2022年
No.6
Filters applied: from 2022/6/1 - 2022/6/30.
1. Science. 2022 Jun 24;376(6600):eabh2841. doi: 10.1126/science.abh2841. Epub 2022
Jun 24.
Tumor necrosis factor induces pathogenic mitochondrial ROS in tuberculosis
through reverse electron transport.
Roca FJ(1), Whitworth LJ(1)(2), Prag HA(3), Murphy MP(1)(3), Ramakrishnan
L(1)(2).
Author information:
(1)Molecular Immunity Unit, Cambridge Institute of Therapeutic Immunology and
Infectious Diseases, Department of Medicine, University of Cambridge, Cambridge
CB2 0AW, UK.
(2)MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.
(3)MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge CB2 0XY,
UK.
Tumor necrosis factor (TNF) is a critical host resistance factor against
tuberculosis. However, excess TNF produces susceptibility by increasing
mitochondrial reactive oxygen species (mROS), which initiate a signaling cascade
to cause pathogenic necrosis of mycobacterium-infected macrophages. In
zebrafish, we identified the mechanism of TNF-induced mROS in tuberculosis.
Excess TNF in mycobacterium-infected macrophages elevates mROS production by
reverse electron transport (RET) through complex I. TNF-activated cellular
glutamine uptake leads to an increased concentration of succinate, a Krebs cycle
intermediate. Oxidation of this elevated succinate by complex II drives RET,
thereby generating the mROS superoxide at complex I. The complex I inhibitor
metformin, a widely used antidiabetic drug, prevents TNF-induced mROS and
necrosis of Mycobacterium tuberculosis-infected zebrafish and human macrophages;
metformin may therefore be useful in tuberculosis therapy.
DOI: 10.1126/science.abh2841
PMCID: PMC7612974
PMID: 35737799 [Indexed for MEDLINE]
2. CA Cancer J Clin. 2022 Jun 23. doi: 10.3322/caac.21731. Online ahead of print.
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;72:000-000.
© 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
3. N Engl J Med. 2022 Jul 14;387(2):120-131. doi: 10.1056/NEJMoa2204619. Epub 2022
Jun 3.
Adagrasib in Non-Small-Cell Lung Cancer Harboring a KRAS(G12C) Mutation.
Jänne PA(1), Riely GJ(1), Gadgeel SM(1), Heist RS(1), Ou SI(1), Pacheco JM(1),
Johnson ML(1), Sabari JK(1), Leventakos K(1), Yau E(1), Bazhenova L(1), Negrao
MV(1), Pennell NA(1), Zhang J(1), Anderes K(1), Der-Torossian H(1), Kheoh T(1),
Velastegui K(1), Yan X(1), Christensen JG(1), Chao RC(1), Spira AI(1).
Author information:
(1)From the Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute
(P.A.J.), and Massachusetts General Hospital (R.S.H.) - both in Boston; the
Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of
Medicine, Memorial Sloan Kettering Cancer Center, and Weill Cornell Medical
College (G.J.R.), and Perlmutter Cancer Center, New York University Langone
Health (J.K.S.), New York, and the Department of Medicine, Roswell Park
Comprehensive Cancer Center, Buffalo (E.Y.) - all in New York; the Henry Ford
Cancer Institute, Detroit (S.M.G.); the University of California Irvine School
of Medicine, Chao Family Comprehensive Cancer Center, Orange (S.-H.I.O.),…
Comment in
N Engl J Med. 2022 Jul 14;387(2):180-183.
N Engl J Med. 2022 Jul 14;387(2):184-186.
BACKGROUND: Adagrasib, a KRASG12C inhibitor, irreversibly and selectively binds
KRASG12C, locking it in its inactive state. Adagrasib showed clinical activity
and had an acceptable adverse-event profile in the phase 1-1b part of the
KRYSTAL-1 phase 1-2 study.
METHODS: In a registrational phase 2 cohort, we evaluated adagrasib (600 mg
orally twice daily) in patients with KRASG12C -mutated non-small-cell lung
cancer (NSCLC) previously treated with platinum-based chemotherapy and
anti-programmed death 1 or programmed death ligand 1 therapy. The primary end
point was objective response assessed by blinded independent central review.
Secondary end points included the duration of response, progression-free
survival, overall survival, and safety.
