RESUMEN
Agents targeting the unique biology of mycosis fungoides and Sézary syndrome are quickly being incorporated into clinical management. With these new therapies, we are now capable of inducing more durable responses and even complete remissions in advanced disease, outcomes which were exceedingly rare with prior therapies. Yet, even this new generation of therapies typically produce objective responses in only a minority of patients. As our therapeutic options increase, we are now challenged with selecting treatments from a growing list of options. To gain the full benefit of these novel agents, we must develop strategies to match treatments for the patients most likely to benefit from them. Here, we consider both the current approaches to treatment selection based on clinical features and the future of molecular biomarker-guided therapy for patients with this heterogeneous disease.
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Micosis Fungoide , Síndrome de Sézary , Neoplasias Cutáneas , Humanos , Síndrome de Sézary/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Micosis Fungoide/tratamiento farmacológicoRESUMEN
Mogamulizumab is a humanized anti-CC chemokine receptor 4 (CCR4) antibody approved for the treatment of mycosis fungoides and Sézary syndrome. Despite almost universal expression of CCR4 in these diseases, most patients eventually develop resistance to mogamulizumab. We tested whether resistance to mogamulizumab is associated with loss of CCR4 expression. We identified 17 patients with mycosis fungoides or Sézary syndrome who either were intrinsically resistant or acquired resistance to mogamulizumab. Low expression of CCR4 by immunohistochemistry or flow cytometry was found in 65% of patients. Novel emergent CCR4 mutations targeting the N-terminal and transmembrane domains were found in 3 patients after disease progression. Emerging CCR4 copy number loss was detected in 2 patients with CCR4 mutations. Acquisition of CCR4 genomic alterations corresponded with loss of CCR4 antigen expression. We also report on outcomes of 3 cutaneous T-cell lymphoma (CTCL) patients with gain-of-function CCR4 mutations treated with mogamulizumab. Our study indicates that resistance to mogamulizumab in CTCL frequently involves loss of CCR4 expression and emergence of CCR4 genomic alterations. This finding has implications for management and monitoring of CTCL patients on mogamulizumab and development of future CCR4-directed therapies.
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Resistencia a Antineoplásicos , Linfoma Cutáneo de Células T , Receptores CCR4 , Neoplasias Cutáneas , Anticuerpos Monoclonales Humanizados , Humanos , Linfoma Cutáneo de Células T/tratamiento farmacológico , Linfoma Cutáneo de Células T/genética , Receptores CCR4/genética , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/genéticaRESUMEN
We present a patient with widespread PCGD-TCL of the bilateral arms and legs, who underwent radiotherapy with 34 Gy in 17 fractions using circumferential VMAT and 3-D printed bolus to the four extremities prior to planned stem cell transplant, who was then found to have progression in the liver, lung, and skin, followed by drastic regression of all in and out-of-field lesions on imaging 1.5 months later. The cause of regression may be related to a radiation-induced abscopal effect from the immunomodulatory effects of radiation, or related to immune reactivation in the setting of cessation of systemic immunosuppressive agents.
RESUMEN
Cancer somatic mutations can generate neoantigens that distinguish malignant from normal cells. However, the personalized identification and validation of neoantigens remains a major challenge. Here we discover neoantigens in human mantle-cell lymphomas by using an integrated genomic and proteomic strategy that interrogates tumour antigen peptides presented by major histocompatibility complex (MHC) class I and class II molecules. We applied this approach to systematically characterize MHC ligands from 17 patients. Remarkably, all discovered neoantigenic peptides were exclusively derived from the lymphoma immunoglobulin heavy- or light-chain variable regions. Although we identified MHC presentation of private polymorphic germline alleles, no mutated peptides were recovered from non-immunoglobulin somatically mutated genes. Somatic mutations within the immunoglobulin variable region were almost exclusively presented by MHC class II. We isolated circulating CD4+ T cells specific for immunoglobulin-derived neoantigens and found these cells could mediate killing of autologous lymphoma cells. These results demonstrate that an integrative approach combining MHC isolation, peptide identification, and exome sequencing is an effective platform to uncover tumour neoantigens. Application of this strategy to human lymphoma implicates immunoglobulin neoantigens as targets for lymphoma immunotherapy.
