalent metastasis.
Most SCLCs have inactivating mutations in TP53 and RB1. We find that loss of YAP
expression is key for SCLC cells to acquire rapid ameboid migration and high
metastatic potential. YAP functions through its target genes CCN1/CCN2 to
inhibit SCLC ameboid migration. RB1 mutation contributes to YAP transcriptional
silencing via E2F7, which recruits the RCOR co-repressor complex to YAP
promoter. We discover that benzamide family HDAC inhibitors stimulate YAP
expression by inhibiting the RCOR-HDAC complex, thereby suppressing SCLC
metastasis and improving survival in a mouse model. Our study unveils the
molecular and cellular basis underlying SCLC's high metastatic potential, the
previously unrecognized role of YAP in suppressing ameboid migration and tumor
metastasis, and the mechanism of YAP transcription regulation involving E2F7,
RCOR, and Sin3 HDAC. This study reveals a therapeutic potential of benzamides
for SCLC treatment.
© 2023. Springer Nature Limited.
DOI: 10.1038/s41467-023-41585-z
PMCID: PMC10516997
PMID: 37739954 [Indexed for MEDLINE]
6. J Cell Biol. 2023 Dec 4;222(12):e202303066. doi: 10.1083/jcb.202303066. Epub
2023 Sep 22.
Peroxisomal ROS control cytosolic Mycobacterium tuberculosis replication in
human macrophages.
Pellegrino E(1), Aylan B(1), Bussi C(1), Fearns A(1), Bernard EM(1), Athanasiadi
N(1), Santucci P(1), Botella L(1), Gutierrez MG(1).
Author information:
(1)Host-pathogen interactions in Tuberculosis Laboratory, The Francis Crick
Institute, London, UK.
Peroxisomes are organelles involved in many metabolic processes including lipid
metabolism, reactive oxygen species (ROS) turnover, and antimicrobial immune
responses. However, the cellular mechanisms by which peroxisomes contribute to
bacterial elimination in macrophages remain elusive. Here, we investigated
peroxisome function in iPSC-derived human macrophages (iPSDM) during infection
with Mycobacterium tuberculosis (Mtb). We discovered that Mtb-triggered
peroxisome biogenesis requires the ESX-1 type 7 secretion system, critical for
cytosolic access. iPSDM lacking peroxisomes were permissive to Mtb wild-type
(WT) replication but were able to restrict an Mtb mutant missing functional
ESX-1, suggesting a role for peroxisomes in the control of cytosolic but not
phagosomal Mtb. Using genetically encoded localization-dependent ROS probes, we
found peroxisomes increased ROS levels during Mtb WT infection. Thus, human
macrophages respond to the infection by increasing peroxisomes that generate ROS
primarily to restrict cytosolic Mtb. Our data uncover a peroxisome-controlled,
ROS-mediated mechanism that contributes to the restriction of cytosolic
bacteria.
© 2023 Pellegrino et al.
DOI: 10.1083/jcb.202303066
PMCID: PMC10515436
PMID: 37737955 [Indexed for MEDLINE]
7. Nat Commun. 2023 Sep 20;14(1):5840. doi: 10.1038/s41467-023-41519-9.
Glycerol contributes to tuberculosis susceptibility in male mice with type 2
diabetes.
Martinez N(1), Smulan LJ(1), Jameson ML(1), Smith CM(2), Cavallo K(1), Bellerose
M(2), Williams J(2), West K(1), Sassetti CM(2), Singhal A(#)(1)(3)(4)(5),
Kornfeld H(#)(6).
Author information:
(1)Department of Medicine, University of Massachusetts Chan Medical School,
Worcester, MA, USA.
(2)Department of Microbiology and Physiological Systems, University of
Massachusetts Chan Medical School, Worcester, MA, USA.
(3)A*STAR Infectious Diseases Labs (ID Labs), Agency for Science, Technology and
Research (A*STAR), Singapore, 138648, Singapore.
(4)Singapore Immunology Network (SIgN), Agency for Science, Technology and
Research (A*STAR), Singapore, 138648, Singapore.
(5)Lee Kong Chian School of Medicine, Nanyang Technological University,
Singapore, 636921, Singapore.
(6)Department of Medicine, University of Massachusetts Chan Medical School,
Worcester, MA, USA. Hardy.Kornfeld@umassmed.edu.
(#)Contributed equally
Diabetes mellitus increases risk for tuberculosis disease and adverse outcomes.
Most people with both conditions have type 2 diabetes, but it is unknown if type
1 and type 2 diabetes have identical effects on tuberculosis susceptibility.
Here we show that male mice receiving a high-fat diet and streptozotocin to
model type 2 diabetes, have higher mortality, more lung pathology, and higher
bacterial burden following Mycobacterium tuberculosis infection compared to mice
treated with streptozotocin or high-fat diet alone. Type 2 diabetes model mice
have elevated plasma glycerol, which is a preferred carbon source for M.
tuberculosis. Infection studies with glycerol kinase mutant M. tuberculosis
reveal that glycerol utilization contributes to the susceptibility of the type 2
diabetes mice. Hyperglycemia impairs protective immunity against M. tuberculosis
in both forms of diabetes, but our data show that elevated glycerol contributes
to an additional adverse effect uniquely relevant to type 2 diabetes.
© 2023. Springer Nature Limited.
DOI: 10.1038/s41467-023-41519-9
PMCID: PMC10511404
PMID: 37730757 [Indexed for MEDLINE]
8. Nat Commun. 2023 Sep 20;14(1):5856. doi: 10.1038/s41467-023-41583-1.
Critical requirement of SOS1 for tumor development and microenvironment
modulation in KRAS(G12D)-driven lung adenocarcinoma.
Baltanás FC(1)(2), García-Navas R(3), Rodríguez-Ramos P(3), Calzada N(3), Cuesta
C(4), Borrajo J(5), Fuentes-Mateos R(3), Olarte-San Juan A(3), Vidaña N(3),
Castellano E(4), Santos E(6).