RESULTS: As of October 15, 2021, a total of 116 patients with KRASG12C -mutated
NSCLC had been treated (median follow-up, 12.9 months); 98.3% had previously
received both chemotherapy and immunotherapy. Of 112 patients with measurable
disease at baseline, 48 (42.9%) had a confirmed objective response. The median
duration of response was 8.5 months (95% confidence interval [CI], 6.2 to 13.8),
and the median progression-free survival was 6.5 months (95% CI, 4.7 to 8.4). As
of January 15, 2022 (median follow-up, 15.6 months), the median overall survival
was 12.6 months (95% CI, 9.2 to 19.2). Among 33 patients with previously
treated, stable central nervous system metastases, the intracranial confirmed
objective response rate was 33.3% (95% CI, 18.0 to 51.8). Treatment-related
adverse events occurred in 97.4% of the patients - grade 1 or 2 in 52.6% and
grade 3 or higher in 44.8% (including two grade 5 events) - and resulted in drug
discontinuation in 6.9% of patients.
CONCLUSIONS: In patients with previously treated KRASG12C -mutated NSCLC,
adagrasib showed clinical efficacy without new safety signals. (Funded by Mirati
Therapeutics; ClinicalTrials.gov number, NCT03785249.).
Copyright © 2022 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2204619
PMID: 35658005 [Indexed for MEDLINE]
4. Cancer Cell. 2022 Jun 13;40(6):603-605. doi: 10.1016/j.ccell.2022.05.010. Epub
2022 Jun 2.
When immunotherapy meets surgery in non-small cell lung cancer.
Herbst RS(1), Wang M(2), Chen L(3).
Author information:
(1)Yale Comprehensive Cancer Center, Yale University School of Medicine, New
Haven, CT 06520-8028, USA. Electronic address: roy.herbst@yale.edu.
(2)Yale Comprehensive Cancer Center, Yale University School of Medicine, New
Haven, CT 06520-8028, USA.
(3)Yale Comprehensive Cancer Center, Yale University School of Medicine, New
Haven, CT 06520-8028, USA; Department of Immunobiology, Yale University School
of Medicine, New Haven, CT 06520, USA.
Comment on
N Engl J Med. 2022 May 26;386(21):1973-1985.
The results of the most recent Checkmate-816 trial in The New England Journal of
Medicine using combination neoadjuvant immunotherapy with platinum-based
chemotherapy in resectable non-small cell lung cancer demonstrate the
effectiveness of neoadjuvant immunotherapy and provide further support that
biology and personalized therapy represent the foundation of lung cancer
treatment.
Copyright © 2022 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ccell.2022.05.010
PMID: 35660136 [Indexed for MEDLINE]
5. Lancet Oncol. 2022 Jun;23(6):781-792. doi: 10.1016/S1470-2045(22)00226-1. Epub
2022 May 13.
Tiragolumab plus atezolizumab versus placebo plus atezolizumab as a first-line
treatment for PD-L1-selected non-small-cell lung cancer (CITYSCAPE): primary and
follow-up analyses of a randomised, double-blind, phase 2 study.
Cho BC(1), Abreu DR(2), Hussein M(3), Cobo M(4), Patel AJ(5), Secen N(6), Lee
KH(7), Massuti B(8), Hiret S(9), Yang JCH(10), Barlesi F(11), Lee DH(12), Ares
LP(13), Hsieh RW(14), Patil NS(14), Twomey P(14), Yang X(14), Meng R(14),
Johnson ML(15).
Author information:
(1)Yonsei Cancer Centre, Yonsei University College of Medicine, Seoul, South
Korea. Electronic address: cbc1971@yuhs.ac.
(2)Hospital Universitario Insular de Gran Canaria, Las Palmas, Spain.
(3)SCRI Florida Cancer Specialists, Leesburg, FL, USA.
…
Comment in
Nat Rev Clin Oncol. 2022 Jul;19(7):428.
Lancet Oncol. 2022 Jun;23(6):695-697.
BACKGROUND: Targeted inhibition of the PD-L1-PD-1 pathway might be further
amplified through combination of PD-1 or PD-L1 inhibitors with novel anti-TIGIT
inhibitory immune checkpoint agents, such as tiragolumab. In the CITYSCAPE
trial, we aimed to assess the preliminary efficacy and safety of tiragolumab
plus atezolizumab (anti-PD-L1) therapy as first-line treatment for
non-small-cell lung cancer (NSCLC).
