RESUMEN
Understanding the evolutionary pathways to metastasis and resistance to immune-checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here, we present the most comprehensive intrapatient metastatic melanoma dataset assembled to date as part of the Posthumous Evaluation of Advanced Cancer Environment (PEACE) research autopsy program, including 222 exome sequencing, 493 panel-sequenced, 161 RNA sequencing, and 22 single-cell whole-genome sequencing samples from 14 ICI-treated patients. We observed frequent whole-genome doubling and widespread loss of heterozygosity, often involving antigen-presentation machinery. We found KIT extrachromosomal DNA may have contributed to the lack of response to KIT inhibitors of a KIT-driven melanoma. At the lesion-level, MYC amplifications were enriched in ICI nonresponders. Single-cell sequencing revealed polyclonal seeding of metastases originating from clones with different ploidy in one patient. Finally, we observed that brain metastases that diverged early in molecular evolution emerge late in disease. Overall, our study illustrates the diverse evolutionary landscape of advanced melanoma. SIGNIFICANCE: Despite treatment advances, melanoma remains a deadly disease at stage IV. Through research autopsy and dense sampling of metastases combined with extensive multiomic profiling, our study elucidates the many mechanisms that melanomas use to evade treatment and the immune system, whether through mutations, widespread copy-number alterations, or extrachromosomal DNA. See related commentary by Shain, p. 1294. This article is highlighted in the In This Issue feature, p. 1275.
Asunto(s)
Neoplasias Encefálicas , Melanoma , Humanos , Melanoma/patología , Mutación , Evolución Molecular , ADNRESUMEN
Wu et al. report that patients with hematologic malignancies have reduced immunity against SARS-CoV-2 Omicron subvariants and Sotrovimab retains neutralizing capacity against all tested Omicron subvariants.
Asunto(s)
COVID-19 , Neoplasias Hematológicas , Neoplasias , Humanos , SARS-CoV-2 , Neoplasias Hematológicas/tratamiento farmacológicoRESUMEN
Patients with blood cancer continue to have a greater risk of inadequate immune responses following three COVID-19 vaccine doses and risk of severe COVID-19 disease. In the context of the CAPTURE study (NCT03226886), we report immune responses in 80 patients with blood cancer who received a fourth dose of BNT162b2. We measured neutralizing antibody titers (NAbTs) using a live virus microneutralization assay against wild-type (WT), Delta, and Omicron BA.1 and BA.2 and T cell responses against WT and Omicron BA.1 using an activation-induced marker (AIM) assay. The proportion of patients with detectable NAb titers and T cell responses after the fourth vaccine dose increased compared with that after the third vaccine dose. Patients who received B cell-depleting therapies within the 12 months before vaccination have the greatest risk of not having detectable NAbT. In addition, we report immune responses in 57 patients with breakthrough infections after vaccination.
Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Neoplasias , Humanos , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacuna BNT162 , Estudios Clínicos como Asunto , COVID-19/prevención & control , Vacunas contra la COVID-19/inmunología , Inmunidad , SARS-CoV-2RESUMEN
Coronavirus disease 2019 (COVID-19) antiviral response in a pan-tumor immune monitoring (CAPTURE) ( NCT03226886 ) is a prospective cohort study of COVID-19 immunity in patients with cancer. Here we evaluated 585 patients following administration of two doses of BNT162b2 or AZD1222 vaccines, administered 12 weeks apart. Seroconversion rates after two doses were 85% and 59% in patients with solid and hematological malignancies, respectively. A lower proportion of patients had detectable titers of neutralizing antibodies (NAbT) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC) versus wild-type (WT) SARS-CoV-2. Patients with hematological malignancies were more likely to have undetectable NAbT and had lower median NAbT than those with solid cancers against both SARS-CoV-2 WT and VOC. By comparison with individuals without cancer, patients with hematological, but not solid, malignancies had reduced neutralizing antibody (NAb) responses. Seroconversion showed poor concordance with NAbT against VOC. Previous SARS-CoV-2 infection boosted the NAb response including against VOC, and anti-CD20 treatment was associated with undetectable NAbT. Vaccine-induced T cell responses were detected in 80% of patients and were comparable between vaccines or cancer types. Our results have implications for the management of patients with cancer during the ongoing COVID-19 pandemic.