Author information:
(1)Lab 1. Cancer Research Center, Institute of Cancer Molecular and Cellular
Biology, CSIC-University of Salamanca and CIBERONC, 37007, Salamanca, Spain.
fcalvo@us.es.
(2)Institute of Biomedicine of Seville (IBiS)/"Virgen del Rocío" University
Hospital/CSIC/University of Seville and Department of Medical Physiology and
Biophysics, University of Seville, Seville, Spain. fcalvo@us.es.
(3)Lab 1. Cancer Research Center, Institute of Cancer Molecular and Cellular
Biology, CSIC-University of Salamanca and CIBERONC, 37007, Salamanca, Spain.
…
The impact of genetic ablation of SOS1 or SOS2 is evaluated in a murine model of
KRASG12D-driven lung adenocarcinoma (LUAD). SOS2 ablation shows some protection
during early stages but only SOS1 ablation causes significant, specific long
term increase of survival/lifespan of the KRASG12D mice associated to markedly
reduced tumor burden and reduced populations of cancer-associated fibroblasts,
macrophages and T-lymphocytes in the lung tumor microenvironment (TME). SOS1
ablation also causes specific shrinkage and regression of LUAD tumoral masses
and components of the TME in pre-established KRASG12D LUAD tumors. The critical
requirement of SOS1 for KRASG12D-driven LUAD is further confirmed by means of
intravenous tail injection of KRASG12D tumor cells into SOS1KO/KRASWT mice, or
of SOS1-less, KRASG12D tumor cells into wildtype mice. In silico analyses of
human lung cancer databases support also the dominant role of SOS1 regarding
tumor development and survival in LUAD patients. Our data indicate that SOS1 is
critically required for development of KRASG12D-driven LUAD and confirm the
validity of this RAS-GEF activator as an actionable therapeutic target in KRAS
mutant LUAD.
© 2023. Springer Nature Limited.
DOI: 10.1038/s41467-023-41583-1
PMCID: PMC10511506
PMID: 37730692 [Indexed for MEDLINE]
9. Nat Commun. 2023 Sep 19;14(1):5803. doi: 10.1038/s41467-023-41431-2.
Identification and characterization of endo-α-, exo-α-, and
exo-β-D-arabinofuranosidases degrading lipoarabinomannan and arabinogalactan of
mycobacteria.
Shimokawa M(#)(1), Ishiwata A(#)(2), Kashima T(#)(3), Nakashima C(3), Li J(3),
Fukushima R(3), Sawai N(1), Nakamori M(1), Tanaka Y(1), Kudo A(1), Morikami
S(1), Iwanaga N(1), Akai G(3), Shimizu N(4), Arakawa T(5), Yamada C(6), Kitahara
K(1), Tanaka K(2)(7), Ito Y(2)(8), Fushinobu S(9)(10), Fujita K(11).
Author information:
(1)Faculty of Agriculture, Kagoshima University, Kagoshima, 890-0065, Japan.
(2)Cluster for Pioneering Research, RIKEN, Saitama, 351-0198, Japan.
(3)Department of Biotechnology, The University of Tokyo, Bunkyo-ku, Tokyo,
113-8657, Japan.
…
Erratum in
Nat Commun. 2023 Oct 9;14(1):6299.
The cell walls of pathogenic and acidophilic bacteria, such as Mycobacterium
tuberculosis and Mycobacterium leprae, contain lipoarabinomannan and
arabinogalactan. These components are composed of D-arabinose, the enantiomer of
the typical L-arabinose found in plants. The unique glycan structures of
mycobacteria contribute to their ability to evade mammalian immune responses. In
this study, we identified four enzymes (two GH183 endo-D-arabinanases, GH172
exo-α-D-arabinofuranosidase, and GH116 exo-β-D-arabinofuranosidase) from
Microbacterium arabinogalactanolyticum. These enzymes completely degraded the
complex D-arabinan core structure of lipoarabinomannan and arabinogalactan in a
concerted manner. Furthermore, through biochemical characterization using
synthetic substrates and X-ray crystallography, we elucidated the mechanisms of
substrate recognition and anomer-retaining hydrolysis for the α- and
β-D-arabinofuranosidic bonds in both endo- and exo-mode reactions. The discovery
of these D-arabinan-degrading enzymes, along with the understanding of their
structural basis for substrate specificity, provides valuable resources for
investigating the intricate glycan architecture of mycobacterial cell wall
polysaccharides and their contribution to pathogenicity.
© 2023. Springer Nature Limited.
DOI: 10.1038/s41467-023-41431-2
PMCID: PMC10509167
PMID: 37726269 [Indexed for MEDLINE]
10. Cancer Discov. 2023 Sep 14. doi: 10.1158/2159-8290.CD-23-0436. Online ahead of print.
Neoadjuvant Durvalumab Alone or Combined with Novel Immuno-Oncology Agents in
Resectable Lung Cancer: The Phase 2 NeoCOAST Platform Trial.
Cascone T(1), Kar G(2), Spicer JD(3), Garcia-Campelo R(4), Weder W(5), Daniel
DB(6), Spigel DR(7), Hussein M(8), Mazieres J(9), Oliveira J(10), Yau EH(11),
Spira AI(12), Anagnostou V(13), Mager R(14), Hamid O(14), Cheng LY(14), Zheng
Y(14), Blando J(15), Tan TH(16), Surace M(14), Rodriguez-Canales J(17),
Gopalakrishnan V(15), Sellman BR(14), Grenga I(18), Soo-Hoo Y(14), Kumar R(19),
McGrath L(20), Forde PM(13).
Author information:
(1)The University of Texas MD Anderson Cancer Center, Houston, United States.
(2)AstraZeneca, Cambridge, United Kingdom.
(3)McGill University Health Centre, Montreal, QC, Canada.