METHODS: CITYSCAPE is a phase 2, randomised, double-blind, placebo-controlled
trial. Patients with chemotherapy-naive, PD-L1-positive (defined as a tumour
proportion score of ≥1% by 22C3 immunohistochemistry pharmDx assay; Dako,
Agilent Technologies, Santa Clara, CA, USA) recurrent or metastatic NSCLC with
measurable disease, Eastern Cooperative Oncology Group performance status of 0
or 1, and no EGFR or ALK alterations were enrolled from 41 clinics in Europe,
Asia, and the USA. Patients were randomly assigned (1:1), via an interactive
voice or web-based response system, to receive tiragolumab (600 mg) plus
atezolizumab (1200 mg) or placebo plus atezolizumab intravenously once every 3
weeks. Investigators and patients were masked to treatment assignment. The
co-primary endpoints were investigator-assessed objective response rate and
progression-free survival as per Response Evaluation Criteria in Solid Tumors
version 1.1 in the intention-to-treat population, analysed after approximately
80 progression-free survival events had been observed in the primary population.
Safety was assessed in all patients who received at least one dose of study
drug. This trial is registered with ClinicalTrials.gov, NCT03563716, and is
ongoing.
FINDINGS: Patients were enrolled between Aug 10, 2018, and March 20, 2019. At
data cutoff for the primary analysis (June 30, 2019), 135 of 275 patients
assessed for eligibility were randomly assigned to receive tiragolumab plus
atezolizumab (67 [50%]) or placebo plus atezolizumab (68 [50%]). In this primary
analysis, after a median follow-up of 5·9 months (4·6-7·6, in the
intention-to-treat population, 21 patients (31·3% [95% CI 19·5-43·2]) in the
tiragolumab plus atezolizumab group versus 11 patients (16·2% [6·7-25·7]) in the
placebo plus atezolizumab group had an objective response (p=0·031). Median
progression-free survival was 5·4 months (95% CI 4·2-not estimable) in the
tiragolumab plus atezolizumab group versus 3·6 months (2·7-4·4) in the placebo
plus atezolizumab group (stratified hazard ratio 0·57 [95% CI 0·37-0·90],
p=0·015). 14 (21%) patients receiving tiragolumab plus atezolizumab and 12 (18%)
patients receiving placebo plus atezolizumab had serious treatment-related
adverse events. The most frequently reported grade 3 or worse treatment-related
adverse event was lipase increase (in six [9%] patients in the tiragolumab plus
atezolizumab group vs two [3%] in the placebo plus atezolizumab group). Two
treatment-related deaths (of pyrexia and infection) occurred in the tiragolumab
plus atezolizumab group.
INTERPRETATION: Tiragolumab plus atezolizumab showed a clinically meaningful
improvement in objective response rate and progression-free survival compared
with placebo plus atezolizumab in patients with chemotherapy-naive,
PD-L1-positive, recurrent or metastatic NSCLC. Tiragolumab plus atezolizumab was
well tolerated, with a safety profile generally similar to that of atezolizumab
alone. These findings demonstrate that tiragolumab plus atezolizumab is a
promising immunotherapy combination for the treatment of previously untreated,
locally advanced unresectable or metastatic NSCLC.
FUNDING: F Hoffmann-La Roche and Genentech.
Copyright © 2022 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1470-2045(22)00226-1
PMID: 35576957 [Indexed for MEDLINE]
6. Lancet Oncol. 2022 Jun;23(6):739-747. doi: 10.1016/S1470-2045(22)00224-8. Epub
2022 May 13.
Adebrelimab or placebo plus carboplatin and etoposide as first-line treatment
for extensive-stage small-cell lung cancer (CAPSTONE-1): a multicentre,
randomised, double-blind, placebo-controlled, phase 3 trial.
Wang J(1), Zhou C(2), Yao W(3), Wang Q(4), Min X(5), Chen G(6), Xu X(7), Li
X(8), Xu F(9), Fang Y(10), Yang R(11), Yu G(12), Gong Y(13), Zhao J(14), Fan
Y(15), Liu Q(16), Cao L(17), Yao Y(18), Liu Y(19), Li X(20), Wu J(21), He Z(22),
Lu K(23), Jiang L(24), Hu C(25), Zhao W(26), Zhang B(27), Shi W(27), Zhang
X(27), Cheng Y(28); CAPSTONE-1 Study Group.