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Presentación de Antígeno/inmunología , Antígenos de Neoplasias/inmunología , Región Variable de Inmunoglobulina/inmunología , Linfoma de Células del Manto/inmunología , Antígenos de Neoplasias/química , Antígenos de Neoplasias/genética , Linfocitos T CD4-Positivos/inmunología , Citotoxicidad Inmunológica , Análisis Mutacional de ADN , Epítopos de Linfocito T/inmunología , Exoma/genética , Genómica , Antígenos HLA-D/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Región Variable de Inmunoglobulina/química , Región Variable de Inmunoglobulina/genética , Inmunoterapia/tendencias , Linfoma de Células del Manto/genética , Linfoma de Células del Manto/patología , Linfoma de Células del Manto/terapia , Mutación , ProteómicaRESUMEN
BACKGROUND: IPH4102 is a first-in-class monoclonal antibody targeting KIR3DL2, a cell surface protein that is expressed in cutaneous T-cell lymphoma, and predominantly in its leukaemic form, Sézary syndrome. We aimed to assess the safety and activity of IPH4102 in cutaneous T-cell lymphoma. METHODS: We did an international, first-in-human, open-label, phase 1 clinical trial with dose-escalation and cohort-expansion parts in five academic hospitals in the USA, France, the UK, and the Netherlands. Eligible patients had histologically confirmed relapsed or refractory primary cutaneous T-cell lymphoma, an Eastern Cooperative Oncology group performance score of 2 or less, were aged 18 years or older, and had received at least two previous systemic therapies. Ten dose levels of IPH4102, administered as an intravenous infusion, ranging from 0·0001 mg/kg to 10 mg/kg, were assessed using an accelerated 3â+â3 design. The primary endpoint was the occurrence of dose-limiting toxicities during the first 2 weeks of treatment, defined as toxicity grade 3 or worse lasting for 8 or more days, except for lymphopenia. Global overall response by cutaneous T-cell lymphoma subtype was a secondary endpoint. Safety and activity analyses were done in the per-protocol population. The study is ongoing and recruitment is complete. This trial is registered with ClinicalTrials.gov, number NCT02593045. FINDINGS: Between Nov 4, 2015, and Nov 20, 2017, 44 patients were enrolled. 35 (80%) patients had Sézary syndrome, eight (18%) had mycosis fungoides, and one (2%) had primary cutaneous T-cell lymphoma, not otherwise specified. In the dose-escalation part, no dose limiting toxicity was reported and the trial's safety committee recommended a flat dose of 750 mg for the cohort-expansion, corresponding to the maximum administered dose. The most common adverse events were peripheral oedema (12 [27%] of 44 patients) and fatigue (nine [20%]), all of which were grade 1-2. Lymphopenia was the most common grade 3 or worse adverse event (three [7%]). One patient developed possibly treatment-related fulminant hepatitis 6 weeks after IPH4102 discontinuation and subsequently died. However, the patient had evidence of human herpes virus-6B infection. Median follow-up was 14·1 months (IQR 11·3-20·5). A confirmed global overall response was achieved in 16 (36·4% [95% CI 23·8-51·1]) of 44 patients, and of those, 15 responses were observed in 35 patients with Sézary syndrome (43% [28·0-59·1]). INTERPRETATION: IPH4102 is safe and shows encouraging clinical activity in patients with relapsed or refractory cutaneous T-cell lymphoma, particularly those with Sézary syndrome. If confirmed in future trials, IPH4102 could become a novel treatment option for these patients. A multi-cohort, phase 2 trial (TELLOMAK) is underway to confirm the activity in patients with Sézary syndrome and explore the role of IPH4102 in other subtypes of T-cell lymphomas that express KIR3DL2. FUNDING: Innate Pharma.