…
Neoadjuvant chemo-immunotherapy improves pathological complete response rate and
event-free survival in patients with resectable non-small-cell lung cancer
(NSCLC), versus chemotherapy alone. NeoCOAST was the first randomized,
multi-drug, platform trial to examine novel neoadjuvant immuno-oncology
combinations for patients with resectable NSCLC, using major pathological
response (MPR) as the primary endpoint. Eighty-three patients received a single
cycle of treatment: 26 received durvalumab (anti-PD-L1) monotherapy, 21 received
durvalumab plus oleclumab (anti-CD73), 20 received durvalumab plus monalizumab
(anti-NKG2A), and 16 received durvalumab plus danvatirsen (anti-STAT3 antisense
oligonucleotide). MPR rates were higher for patients in the combination arms,
versus durvalumab alone. Safety profiles for the combinations were similar to
that of durvalumab alone. Multiplatform immune profiling suggested improved MPR
rates in the durvalumab plus oleclumab and durvalumab plus monalizumab arms were
associated with enhanced effector immune infiltration of tumors, interferon
responses and markers of tertiary lymphoid structure formation, and systemic
functional immune-cell activation.
DOI: 10.1158/2159-8290.CD-23-0436
PMID: 37707791
11. Lancet Infect Dis. 2023 Sep 8:S1473-3099(23)00372-9. doi:
10.1016/S1473-3099(23)00372-9. Online ahead of print.
Burden of tuberculosis among vulnerable populations worldwide: an overview of
systematic reviews.
Litvinjenko S(1), Magwood O(2), Wu S(1), Wei X(3).
Author information:
(1)Dalla Lana School of Public Health, University of Toronto, Toronto, ON,
Canada.
(2)Bruyère Research Institute, Ottawa, ON, Canada; Interdisciplinary School of
Health Sciences, Faculty of Health Sciences, University of Ottawa, Ottawa, ON,
Canada.
(3)Dalla Lana School of Public Health, University of Toronto, Toronto, ON,
Canada. Electronic address: xiaolin.wei@utoronto.ca.
Erratum in
Lancet Infect Dis. 2023 Nov;23(11):e467.
BACKGROUND: Tuberculosis is a communicable disease of public health concern that
inequitably impacts the most vulnerable populations worldwide. Vulnerable
populations are those with a high risk for tuberculosis disease and whose
disadvantaged or marginalised socioeconomic position limits their access to the
health system. We conducted an overview of reviews that aimed to assess the
burden (ie, prevalence and incidence) of tuberculosis disease among 12
vulnerable populations globally.
METHODS: We did an overview of reviews using a systematic search in MEDLINE,
Embase, and the Cochrane Database for Systematic Reviews for articles published
in English, French, and Chinese, from Jan 1, 2010 to March 8, 2023. We did an
initial search on Oct 28, 2021, and updated our search on March 8, 2023. We
included systematic and scoping reviews reporting on the prevalence or incidence
of active tuberculosis among 12 vulnerable populations. Evidence gaps were
supplemented with primary or secondary database studies. Study characteristics
and outcome data related to tuberculosis burden were tabulated, including
prevalence ratios and incidence rate ratios, and evidence was synthesised
narratively. This trial is registered with PROSPERO (CRD42022324421).
RESULTS: We screened 13 169 citations and included 44 publications (23 reviews
and 21 primary or database studies) in the final synthesis. The
comprehensiveness and methodological quality of the evidence differed across
population groups. Prevalence of more than 1000 cases per 100 000 were reported
in all vulnerable populations. On the basis of pooled estimates, prevalence
ratios were often more than 25 among people experiencing homelessness,
incarcerated populations, refugees, asylum seekers, and people living with HIV
compared with the general population. Incidence was infrequently reported, with
the best-available incidence rate ratios documented for people who were
incarcerated. There was scarce evidence specific to miners, nomadic populations,
sex workers, men who have sex with men, and transgender individuals.
INTERPRETATION: The burden of tuberculosis is substantially higher among
vulnerable populations than general populations, suggesting a need for improved
integration of these groups, including dedicated efforts for their
identification, targeted screening and prevention measures, as well as treatment
support.
FUNDING: WHO.
Copyright © 2023 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1473-3099(23)00372-9
PMID: 37696278
12. PLoS Med. 2023 Sep 8;20(9):e1004278. doi: 10.1371/journal.pmed.1004278.
eCollection 2023 Sep.
Tuberculosis prevalence after 4 years of population-wide systematic TB symptom
screening and universal testing and treatment for HIV in the HPTN 071 (PopART)
community-randomised trial in Zambia and South Africa: A cross-sectional survey
(TREATS).
Klinkenberg E(1)(2)(3), Floyd S(1), Shanaube K(4), Mureithi L(5), Gachie
T(1)(4), de Haas P(3), Kosloff B(1)(4), Dodd PJ(6), Ruperez M(1), Wapamesa C(4),
Burnett JM(5), Kalisvaart N(3), Kasese N(4), Vermaak R(5), Schaap A(1)(4),
Fidler S(7), Hayes R(1), Ayles H(1)(4); TREATS study team.
Author information:
(1)London School of Hygiene & Tropical Medicine (LSHTM), London, United Kingdom.
(2)Department of Global Health and Amsterdam Institute for Global Health and
Development, Amsterdam University Medical Center, Amsterdam, the Netherlands.
(3)KNCV Tuberculosis Foundation, Hague, the Netherlands.
…
BACKGROUND: Tuberculosis (TB) prevalence remains persistently high in many
settings, with new or expanded interventions required to achieve substantial
reductions. The HIV Prevention Trials Network (HPTN) 071 (PopART)
community-randomised trial randomised 14 communities to receive the "PopART"
intervention during 2014 to 2017 (7 arm A and 7 arm B communities) and 7
communities to receive standard-of-care (arm C). The intervention was delivered
door-to-door by community HIV care providers (CHiPs) and included universal HIV
testing, facilitated linkage to HIV care at government health clinics, and
systematic TB symptom screening. The Tuberculosis Reduction through Expanded
Anti-retroviral Treatment and Screening (TREATS) study aimed to measure the
impact of delivering the PopART intervention on TB outcomes, in communities with
high HIV and TB prevalence.