Collaborators: Cheng Y, Wang J, Zhou C, Yao W, Wang Q, Min X, Chen G, Xu X, Li
X, Xu F, Fang Y, Yang R, Yu G, Gong Y, Zhao J, Fan Y, Liu Q, Cao L, Yao Y, Liu
Y, Li X, Wu J, He Z, Lu K, Jiang L, Hu C, Zhao W, Yu H, Zhao J, Wu G, Huang D,
Chen C, Ding C, Zhang B, Wang X, Luo H, Li B, Zhang S, Lu H, Shi M, Chen X, Guo
Y, Liu H, Liu J, Gao H, Hu S, Hong Q, Li Q, Zhang B, Shi W, Zhang X.
Author information:
(1)Department of Medical Oncology, National Cancer Center, National Clinical
Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences
& Peking Union Medical College, Beijing, China.
(2)Department of Medical Oncology, Shanghai Pulmonary Hospital, Shanghai, China.
(3)Department of Thoracic Oncology, Sichuan Cancer Hospital & Institute,
Chengdu, China.
…
Comment in
Lancet Oncol. 2022 Jun;23(6):692-693.
BACKGROUND: Extensive-stage small-cell lung cancer (ES-SCLC) is associated with
poor prognosis and treatment options are scarce. Immunotherapy has shown robust
clinical activity in ES-SCLC in previous phase 3 trials. We aimed to assess the
efficacy and safety of adebrelimab (SHR-1316), a novel anti-PD-L1 antibody, with
standard chemotherapy as a first-line treatment for ES-SCLC.
METHODS: The CAPSTONE-1 study was a randomised, double-blind,
placebo-controlled, phase 3 trial, done in 47 tertiary hospitals in China. Key
inclusion criteria were patients aged 18-75 years, with previously untreated
histologically or cytologically confirmed ES-SCLC and an Eastern Cooperative
Oncology Group (ECOG) performance status of 0-1. Eligible patients were randomly
assigned (1:1) to receive four to six cycles of carboplatin (area under the
curve of 5 mg/mL per min, day 1 of each cycle) and etoposide (100 mg/m2 of
body-surface area, on days 1-3 of each cycle) with either adebrelimab (20 mg/kg,
day 1 of each cycle) or matching placebo, followed by maintenance therapy with
adebrelimab or placebo. All treatments were given intravenously in 21-day
cycles. Randomisation was done using a centralised interactive web response
system with a block size of four, stratified by liver metastases, brain
metastases, and lactate dehydrogenase concentration. The primary endpoint was
overall survival in patients who received at least one dose of study medication.
Safety was analysed in the as-treated population. This study is complete and
registered with ClinicalTrials.gov, NCT03711305.
FINDINGS: Between Dec 26, 2018, and Sept 4, 2020, 462 eligible patients were
enrolled and randomly assigned: 230 (50%) patients received adebrelimab plus
chemotherapy (adebrelimab group) and 232 (50%) patients received placebo plus
chemotherapy (placebo group). At data cutoff (Oct 8, 2021), median follow-up was
13·5 months (IQR 8·9-20·1). Median overall survival was significantly improved
in the adebrelimab group (median 15·3 months [95% CI 13·2-17·5]) compared with
the placebo group (12·8 months [11·3-13·7]; hazard ratio 0·72 [95% CI
0·58-0·90]; one-sided p=0·0017). The most common treatment-related grade 3 or 4
adverse events were decreased neutrophil count (174 [76%] patients in the
adebrelimab group and 175 [75%] patients in the placebo group), decreased white
blood cell count (106 [46%] and 88 [38%]), decreased platelet count (88 [38%]
and 78 [34%]), and anaemia (64 [28%] and 66 [28%]). Treatment-related serious
adverse events occurred in 89 (39%) patients in the adebrelimab group and 66
(28%) patients in the placebo group. Four treatment-related deaths were
reported: two each in the adebrelimab group (respiratory failure and
interstitial lung disease and pneumonia) and placebo group (multiple organ
dysfunction and unknown cause of death).
INTERPRETATION: Adding adebrelimab to chemotherapy significantly improved
overall survival with an acceptable safety profile in patients with ES-SCLC,
supporting this combination as a new first-line treatment option for this
population.
FUNDING: Jiangsu Hengrui Pharmaceuticals.
Copyright © 2022 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1470-2045(22)00224-8
PMID: 35576956 [Indexed for MEDLINE]
7. Lancet Infect Dis. 2022 Jun 27:S1473-3099(22)00222-5. doi:
10.1016/S1473-3099(22)00222-5. Online ahead of print.
Safety and immunogenicity of VPM1002 versus BCG in South African newborn babies:
a randomised, phase 2 non-inferiority double-blind controlled trial.