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Antineoplásicos Inmunológicos/administración & dosificación , Linfoma Cutáneo de Células T/tratamiento farmacológico , Receptores KIR3DL2/antagonistas & inhibidores , Neoplasias Cutáneas/tratamiento farmacológico , Anciano , Antineoplásicos Inmunológicos/efectos adversos , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológicoRESUMEN
Heterochromatin integrity is crucial for genome stability and regulation of gene expression, but the factors involved in mammalian heterochromatin biology are only incompletely understood. Here we identify the oncoprotein DEK, an abundant nuclear protein with a previously enigmatic in vivo function, as a Suppressor of Variegation [Su(var)] that is crucial to global heterochromatin integrity. We show that DEK interacts directly with Heterochromatin Protein 1 α (HP1α) and markedly enhances its binding to trimethylated H3K9 (H3K9me3), which is key for maintaining heterochromatic regions. Loss of Dek in Drosophila leads to a Su(var) phenotype and global reduction in heterochromatin. Thus, these findings show that DEK is a key factor in maintaining the balance between heterochromatin and euchromatin in vivo.
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Proteínas Cromosómicas no Histona/metabolismo , Heterocromatina/genética , Heterocromatina/metabolismo , Proteínas Oncogénicas/metabolismo , Animales , Ciclo Celular/efectos de los fármacos , Homólogo de la Proteína Chromobox 5 , Proteínas Cromosómicas no Histona/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Regulación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Inestabilidad Genómica/genética , Células HEK293 , Células HeLa , Inhibidores de Histona Desacetilasas/farmacología , Histonas/metabolismo , Humanos , Microscopía Electrónica de Transmisión , Proteínas Oncogénicas/genética , Proteínas de Unión a Poli-ADP-Ribosa , Unión Proteica , Receptores de la Familia Eph/genética , Receptores de la Familia Eph/metabolismo , Células Tumorales CultivadasRESUMEN
Immunopeptidomes promise novel surface markers as ideal immunotherapy targets, but their characterization by mass spectrometry (MS) remains challenging. Until recently, cell numbers exceeding 109 were needed to survey thousands of HLA ligands. Such limited analytical sensitivity has historically constrained the types of clinical specimens that can be evaluated to cell cultures or bulk tissues. Measuring immunopeptidomes from purified cell subpopulations would be preferable for many applications, particularly those evaluating rare, primary hematopoietic cell lineages. Here, we test the feasibility of immunopeptidome profiling from limited numbers of primary purified human regulatory T cells (TReg ), conventional T cells (Tconv ), and activated T cells. The combined T cell immunopeptide dataset reported here contains 13 804 unique HLA ligands derived from 5049 proteins. Of these, more than 700 HLA ligands were derived from 82 proteins that we exclusively identified from TReg -enriched cells. This study 1) demonstrates that primary, lineage-enriched T cell subpopulations recovered from single donors are compatible with immunopeptidome analysis; 2) presents new TReg -biased ligand candidates; and 3) supports immunopeptidome surveys' value for revealing T cell biology that may not be apparent from expression data alone. Taken together, these findings open up new avenues for targeting TReg and abrogating their suppressive functions to treat cancer.
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Biomarcadores/análisis , Epítopos/metabolismo , Antígenos HLA/metabolismo , Fragmentos de Péptidos/metabolismo , Linfocitos T/clasificación , Linfocitos T/metabolismo , Presentación de Antígeno/inmunología , Epítopos/inmunología , Antígenos HLA/análisis , Antígenos HLA/inmunología , Humanos , Inmunoterapia , Fragmentos de Péptidos/análisis , Fragmentos de Péptidos/inmunología , Linfocitos T/inmunología , Donantes de TejidosRESUMEN
Heterogeneity in the tumor microenvironment (TME) of follicular lymphomas (FLs) can affect clinical outcomes. Current immunotherapeutic strategies, including antibody- and cell-based therapies, variably overcome pro-tumorigenic mechanisms for sustained disease control. Modeling the intact FL TME, with its native, syngeneic tumor-infiltrating leukocytes, is a major challenge. Here, we describe an organoid culture method for cultivating patient-derived lymphoma organoids (PDLOs), which include cells from the native FL TME. We define the robustness of this method by successfully culturing cryopreserved FL specimens from diverse patients and demonstrate the stability of TME cellular composition, tumor somatic mutations, gene expression profiles, and B/T cell receptor dynamics over 3 weeks. PDLOs treated with CD3:CD19 and CD3:CD20 therapeutic bispecific antibodies showed B cell killing and T cell activation. This stable system offers a robust platform for advancing precision medicine efforts in FL through patient-specific modeling, high-throughput screening, TME signature identification, and treatment response evaluation.