METHODS AND FINDINGS: The study population of the HPTN 071 (PopART) trial
included individuals aged ≥15 years living in 21 urban and peri-urban
communities in Zambia and South Africa, with a total population of approximately
1 million and an adult HIV prevalence of around 15% at the time of the trial.
Two sputum samples for TB testing were provided to CHiPs by individuals who
reported ≥1 TB suggestive symptom (a cough for ≥2 weeks, unintentional weight
loss ≥1.5 kg in the last month, or current night sweats) or that a household
member was currently on TB treatment. Antiretroviral therapy (ART) was offered
universally at clinics in arm A and according to local guidelines in arms B and
C. The TREATS study was conducted in the same 21 communities as the HPTN 071
(PopART) trial between 2017 and 2022, and TB prevalence was a co-primary
endpoint of the TREATS study. The primary comparison was between the PopART
intervention (arms A and B combined) and the standard-of-care (arm C). During
2019 to 2021, a TB prevalence survey was conducted among randomly selected
individuals aged ≥15 years (approximately 1,750 per community in arms A and B,
approximately 3,500 in arm C). Participants were screened on TB symptoms and
chest X-ray, with diagnostic testing using Xpert-Ultra followed by culture for
individuals who screened positive. Sputum eligibility was determined by the
presence of a cough for ≥2 weeks, or ≥2 of 5 "TB suggestive" symptoms (cough,
weight loss for ≥4 weeks, night sweats, chest pain, and fever for ≥2 weeks), or
chest X-ray CAD4TBv5 score ≥50, or no available X-ray results. TB prevalence was
compared between trial arms using standard methods for cluster-randomised
trials, with adjustment for age, sex, and HIV status, and multiple imputation
was used for missing data on prevalent TB. Among 83,092 individuals who were
eligible for the survey, 49,556 (59.6%) participated, 8,083 (16.3%) screened
positive, 90.8% (7,336/8,083) provided 2 sputum samples for Xpert-Ultra testing,
and 308 (4.2%) required culture confirmation. Overall, estimated TB prevalence
was 0.92% (457/49,556). The geometric means of 7 community-level prevalence
estimates were 0.91%, 0.70%, and 0.69% in arms A, B, and C, respectively, with
no evidence of a difference comparing arms A and B combined with arm C (adjusted
prevalence ratio 1.14, 95% confidence interval, CI [0.67, 1.95], p = 0.60). TB
prevalence was higher among people living with HIV than HIV-negative
individuals, with an age-sex-community adjusted odds ratio of 2.29 [95% CI 1.54,
3.41] in Zambian communities and 1.61 [95% CI 1.13, 2.30] in South African
communities. The primary limitations are that the study was powered to detect
only large reductions in TB prevalence in the intervention arm compared with
standard-of-care, and the between-community variation in TB prevalence was
larger than anticipated.
CONCLUSIONS: There was no evidence that the PopART intervention reduced TB
prevalence. Systematic screening for TB that is based on symptom screening alone
may not be sufficient to achieve a large reduction in TB prevalence over a
period of several years. Including chest X-ray screening alongside TB symptom
screening could substantially increase the sensitivity of systematic screening
for TB.
TRIAL REGISTRATION: The TREATS study was registered with ClinicalTrials.gov
Identifier: NCT03739736 on November 14, 2018. The HPTN 071 (PopART) trial was
registered at ClinicalTrials.gov under number NCT01900977 on July 17, 2013.
Copyright: © 2023 Klinkenberg et al. This is an open access article distributed
under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the
original author and source are credited.
DOI: 10.1371/journal.pmed.1004278
PMCID: PMC10490889
PMID: 37682971 [Indexed for MEDLINE]
13. Nat Commun. 2023 Sep 7;14(1):5507. doi: 10.1038/s41467-023-41246-1.
Heterogeneity in M. tuberculosis β-lactamase inhibition by Sulbactam.
Malla TN(1), Zielinski K(2), Aldama L(3),…
Author information:
(1)Physics Department, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
(2)School of Applied and Engineering Physics, Cornell University, Ithaca, NY,
USA.
(3)Department of Biology, Northeastern Illinois University, Chicago, IL, USA.
…
Update of
Res Sq. 2023 Jan 10;:
For decades, researchers have elucidated essential enzymatic functions on the
atomic length scale by tracing atomic positions in real-time. Our work builds on
possibilities unleashed by mix-and-inject serial crystallography (MISC) at X-ray
free electron laser facilities. In this approach, enzymatic reactions are
triggered by mixing substrate or ligand solutions with enzyme microcrystals.
Here, we report in atomic detail (between 2.2 and 2.7 Å resolution) by
room-temperature, time-resolved crystallography with millisecond time-resolution
(with timepoints between 3 ms and 700 ms) how the Mycobacterium tuberculosis
enzyme BlaC is inhibited by sulbactam (SUB). Our results reveal ligand binding
heterogeneity, ligand gating, cooperativity, induced fit, and conformational
selection all from the same set of MISC data, detailing how SUB approaches the
catalytic clefts and binds to the enzyme noncovalently before reacting to a
trans-enamine. This was made possible in part by the application of singular
value decomposition to the MISC data using a program that remains functional
even if unit cell parameters change up to 3 Å during the reaction.
© 2023. Springer Nature Limited.
DOI: 10.1038/s41467-023-41246-1
PMCID: PMC10485065
PMID: 37679343 [Indexed for MEDLINE]
14. Nat Commun. 2023 Sep 6;14(1):5472. doi: 10.1038/s41467-023-40545-x.
NAD(H) homeostasis underlies host protection mediated by glycolytic myeloid
cells in tuberculosis.
Pacl HT(1), Chinta KC(1), Reddy VP(1), Nadeem S(1), Sevalkar RR(1), Nargan K(2),
Lumamba K(2), Naidoo T(2)(3), Glasgow JN(1), Agarwal A(4), Steyn AJC(5)(6)(7).
Author information:
(1)Department of Microbiology, University of Alabama at Birmingham, Birmingham,
AL, USA.