Cotton MF(1), Madhi SA(2), Luabeya AK(3), Tameris M(3), Hesseling AC(4), Shenje
J(3), Schoeman E(3), Hatherill M(5), Desai S(6), Kapse D(6), Brückner S(7), Koen
A(2), Jose L(2), Moultrie A(2), Bhikha S(2), Walzl G(8), Gutschmidt A(8), Kotze
LA(8), Allies DL(8), Loxton AG(8), Shaligram U(6), Abraham M(9), Johnstone
H(10), Grode L(7), Kaufmann SHE(11), Kulkarni PS(12).
Author information:
(1)Tygerberg Academic Hospital, Parow Valley, South Africa.
(2)South African Medical Research Council Vaccines and Infectious Diseases
Analytical Research Unit, Faculty of Health Sciences, Johannesburg, South
Africa; Department of Science/National Research Foundation-Vaccine Preventable
Diseases, Johannesburg, South Africa; University of the Witwatersrand,
Johannesburg, South Africa.
(3)South African Tuberculosis Vaccine Initiative (SATVI), Institute of
Infectious Disease and Molecular Medicine and Department of Pathology,
University of Cape Town, Cape Town, South Africa.
…
BACKGROUND: Tuberculosis is a major public health problem worldwide.
Immunisation with Mycobacterium bovis BCG vaccine is partially effective in
infants, reducing the incidence of miliary and tuberculosis meningitis, but is
less effective against pulmonary tuberculosis. We aimed to compare safety and
immunogenicity of VPM1002-a recombinant BCG vaccine developed to address this
gap-with BCG in HIV exposed and HIV unexposed newborn babies.
METHODS: This double-blind, randomised, active controlled phase 2 study was
conducted at four health centres in South Africa. Eligible neonates were aged 12
days or younger with a birthweight of 2·5-4·2 kg, and could be HIV exposed
(seropositive mothers) or unexposed (seronegative mothers). Newborn babies were
excluded if they had acute or chronic illness, fever, hypothermia, sepsis,
cancer, or congenital malformation, or if they received blood products or
immunosuppressive therapy. Participants were excluded if their mothers (aged ≥18
years) had active tuberculosis disease, diabetes, a history of immunodeficiency
except for HIV, hepatitis B or syphilis seropositivity, received blood products
in the preceding 6 months, any acute infectious disease, or any suspected
substance abuse. Participants were randomly assigned to VPM1002 or BCG
vaccination in a 3:1 ratio, stratified by HIV status using the random number
generator function in SAS, using a block size of eight paticipants. The primary
outcome was non-inferiority (margin 15%) of VPM1002 to BCG vaccine in terms of
incidence of grade 3-4 adverse drug reactions or ipsilateral or generalised
lymphadenopathy of 10 mm or greater in diameter by 12 months. The primary
outcome was assessed in all vaccinated participants (safety population) at
regular follow-up visits until 12 months after vaccination. Secondary
immunogenicity outcomes were interferon-γ levels and percentages of
multifunctional CD4+ and CD8+ T cells among all lymphocytes across the 12 month
study period. The study was registered with ClinicalTrials.gov, NCT02391415.
FINDINGS: Between June 4, 2015 and Oct 16, 2017, 416 eligible newborn babies
were randomly assigned and received study vaccine. Seven (2%) of 312
participants in the VPM1002 group had a grade 3-4 vaccine-related adverse
reaction or lymphadenopathy of 10 mm or greater in diameter compared with 34
(33%) of 104 participants in the BCG group (risk difference -30·45% [95% CI
-39·61% to -21·28%]; pnon-inferiority<0·0001); VPM1002 was thus non-inferior to
BCG for the primary outcome. Incidence of severe injection site reactions was
lower with VPM1002 than BCG: scarring occurred in 65 (21%) participants in the
VPM1002 group versus 77 (74%) participants in the BCG group (p<0·0001);
ulceration occurred in one (<1%) versus 15 (14%; p<0·0001); and abscess
formation occurred in five (2%) versus 23 (22%; p<0·0001). Restimulated IFNγ
concentrations were lower in the VPM1002 group than the BCG group at week 6,
week 12, month 6, and month 12. The percentage of multifunctional CD4+ T cells
was higher in the VPM1002 group than the BCG group at day 14 but lower at week
6, week 12, month 6, and month 12. The percentage of multifunctional CD8+ T
cells was lower in the VPM1002 group than the BCG group at week 6, week 12, and
month 6, but did not differ at other timepoints.