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Linfoma Folicular , Humanos , Linfoma Folicular/terapia , Linfoma Folicular/diagnóstico , Linfoma Folicular/genética , Microambiente Tumoral , Linfocitos B , Receptores de Antígenos de Linfocitos T , OrganoidesRESUMEN
Cutaneous T cell lymphomas (CTCLs) are skin cancers with poor survival rates and limited treatments. While immunotherapies have shown some efficacy, the immunological consequences of administering immune-activating agents to CTCL patients have not been systematically characterized. We apply a suite of high-dimensional technologies to investigate the local, cellular, and systemic responses in CTCL patients receiving either mono- or combination anti-PD-1 plus interferon-gamma (IFN-γ) therapy. Neoplastic T cells display no evidence of activation after immunotherapy. IFN-γ induces muted endogenous immunological responses, while anti-PD-1 elicits broader changes, including increased abundance of CLA+CD39+ T cells. We develop an unbiased multi-omic profiling approach enabling discovery of immune modules stratifying patients. We identify an enrichment of activated regulatory CLA+CD39+ T cells in non-responders and activated cytotoxic CLA+CD39+ T cells in leukemic patients. Our results provide insights into the effects of immunotherapy in CTCL patients and a generalizable framework for multi-omic analysis of clinical trials.
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Inmunoterapia , Linfoma Cutáneo de Células T , Humanos , Linfoma Cutáneo de Células T/inmunología , Linfoma Cutáneo de Células T/terapia , Linfoma Cutáneo de Células T/patología , Inmunoterapia/métodos , Interferón gamma/metabolismo , Interferón gamma/inmunología , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/terapia , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/tratamiento farmacológico , Masculino , Femenino , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , MultiómicaRESUMEN
ABSTRACT: In situ vaccination (ISV) triggers an immune response to tumor-associated antigens at 1 tumor site, which can then tackle the disease throughout the body. Here, we report clinical and biological results of a phase 1/2 ISV trial in patients with low-grade lymphoma, combining an intratumoral toll-like receptor 9 (TLR9) agonist with local low-dose radiation and ibrutinib (an inhibitor of B- and T-cell kinases). Adverse events were predominately low grade. The overall response rate was 50%, including 1 complete response. All patients experienced tumor reduction at distant sites. Single-cell analyses of serial fine needle aspirates from injected and uninjected tumors revealed correlates of clinical response, such as lower CD47 and higher major histocompatibility complex class II expression on tumor cells, enhanced T-cell and natural killer cell effector function, and reduced immune suppression from transforming growth factor ß and inhibitory T regulatory 1 cells. Although changes at the local injected site were more pronounced, changes at distant uninjected sites were more often associated with clinical responses. Functional immune response assays and tracking of T-cell receptor sequences provided evidence of treatment-induced tumor-specific T-cell responses. Induction of immune effectors and reversal of negative regulators were both important in producing clinically meaningful tumor responses. The trial was registered at www.clinicaltrials.gov as #NCT02927964.