(2)Africa Health Research Institute, University of KwaZulu Natal, Durban, South
Africa.
(3)Department of Laboratory Medicine and Pathology, Walter Sisulu University,
Eastern Cape, South Africa.
…
Mycobacterium tuberculosis (Mtb) disrupts glycolytic flux in infected myeloid
cells through an unclear mechanism. Flux through the glycolytic pathway in
myeloid cells is inextricably linked to the availability of NAD+, which is
maintained by NAD+ salvage and lactate metabolism. Using lung tissue from
tuberculosis (TB) patients and myeloid deficient LDHA (LdhaLysM-/-) mice, we
demonstrate that glycolysis in myeloid cells is essential for protective
immunity in TB. Glycolytic myeloid cells are essential for the early recruitment
of multiple classes of immune cells and IFNγ-mediated protection. We identify
NAD+ depletion as central to the glycolytic inhibition caused by Mtb. Lastly, we
show that the NAD+ precursor nicotinamide exerts a host-dependent,
antimycobacterial effect, and that nicotinamide prophylaxis and treatment reduce
Mtb lung burden in mice. These findings provide insight into how Mtb alters host
metabolism through perturbation of NAD(H) homeostasis and reprogramming of
glycolysis, highlighting this pathway as a potential therapeutic target.
© 2023. Springer Nature Limited.
DOI: 10.1038/s41467-023-40545-x
PMCID: PMC10482943
PMID: 37673914 [Indexed for MEDLINE]
15. PLoS Med. 2023 Sep 6;20(9):e1004285. doi: 10.1371/journal.pmed.1004285.
eCollection 2023 Sep.
Cost-effectiveness analysis of interventions to improve diagnosis and preventive
therapy for paediatric tuberculosis in 9 sub-Saharan African countries: A
modelling study.
Mafirakureva N(1), Mukherjee S(2), de Souza M(2), Kelly-Cirino C(2), Songane
MJP(2), Cohn J(3), Lemaire JF(2), Casenghi M(2), Dodd PJ(1).
Author information:
(1)Sheffield Centre for Health and Related Research, University of Sheffield,
Sheffield, United Kingdom.
(2)Elizabeth Glaser Pediatric AIDS Foundation (EGPAF), Washington, DC, United
States of America.
(3)Division of Infectious Diseases, University of Pennsylvania School of
Medicine, Philadelphia, Pennsylvania, United States of America.
BACKGROUND: Over 1 million children aged 0 to 14 years were estimated to develop
tuberculosis in 2021, resulting in over 200,000 deaths. Practical interventions
are urgently needed to improve diagnosis and antituberculosis treatment (ATT)
initiation in children aged 0 to 14 years and to increase coverage of
tuberculosis preventive therapy (TPT) in children at high risk of developing
tuberculosis disease. The multicountry CaP-TB intervention scaled up
facility-based intensified case finding and strengthened household contact
management and TPT provision at HIV clinics. To add to the limited
health-economic evidence on interventions to improve ATT and TPT in children, we
evaluated the cost-effectiveness of the CaP-TB intervention.
METHODS AND FINDINGS: We analysed clinic-level pre/post data to quantify the
impact of the CaP-TB intervention on ATT and TPT initiation across 9 sub-Saharan
African countries. Data on tuberculosis diagnosis and ATT/TPT initiation counts
with corresponding follow-up time were available for 146 sites across the 9
countries prior to and post project implementation, stratified by 0 to 4 and 5
to 14 year age-groups. Preintervention data were retrospectively collected from
facility registers for a 12-month period, and intervention data were
prospectively collected from December 2018 to June 2021 using project-specific
forms. Bayesian generalised linear mixed-effects models were used to estimate
country-level rate ratios for tuberculosis diagnosis and ATT/TPT initiation. We
analysed project expenditure and cascade data to determine unit costs of
intervention components and used mathematical modelling to project health
impact, health system costs, and cost-effectiveness. Overall, ATT and TPT
initiation increased, with country-level incidence rate ratios varying between
0.8 (95% uncertainty interval [UI], 0.7 to 1.0) and 2.9 (95% UI, 2.3 to 3.6) for
ATT and between 1.6 (95% UI, 1.5 to 1.8) and 9.8 (95% UI, 8.1 to 11.8) for TPT.
We projected that for every 100 children starting either ATT or TPT at baseline,
the intervention package translated to between 1 (95% UI, -1 to 3) and 38 (95%
UI, 24 to 58) deaths averted, with a median incremental cost-effectiveness ratio
(ICER) of US$634 per disability-adjusted life year (DALY) averted. ICERs ranged
between US$135/DALY averted in Democratic of the Congo and US$6,804/DALY averted
in Cameroon. The main limitation of our study is that the impact is based on
pre/post comparisons, which could be confounded.
CONCLUSIONS: In most countries, the CaP-TB intervention package improved
tuberculosis treatment and prevention services for children aged under 15 years,
but large variation in estimated impact and ICERs highlights the importance of
local context.
TRIAL REGISTRATION: This evaluation is part of the TIPPI study, registered with
ClinicalTrials.gov (NCT03948698).
Copyright: © 2023 Mafirakureva et al. This is an open access article distributed
under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the
original author and source are credited.
DOI: 10.1371/journal.pmed.1004285
PMCID: PMC10511115
PMID: 37672524 [Indexed for MEDLINE]
16. Nat Commun. 2023 Sep 2;14(1):5332. doi: 10.1038/s41467-023-40813-w.
Atezolizumab plus stereotactic ablative radiotherapy for medically inoperable
patients with early-stage non-small cell lung cancer: a multi-institutional
phase I trial.
Monjazeb AM(#)(1), Daly ME(#)(2), Luxardi G(1), Maverakis E(1), Merleev AA(1),
Marusina AI(1), Borowsky A(1), Mirhadi A(3), Shiao SL(3), Beckett L(1), Chen
S(1), Eastham D(4), Li T(1), Vick LV(1), McGee HM(5), Lara F(1), Garcia L(1),
Morris LA(1), Canter RJ(1), Riess JW(1), Schalper KA(6), Murphy WJ(1), Kelly
K(1)(7).