INTERPRETATION: VPM1002 was less reactogenic than BCG and was not associated
with any serious safety concern. Both vaccines were immunogenic, although
responses were higher with the BCG vaccine. VPM1002 is currently being studied
for efficacy and safety in a multicentric phase 3 clinical trial in babies in
sub-Saharan Africa.
FUNDING: Serum Institute of India.
Copyright © 2022 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1473-3099(22)00222-5
PMID: 35772447
8. Nat Commun. 2022 Jun 17;13(1):3500. doi: 10.1038/s41467-022-30908-1.
Addressing challenges with real-world synthetic control arms to demonstrate the
comparative effectiveness of Pralsetinib in non-small cell lung cancer.
Popat S(1), Liu SV(2), Scheuer N(3), Hsu GG(4), Lockhart A(4), Ramagopalan
SV(5), Griesinger F(6), Subbiah V(7).
Author information:
(1)Royal Marsden Hospital and Institute of Cancer Research, London, UK.
(2)Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC,
USA.
(3)Roche Products Ltd, Welwyn Garden City, UK.
(4)Cytel, Inc, Waltham, MA, USA.
(5)Global Access, F. Hoffmann-La Roche, Basel, Switzerland.
sreeram.ramagopalan@roche.com.
(6)Department of Medical Oncology, Pius-Hospital Oldenburg, Oldenburg, Germany.
(7)The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
vsubbiah@mdanderson.org.
As advanced non-small cell lung cancer (aNSCLC) is being increasingly divided
into rare oncogene-driven subsets, conducting randomised trials becomes
challenging. Using real-world data (RWD) to construct control arms for
single-arm trials provides an option for comparative data. However,
non-randomised treatment comparisons have the potential to be biased and cause
concern for decision-makers. Using the example of pralsetinib from a RET
fusion-positive aNSCLC single-arm trial (NCT03037385), we demonstrate a relative
survival benefit when compared to pembrolizumab monotherapy and pembrolizumab
with chemotherapy RWD cohorts. Quantitative bias analyses show that results for
the RWD-trial comparisons are robust to data missingness, potential poorer
outcomes in RWD and residual confounding. Overall, the study provides evidence
in favour of pralsetinib as a first-line treatment for RET fusion-positive
aNSCLC. The quantification of potential bias performed in this study can be used
as a template for future studies of this nature.
© 2022. The Author(s).
DOI: 10.1038/s41467-022-30908-1
PMCID: PMC9205915
PMID: 35715405 [Indexed for MEDLINE]
9. J Clin Oncol. 2022 Jun 17:JCO2200873. doi: 10.1200/JCO.22.00873. Online ahead of print.
Neoadjuvant Chemotherapy Plus Immunotherapy in Early-Stage Resectable
Non-Small-Cell Lung Cancer.
Passaro A(1), Attili I(1), de Marinis F(1).
Author information:
(1)Division of Thoracic Oncology, European Institute of Oncology IRCCS, Milan,
Italy.
The Oncology Grand Rounds series is designed to place original reports published
in the Journal into clinical context. A case presentation is followed by a
description of diagnostic and management challenges, a review of the relevant
literature, and a summary of the authors' suggested management approaches. The
goal of this series is to help readers better understand how to apply the
results of key studies, including those published in the Journal of Clinical
Oncology, to patients seen in their own clinical practice.
DOI: 10.1200/JCO.22.00873
PMID: 35714306
10. Annu Rev Microbiol. 2022 Jun 16. doi: 10.1146/annurev-micro-121321-093031.
Online ahead of print.
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. Expected final online publication date for the
Annual Review of Microbiology, Volume 76 is September 2022. Please see
http://www.annualreviews.org/page/journal/pubdates for revised estimates.
DOI: 10.1146/annurev-micro-121321-093031
PMID: 35709500
11. Nat Commun. 2022 Jun 7;13(1):3155. doi: 10.1038/s41467-022-30914-3.
Viral coinfection promotes tuberculosis immunopathogenesis by type I IFN
signaling-dependent impediment of Th1 cell pulmonary influx.
Kang TG(#)(1)(2), Kwon KW(#)(3), Kim K(1)(4), Lee I(5), Kim MJ(1)(2), Ha
SJ(6)(7), Shin SJ(8)(9).
Author information:
(1)Department of Biochemistry, College of Life Science & Biotechnology, Yonsei
University, Seoul, 03722, Republic of Korea.
(2)Brain Korea 21 (BK21) FOUR Program, Yonsei Education & Research Center for
Biosystems, Yonsei University, Seoul, 03722, Republic of Korea.