Asunto(s)
Vacuna BNT162/inmunología , COVID-19/prevención & control , ChAdOx1 nCoV-19/inmunología , Neoplasias/inmunología , SARS-CoV-2/inmunología , Anciano , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Vacuna BNT162/administración & dosificación , COVID-19/sangre , COVID-19/inmunología , ChAdOx1 nCoV-19/administración & dosificación , Femenino , Humanos , Inmunidad Celular , Inmunogenicidad Vacunal , Masculino , Persona de Mediana Edad , Neoplasias/sangre , Neoplasias/complicaciones , Estudios Prospectivos , Linfocitos T/inmunologíaRESUMEN
CAPTURE (NCT03226886) is a prospective cohort study of COVID-19 immunity in patients with cancer. Here we evaluated 585 patients following administration of two doses of BNT162b2 or AZD1222 vaccines, administered 12 weeks apart. Seroconversion rates after two doses were 85% and 59% in patients with solid and hematological malignancies, respectively. A lower proportion of patients had detectable neutralizing antibody titers (NAbT) against SARS-CoV-2 variants of concern (VOCs) vs wildtype (WT). Patients with hematological malignancies were more likely to have undetectable NAbT and had lower median NAbT vs solid cancers against both WT and VOCs. In comparison with individuals without cancer, patients with haematological, but not solid, malignancies had reduced NAb responses. Seroconversion showed poor concordance with NAbT against VOCs. Prior SARS-CoV-2 infection boosted NAb response including against VOCs, and anti-CD20 treatment was associated with undetectable NAbT. Vaccine-induced T-cell responses were detected in 80% of patients, and were comparable between vaccines or cancer types. Our results have implications for the management of cancer patients during the ongoing COVID-19 pandemic.
Asunto(s)
Inmunidad Adaptativa/inmunología , Anticuerpos Neutralizantes/inmunología , Vacunas contra la COVID-19/inmunología , COVID-19/inmunología , Carcinoma de Células Renales/complicaciones , Neoplasias Renales/complicaciones , SARS-CoV-2/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Vacuna BNT162/administración & dosificación , Vacuna BNT162/inmunología , COVID-19/complicaciones , COVID-19/epidemiología , Vacunas contra la COVID-19/administración & dosificación , ChAdOx1 nCoV-19/administración & dosificación , ChAdOx1 nCoV-19/inmunología , Femenino , Humanos , Inmunogenicidad Vacunal/inmunología , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Pandemias/prevención & control , Estudios Prospectivos , SARS-CoV-2/genética , SARS-CoV-2/fisiología , Linfocitos T/inmunología , Linfocitos T/virología , Vacunación/métodosAsunto(s)
Anticuerpos Neutralizantes/biosíntesis , Anticuerpos Antivirales/biosíntesis , Vacunas contra la COVID-19/inmunología , COVID-19/prevención & control , Neoplasias Hematológicas/inmunología , Inmunización Secundaria , SARS-CoV-2/inmunología , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , COVID-19/complicaciones , COVID-19/epidemiología , Neoplasias Hematológicas/complicaciones , Humanos , Inmunogenicidad Vacunal , Neoplasias/complicaciones , Neoplasias/inmunología , Evaluación de SíntomasRESUMEN
IMPORTANCE: Our study indicates a prototype blood-based variant Creutzfeldt-Jakob disease (vCJD) assay has sufficient sensitivity and specificity to justify a large study comparing vCJD prevalence in the United Kingdom with a bovine spongiform encephalopathy-unexposed population. In a clinical diagnostic capacity, the assay's likelihood ratios dramatically change an individual's pretest disease odds to posttest probabilities and can confirm vCJD infection. OBJECTIVES: To determine the diagnostic accuracy of a prototype blood test for vCJD and hence its suitability for clinical use and for screening prion-exposed populations. DESIGN, SETTING, AND PARTICIPANTS: Retrospective, cross-sectional diagnostic study of blood samples from national blood collection and prion disease centers in the United States and United Kingdom. Anonymized samples were representative of the US blood donor population (n = 5000), healthy UK donors (n = 200), patients with nonprion neurodegenerative diseases (n = 352), patients in whom a prion disease diagnosis was likely (n = 105), and patients with confirmed vCJD (n = 10). MAIN OUTCOME AND MEASURE: Presence of vCJD infection determined by a prototype test (now in clinical diagnostic use) that captures, enriches, and detects disease-associated prion protein from whole blood using stainless steel powder. RESULTS: The assay's specificity among the presumed negative American donor samples was 100% (95% CI, 99.93%-100%) and was confirmed in a healthy UK cohort (100% specificity; 95% CI, 98.2%-100%). Of potentially cross-reactive blood samples from patients with nonprion neurodegenerative diseases, no samples tested positive (100% specificity; 95% CI, 98.9%-100%). Among National Prion Clinic referrals in whom a prion disease diagnosis was likely, 2 patients with sporadic CJD tested positive (98.1% specificity; 95% CI, 93.3%-99.8%). Finally, we reconfirmed but could not refine our previous sensitivity estimate in a small blind panel of samples from unaffected individuals and patients with vCJD (70% sensitivity; 95% CI, 34.8%-93.3%). CONCLUSIONS AND RELEVANCE: In conjunction with the assay's established high sensitivity (71.4%; 95% CI, 47.8%-88.7%), the extremely high specificity supports using the assay to screen for vCJD infection in prion-exposed populations. Additionally, the lack of cross-reactivity and false positives in a range of nonprion neurodegenerative diseases supports the use of the assay in patient diagnosis.