Author information:
(1)UC Davis Health, Sacramento, CA, 95817, USA.
(2)UC Davis Health, Sacramento, CA, 95817, USA. medaly@ucdavis.edu.
(3)Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
…
Stereotactic ablative radiotherapy (SABR) is a standard-of-care for
medically-inoperable-early-stage non-small cell lung cancer (NSCLC). One third
of patients progress and chemotherapy is rarely used in this population. We
questioned if addition of the immune-checkpoint-inhibitor (ICI) atezolizumab to
standard-of-care SABR can improve outcomes. We initiated a multi-institutional
single-arm phase I study (NCT02599454) enrolling twenty patients with the
primary endpoint of maximum tolerated dose (MTD); secondary endpoints of safety
and efficacy; and exploratory mechanistic correlatives. Treatment is well
tolerated and full dose atezolizumab (1200 mg) is the MTD. Efficacy signals
include early responses (after 2 cycles of ICI, before initiation of SABR) in
17% of patients. Biomarkers of functional adaptive immunity, including T cell
activation in the tumor and response to ex-vivo stimulation by circulating T
cells, are highly predictive of benefit. These results require validation and
are being tested in a phase III randomized trial.
© 2023. Springer Nature Limited.
DOI: 10.1038/s41467-023-40813-w
PMCID: PMC10474145
PMID: 37658083 [Indexed for MEDLINE]
17. Nat Commun. 2023 Sep 1;14(1):5312. doi: 10.1038/s41467-023-40976-6.
Addressing mechanism bias in model-based impact forecasts of new tuberculosis
vaccines.
Tovar M(1)(2), Moreno Y(1)(2)(3), Sanz J(4)(5).
Author information:
(1)Institute for Biocomputation and Physics of Complex Systems (BIFI),
University of Zaragoza, Zaragoza, 50009, Spain.
(2)Department of Theoretical Physics, University of Zaragoza, Zaragoza, 50009,
Spain.
(3)Centai Institute S.p.A, 10138, Torino, Italy.
…
In tuberculosis (TB) vaccine development, multiple factors hinder the design and
interpretation of the clinical trials used to estimate vaccine efficacy. The
complex transmission chain of TB includes multiple routes to disease, making it
hard to link the vaccine efficacy observed in a trial to specific protective
mechanisms. Here, we present a Bayesian framework to evaluate the compatibility
of different vaccine descriptions with clinical trial outcomes, unlocking impact
forecasting from vaccines whose specific mechanisms of action are unknown.
Applying our method to the analysis of the M72/AS01E vaccine trial -conducted on
IGRA+ individuals- as a case study, we found that most plausible models for this
vaccine needed to include protection against, at least, two over the three
possible routes to active TB classically considered in the literature: namely,
primary TB, latent TB reactivation and TB upon re-infection. Gathering new data
regarding the impact of TB vaccines in various epidemiological settings would be
instrumental to improve our model estimates of the underlying mechanisms.
© 2023. Springer Nature Limited.
DOI: 10.1038/s41467-023-40976-6
PMCID: PMC10474143
PMID: 37658078 [Indexed for MEDLINE]
18. J Clin Oncol. 2023 Sep 1:JCO2300179. doi: 10.1200/JCO.23.00179. Online ahead of print.
Five-Year Overall Survival Analysis of the JIPANG Study: Pemetrexed or
Vinorelbine Plus Cisplatin for Resected Stage II-IIIA Nonsquamous Non-Small-Cell
Lung Cancer.
Kenmotsu H(1), Yamamoto N(2), Misumi T(3), Yoh K(4), Saito H(5), Sugawara S(6),
Yamazaki K(7), Nakagawa K(8), Sugio K(9), Seto T(10), Toyooka S(11), Date H(12),
Mitsudomi T(13), Okamoto I(14), Yokoi K(15), Saka H(16), Okamoto H(17),
Takiguchi Y(18), Takahashi T(1), Tsuboi M(19).
Author information:
(1)Division of Thoracic Oncology, Shizuoka Cancer Center, Nagaizumi-cho
Sunto-gun, Japan.
(2)Internal Medicine III, Wakayama Medical University, Wakayama, Japan.
(3)Department of Data Science, National Cancer Center Hospital East, Kashiwa,
Japan.
…
Clinical trials frequently include multiple end points that mature at different
times. The initial report, typically based on the primary end point, may be
published when key planned co-primary or secondary analyses are not yet
available. Clinical Trial Updates provide an opportunity to disseminate
additional results from studies, published in JCO or elsewhere, for which the
primary end point has already been reported.The JIPANG study is an open-label
phase III trial evaluating the efficacy of pemetrexed plus cisplatin (PemP)
versus vinorelbine plus cisplatin (NP) as adjuvant chemotherapy in patients with
stage II-IIIA nonsquamous non-small-cell lung cancer (NSCLC). Here, we report
the long follow-up overall survival (OS) data. Eligible patients were randomly
assigned to receive either PemP or NP. The primary end point was recurrence-free
survival (RFS), and the secondary end point included OS. This analysis was
performed using data collected 5 years after the last patient enrollment. Among
804 patients enrolled, 783 patients were eligible (384 for NP and 389 for PemP).
The updated median RFS was 37.5 months in the NP arm and 43.4 months in the PemP
arm with a hazard ratio of 0.95 (95% CI, 0.79 to 1.14). At a median follow-up of
77.3 months, the OS rates at 3 and 5 years were 84.1% and 75.6% versus 87.0% and
75.0% with a hazard ratio of 1.04 (95% CI, 0.81 to 1.34). This long-term
follow-up analysis showed that PemP had similar efficacy to NP in both RFS and
OS for this population, with one of the longest OS data compared with the
historical data.