(3)Department of Microbiology, Graduate School of Medical Science, Brain Korea
21 Project, Yonsei University College of Medicine, Seoul, 03722, Republic of
Korea.
…
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is often
exacerbated upon coinfection, but the underlying immunological mechanisms remain
unclear. Here, to elucidate these mechanisms, we use an Mtb and lymphocytic
choriomeningitis virus coinfection model. Viral coinfection significantly
suppresses Mtb-specific IFN-γ production, with elevated bacterial loads and
hyperinflammation in the lungs. Type I IFN signaling blockade rescues the
Mtb-specific IFN-γ response and ameliorates lung immunopathology. Single-cell
sequencing, tissue immunofluorescence staining, and adoptive transfer
experiments indicate that viral infection-induced type I IFN signaling could
inhibit CXCL9/10 production in myeloid cells, ultimately impairing pulmonary
migration of Mtb-specific CD4+ T cells. Thus, our study suggests that augmented
and sustained type I IFNs by virus coinfection prior to the pulmonary
localization of Mtb-specific Th1 cells exacerbates TB immunopathogenesis by
impeding the Mtb-specific Th1 cell influx. Our study highlights a negative
function of viral coinfection-induced type I IFN responses in delaying
Mtb-specific Th1 responses in the lung.
© 2022. The Author(s).
DOI: 10.1038/s41467-022-30914-3
PMCID: PMC9174268
PMID: 35672321 [Indexed for MEDLINE]
12. J Exp Med. 2022 Jun 6;219(6):e20220445. doi: 10.1084/jem.20220445. Epub 2022 May 11.
Drug development challenges in nontuberculous mycobacterial lung disease: TB to
the rescue.
Dartois V(1)(2), Dick T(1)(2)(3).
Author information:
(1)Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ.
(2)Department of Medical Sciences, Hackensack Meridian School of Medicine,
Nutley, NJ.
(3)Department of Microbiology and Immunology, Georgetown University, Washington,
DC.
Nontuberculous mycobacterial pulmonary disease (NTM-PD) is treated with multiple
repurposed drugs. Chemotherapy is long and often toxic, includes parenteral
drugs, and suffers from poor cure rates. There is an urgent need for more
efficacious, tolerated, and oral antibiotics optimized towards the treatment of
NTM-PD, adapted to the spectrum of disease. In contrast to the empty NTM
pipeline, drug development for the related tuberculosis lung disease has
experienced a renaissance. Here, we argue that applying lessons learned from
tuberculosis will facilitate the discovery of curative oral regimens for NTM-PD.
© 2022 Dartois and Dick.
DOI: 10.1084/jem.20220445
PMCID: PMC9098649
PMID: 35543723 [Indexed for MEDLINE]
13. J Clin Oncol. 2022 Jun 10;40(17):1916-1928. doi: 10.1200/JCO.21.02010. Epub 2022
Mar 10.
Artificial Intelligence-Powered Spatial Analysis of Tumor-Infiltrating
Lymphocytes as Complementary Biomarker for Immune Checkpoint Inhibition in
Non-Small-Cell Lung Cancer.
Park S(1), Ock CY(2), Kim H(3), Pereira S(2), Park S(2), Ma M(2), Choi S(4), Kim
S(5), Shin S(2), Aum BJ(2), Paeng K(2), Yoo D(2), Cha H(1), Park S(1), Suh
KJ(6), Jung HA(1), Kim SH(6), Kim YJ(6), Sun JM(1), Chung JH(3), Ahn JS(1), Ahn
MJ(1), Lee JS(6), Park K(1), Song SY(4), Bang YJ(7), Choi YL(4), Mok TS(8), Lee
SH(1)(9).
Author information:
(1)Division of Hematology-Oncology, Department of Medicine, Samsung Medical
Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of
Korea.
(2)Lunit, Seoul, Republic of Korea.
(3)Department of Pathology, Seoul National University Bundang Hospital,
Seongnam, Republic of Korea.
…
PURPOSE: Biomarkers on the basis of tumor-infiltrating lymphocytes (TIL) are
potentially valuable in predicting the effectiveness of immune checkpoint
inhibitors (ICI). However, clinical application remains challenging because of
methodologic limitations and laborious process involved in spatial analysis of
TIL distribution in whole-slide images (WSI).