DOI: 10.1200/JCO.23.00179
PMID: 37656928
19. J Clin Invest. 2023 Sep 1;133(17):e163128. doi: 10.1172/JCI163128.
Autotaxin suppresses cytotoxic T cells via LPAR5 to promote anti-PD-1 resistance
in non-small cell lung cancer.
Konen JM(1)(2), Rodriguez BL(1), Wu H(1), Fradette JJ(1), Gibson L(1)(3), Diao
L(4), Wang J(4), Schmidt S(5), Wistuba II(6), Zhang J(1), Gibbons DL(1)(7).
Author information:
(1)Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD
Anderson Cancer Center, Houston, Texas, USA.
(2)Department of Hematology and Medical Oncology, Emory University, Atlanta,
Georgia, USA.
(3)Department of Surgical Oncology.
…
Non-small cell lung cancers that harbor concurrent KRAS and TP53 (KP) mutations
are immunologically warm tumors with partial responsiveness to anti-PD-(L)1
blockade; however, most patients observe little or no durable clinical benefit.
To identify novel tumor-driven resistance mechanisms, we developed a panel of KP
murine lung cancer models with intrinsic resistance to anti-PD-1 and queried
differential gene expression between these tumors and anti-PD-1-sensitive
tumors. We found that the enzyme autotaxin (ATX), and the metabolite it
produces, lysophosphatidic acid (LPA), were significantly upregulated in
resistant tumors and that ATX directly modulated antitumor immunity, with its
expression negatively correlating with total and effector tumor-infiltrating
CD8+ T cells. Pharmacological inhibition of ATX, or the downstream receptor
LPAR5, in combination with anti-PD-1 was sufficient to restore the antitumor
immune response and efficaciously control lung tumor growth in multiple KP tumor
models. Additionally, ATX was significantly correlated with inflammatory gene
signatures, including a CD8+ cytolytic score in multiple lung adenocarcinoma
patient data sets, suggesting that an activated tumor-immune microenvironment
upregulates ATX and thus provides an opportunity for cotargeting to prevent
acquired resistance to anti-PD-1 treatment. These data reveal the ATX/LPA axis
as an immunosuppressive pathway that diminishes the immune checkpoint blockade
response in lung cancer.
DOI: 10.1172/JCI163128
PMCID: PMC10471170
PMID: 37655662 [Indexed for MEDLINE]
20. Adv Mater. 2023 Oct;35(42):e2303718. doi: 10.1002/adma.202303718. Epub 2023 Sep 20.
Non-Pore Dependent and MMP-9 Responsive Gelatin/Silk Fibroin Composite
Microparticles as Universal Delivery Platform for Inhaled Treatment of Lung
Cancer.
Gou S(1), Wang G(2), Zou Y(1), Geng W(1), He T(1), Qin Z(1), Che L(2), Feng
Q(1), Cai K(1).
Author information:
(1)Key laboratory of Biorheological Science and Technology, Ministry of
Educations, Collage of Bioengineering, Chongqing University, Chongqing, 40044,
China.
(2)Department of Orthopedic, Shanghai General Hospital, Shanghai Jiao Tong
University School of Medicine, 200080, Shanghai, China.
Developing a drug delivery platform that possesses universal drug loading
capacity to meet various requirements of cancer treatment is a challenging yet
interesting task. Herein, a self-assembled gelatin/silk fibroin composite (GSC)
particle based drug delivery system is developed via microphase separation
followed by desolvation process. Thanks to its preassembled microphase stage,
this GSC system is suitable for varying types of drugs. The desolvation process
fix drugs inside GSC rapidly and densify the GSC structure, thereby achieving
efficient drug loading and providing comprehensive protection for loaded drugs.
Actually, the size of this brand-new non-pore dependent drug delivery system can
be easily adjusted from 100 nm to 20 µm to fit different scenarios. This work
selects GSC with 3 µm diameter as the universal inhaled drug delivery platform,
which shows an excellent transmucosal penetration and lung retention ability.
Additionally, the MMP-9 sensitive degradation property of GSC enhances the
targeted efficiency of drugs and reduces side effects. Intestinally, GSC can
self-amplify the regulation of innate immunity to reverse the cancerous
microenvironment into an antitumor niche, significantly improving the
therapeutic effect of drugs. This study of GSC universal drug platform provides
a new direction to develop the next-generation of drug delivery system for lung
cancer.
© 2023 Wiley-VCH GmbH.
DOI: 10.1002/adma.202303718
PMID: 37625141 [Indexed for MEDLINE]
21. J Exp Med. 2023 Sep 4;220(9):e20230859. doi: 10.1084/jem.20230859. Epub 2023 Aug 8.
A half-century of research on tuberculosis: Successes and challenges.
Bloom BR(1).
Author information:
(1)Immunology and Infectious Diseases, Harvard T.H. Chan School of Public
Health, Boston, MA, USA.
Great progress has been made over the past half-century, but TB remains a
formidable global health problem, particularly in low- and middle-income
countries. Understanding the mechanisms of pathogenesis and necessary and
sufficient conditions for protection are critical. The need for inexpensive and
sensitive point-of-care diagnostic tests for earlier detection of infection and
disease, shorter and less-toxic drug regimens for drug-sensitive and -resistant
TB, and a more effective vaccine than BCG is immense. New and better tools,
greater support for international research, collaborations, and training will be
required to dramatically reduce the burden of this devastating disease which
still kills 1.6 million people annually.
© 2023 Bloom.
DOI: 10.1084/jem.20230859
PMCID: PMC10407785
PMID: 37552470 [Indexed for MEDLINE]
22. Nat Rev Clin Oncol. 2023 Sep;20(9):624-639. doi: 10.1038/s41571-023-00798-3.
Epub 2023 Jul 21.
The global burden of lung cancer: current status and future trends.
Leiter A(1), Veluswamy RR(2)(3), Wisnivesky JP(4).
Author information:
(1)Division of Endocrinology, Diabetes, and Bone Diseases, Department of
Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
amanda.leiter@mssm.edu.
(2)Division of Hematology and Oncology, Department of Medicine, Icahn School of
Medicine at Mount Sinai, New York, NY, USA.