METHODS: We have developed an artificial intelligence (AI)-powered WSI analyzer
of TIL in the tumor microenvironment that can define three immune phenotypes
(IPs): inflamed, immune-excluded, and immune-desert. These IPs were correlated
with tumor response to ICI and survival in two independent cohorts of patients
with advanced non-small-cell lung cancer (NSCLC).
RESULTS: Inflamed IP correlated with enrichment in local immune cytolytic
activity, higher response rate, and prolonged progression-free survival compared
with patients with immune-excluded or immune-desert phenotypes. At the WSI
level, there was significant positive correlation between tumor proportion score
(TPS) as determined by the AI model and control TPS analyzed by pathologists (P
< .001). Overall, 44.0% of tumors were inflamed, 37.1% were immune-excluded, and
18.9% were immune-desert. Incidence of inflamed IP in patients with programmed
death ligand-1 TPS at < 1%, 1%-49%, and ≥ 50% was 31.7%, 42.5%, and 56.8%,
respectively. Median progression-free survival and overall survival were,
respectively, 4.1 months and 24.8 months with inflamed IP, 2.2 months and 14.0
months with immune-excluded IP, and 2.4 months and 10.6 months with
immune-desert IP.
CONCLUSION: The AI-powered spatial analysis of TIL correlated with tumor
response and progression-free survival of ICI in advanced NSCLC. This is
potentially a supplementary biomarker to TPS as determined by a pathologist.
DOI: 10.1200/JCO.21.02010
PMCID: PMC9177249
PMID: 35271299 [Indexed for MEDLINE]
14. J Clin Oncol. 2022 Jun 1;40(16):1755-1762. doi: 10.1200/JCO.21.01745. Epub 2022
Feb 14.
Effect of an Antiracism Intervention on Racial Disparities in Time to Lung
Cancer Surgery.
Charlot M(1)(2)(3), Stein JN(1)(4), Damone E(5), Wood I(6), Forster M(7), Baker
S(3)(8), Emerson M(2)(5), Samuel-Ryals C(2)(3)(9), Yongue C(3)(10), Eng
E(2)(3)(4), Manning M(3)(11), Deal A(2), Cykert S(2)(3)(6).
Author information:
(1)Division of Oncology, Department of Medicine, University of North Carolina,
Chapel Hill, NC.
(2)University of North Carolina Lineberger Comprehensive Cancer Center, Chapel
Hill, NC.
(3)Greensboro Health Disparities Collaborative, Greensboro, NC.
…
Comment in
J Clin Oncol. 2022 Jun 1;40(16):1718-1720.
PURPOSE: Timely lung cancer surgery is a metric of high-quality cancer care and
improves survival for early-stage non-small-cell lung cancer. Historically,
Black patients experience longer delays to surgery than White patients and have
lower survival rates. Antiracism interventions have shown benefits in reducing
racial disparities in lung cancer treatment.
METHODS: We conducted a secondary analysis of Accountability for Cancer Care
through Undoing Racism and Equity, an antiracism prospective pragmatic trial, at
five cancer centers to assess the impact on overall timeliness of lung cancer
surgery and racial disparities in timely surgery. The intervention consisted of
(1) a real-time warning system to identify unmet care milestones, (2)
race-specific feedback on lung cancer treatment rates, and (3) patient
navigation. The primary outcome was surgery within 8 weeks of diagnosis. Risk
ratios (RRs) and 95% CIs were estimated using log-binomial regression and
adjusted for clinical and demographic factors.
RESULTS: A total of 2,363 patients with stage I and II non-small-cell lung
cancer were included in the analyses: intervention (n = 263), retrospective
control (n = 1,798), and concurrent control (n = 302). 87.1% of Black patients
and 85.4% of White patients in the intervention group (P = .13) received surgery
within 8 weeks of diagnosis compared with 58.7% of Black patients and 75.0% of
White patients in the retrospective group (P < .01) and 64.9% of Black patients
and 73.2% of White patients (P = .29) in the concurrent group. Black patients in
the intervention group were more likely to receive timely surgery than Black
patients in the retrospective group (RR 1.43; 95% CI, 1.26 to 1.64). White
patients in the intervention group also had timelier surgery than White patients
in the retrospective group (RR 1.10; 95% CI, 1.02 to 1.18).
CONCLUSION: Accountability for Cancer Care through Undoing Racism and Equity is
associated with timelier lung cancer surgery and reduction of the racial gap in
timely surgery.
DOI: 10.1200/JCO.21.01745
PMCID: PMC9148687
PMID: 35157498 [Indexed for MEDLINE]