(3)Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York,
NY, USA.
…
Lung cancer is the leading cause of cancer-related death worldwide. However,
lung cancer incidence and mortality rates differ substantially across the world,
reflecting varying patterns of tobacco smoking, exposure to environmental risk
factors and genetics. Tobacco smoking is the leading risk factor for lung
cancer. Lung cancer incidence largely reflects trends in smoking patterns, which
generally vary by sex and economic development. For this reason, tobacco control
campaigns are a central part of global strategies designed to reduce lung cancer
mortality. Environmental and occupational lung cancer risk factors, such as
unprocessed biomass fuels, asbestos, arsenic and radon, can also contribute to
lung cancer incidence in certain parts of the world. Over the past decade,
large-cohort clinical studies have established that low-dose CT screening
reduces lung cancer mortality, largely owing to increased diagnosis and
treatment at earlier disease stages. These data have led to recommendations that
individuals with a high risk of lung cancer undergo screening in several
economically developed countries and increased implementation of screening
worldwide. In this Review, we provide an overview of the global epidemiology of
lung cancer. Lung cancer risk factors and global risk reduction efforts are also
discussed. Finally, we summarize lung cancer screening policies and their
implementation worldwide.
© 2023. Springer Nature Limited.
DOI: 10.1038/s41571-023-00798-3
PMID: 37479810 [Indexed for MEDLINE]
23 J Clin Oncol. 2023 Sep 20;41(27):4430-4432. doi: 10.1200/JCO.23.01261. Epub 2023 Jul 20.
Management of Stage III Non-Small-Cell Lung Cancer: ASCO Guideline Rapid
Recommendation Update.
Singh N(1), Daly ME(2), Ismaila N(3); Management of Stage III NSCLC Guideline
Expert Panel.
Collaborators: Daly ME, Singh N, Antonoff MB, Arenberg DA, Bradley J, David E,
Detterbeck F, Früh M, Gubens MA, Moore AC, Padda SK, Patel JD, Phillips T, Qin
A, Robinson C, Simone CB 2nd.
Author information:
(1)Postgraduate Institute of Medical Education & Research, Chandigarh, India.
(2)University of California Davis Comprehensive Cancer Center, Sacramento, CA.
(3)American Society of Clinical Oncology, Alexandria, VA.
ASCO Rapid Recommendations Updates highlight revisions to select ASCO guideline
recommendations as a response to the emergence of new and practice-changing
data. The rapid updates are supported by an evidence review and follow the
guideline development processes outlined in the ASCO Guideline Methodology
Manual. The goal of these articles is to disseminate updated recommendations, in
a timely manner, to better inform health practitioners and the public on the
best available cancer care options. See the Appendix for disclaimers and other
important information (Appendix 1 and Appendix 2, online only).
DOI: 10.1200/JCO.23.01261
PMID: 37471673 [Indexed for MEDLINE]
24. J Clin Oncol. 2023 Sep 10;41(26):4218-4225. doi: 10.1200/JCO.23.00152. Epub 2023 Jun 29.
Safety, Tolerability, and Antitumor Activity of Zipalertinib Among Patients With
Non-Small-Cell Lung Cancer Harboring Epidermal Growth Factor Receptor Exon 20
Insertions.
Piotrowska Z(1), Tan DS(2), Smit EF(3), Spira AI(4), Soo RA(5), Nguyen D(6), Lee
VH(7), Yang JC(8), Velcheti V(9), Wrangle JM(10), Socinski MA(11), Koczywas
M(6), Janik JE(12), Jones J(12), Yu HA(13).
Author information:
(1)Massachusetts General Hospital, Boston, MA.
(2)National Cancer Centre Singapore, Singapore, Singapore.
(3)Department of Pulmonary Diseases, Leiden University Medical Center, Leiden,
the Netherlands.
…
Comment in
J Clin Oncol. 2023 Sep 10;41(26):4200-4203.
PURPOSE: Although several agents targeting epidermal growth factor receptor
(EGFR) exon 20 insertions (ex20ins) have recently been approved by the US Food
and Drug Administration, toxicities related to the inhibition of wild-type (WT)
EGFR are common with these agents and affect overall tolerability. Zipalertinib
(CLN-081, TAS6417) is an oral EGFR tyrosine kinase inhibitor (TKI) with a novel
pyrrolopyrimidine scaffold leading to enhanced selectivity for EGFR
ex20ins-mutant versus WT EGFR with potent inhibition of cell growth in EGFR
ex20ins-positive cell lines.
METHODS: This phase 1/2a study of zipalertinib enrolled patients with recurrent
or metastatic EGFR ex20ins-mutant non-small-cell lung cancer (NSCLC) previously
treated with platinum-based chemotherapy.
RESULTS: Seventy-three patients were treated with zipalertinib at dose levels
including 30, 45, 65, 100, and 150 mg orally twice a day. Patients were
predominantly female (56%), had a median age of 64 years, and were heavily
pretreated (median previous systemic therapies 2, range 1-9). Thirty six percent
of patients had received previous non-ex20ins EGFR TKIs and 3/73 (4.1%) patients
received previous EGFR ex20ins TKIs. The most frequently reported
treatment-related adverse events of any grade included rash (80%), paronychia
(32%), diarrhea (30%), and fatigue (21%). No cases of grade 3 or higher
drug-related rash or diarrhea were observed at 100 mg twice a day or below.
Objective responses occurred across all zipalertinib dose levels tested, with
confirmed partial response (PR) observed in 28/73 (38.4%) response-evaluable
patients. Confirmed PRs were seen in 16/39 (41%) response-evaluable patients at
the dose of 100 mg twice a day.
CONCLUSION: Zipalertinib has encouraging preliminary antitumor activity in
heavily pretreated patients with EGFR ex20ins-mutant NSCLC, with an acceptable
safety profile, including low frequency of high-grade diarrhea and rash.
DOI: 10.1200/JCO.23.00152
PMID: 37384848 [Indexed for MEDLINE]