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Linfoma no Hodgkin , Linfoma , Neoplasias , Humanos , Neoplasias/terapia , Linfoma/terapia , Linfoma no Hodgkin/tratamiento farmacológico , Adyuvantes Inmunológicos , Vacunación , Análisis de la Célula IndividualRESUMEN
High-throughput sequencing of the T-cell receptor beta (TRB) and gamma (TRG) loci is increasingly utilized due to its high sensitivity, specificity, and versatility in the diagnosis of various T-cell malignancies. Application of these technologies for tracking disease burden can be valuable in detecting recurrence, determining response to therapy, guiding future management of patients, and establishing endpoints for clinical trials. In this study, the performance of the commercially available LymphoTrack high-throughput sequencing assay was assessed for determining residual disease burden in patients with various T-cell malignancies. A custom bioinformatics pipeline and database was also developed to facilitate minimal/measurable residual disease analysis and clinical reporting. This assay demonstrated excellent test performance characteristics, achieving a sensitivity of 1 of 100,000 T-cell equivalents for the DNA inputs evaluated and high concordance with orthogonal testing methods. This assay was further utilized to correlate disease burden in several patients, demonstrating its potential utility for monitoring patients with T-cell malignancies.
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Linfoma , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Linfocitos T , Receptores de Antígenos de Linfocitos T/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Neoplasia Residual/diagnóstico , Neoplasia Residual/genéticaRESUMEN
Cutaneous T-cell lymphomas (CTCL) are a clinically and molecularly heterogeneous class of lymphomas of the skin-homing T cell, and their genetic profiles are not fully characterized. Previously, rearrangements of the Lysine Methyltransferase 2A (KMT2A) gene have been identified as driver mutations only in acute leukemias. KMT2A plays a role in epigenetic regulation, and cancers with such rearrangements are responsive to epigenetic therapy including hypomethylating agents. Here, we report two cases of CTCL with novel genetic profiles. KMT2A rearrangements were identified in two aggressive cases of mycosis fungoides with large cell transformation. A KMT2A::DSCAML1 gene rearrangement was seen in Case 1, while a KMT2A::MAPRE1 fusion was identified in Case 2. These cases demonstrate that KMT2A rearrangements can be found in primary CTCLs rather than solely acute leukemias, illustrating the importance of correlating molecular findings with clinical and histologic features in diagnosis. Additionally, this finding suggests that the subset of CTCLs driven by aberrancy of the KMT2A pathway may be responsive to therapy with hypomethylating agents or menin inhibitors, as seen in acute leukemias.
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Leucemia , Linfoma Cutáneo de Células T , Micosis Fungoide , Neoplasias Cutáneas , Humanos , Epigénesis Genética , Micosis Fungoide/diagnóstico , Neoplasias Cutáneas/diagnósticoRESUMEN
Follicular lymphomas (FL) are characterized by BCL2 translocations, often detectable in blood years before FL diagnosis, but also observed in aging healthy individuals, suggesting additional lesions are required for lymphomagenesis. We directly characterized early cooperating mutations by ultradeep sequencing of prediagnostic blood and tissue specimens from 48 subjects who ultimately developed FL. Strikingly, CREBBP lysine acetyltransferase (KAT) domain mutations were the most commonly observed precursor lesions, and largely distinguished patients developing FL (14/48, 29%) from healthy adults with or without detected BCL2 rearrangements (0/13, P = 0.03 and 0/20, P = 0.007, respectively). CREBBP variants were detectable a median of 5.8 years before FL diagnosis, were clonally selected in FL tumors, and appeared restricted to the committed B-cell lineage. These results suggest that mutations affecting the CREBBP KAT domain are common lesions in FL cancer precursor cells (CPC), with the potential for discriminating subjects at risk of developing FL or monitoring residual disease. SIGNIFICANCE: Our study provides direct evidence for recurrent genetic aberrations preceding FL diagnosis, revealing the combination of BCL2 translocation with CREBBP KAT domain mutations as characteristic committed lesions of FL CPCs. Such prediagnostic mutations are detectable years before clinical diagnosis and may help discriminate individuals at risk for lymphoma development. This article is highlighted in the In This Issue feature, p. 1275.
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Linfoma Folicular , Adulto , Humanos , Linfoma Folicular/genética , Linfoma Folicular/patología , Linfocitos B , Mutación , Reordenamiento Génico , Proteínas Proto-Oncogénicas c-bcl-2/genética , Translocación GenéticaRESUMEN
Most relapsed/refractory large B cell lymphoma (r/rLBCL) patients receiving anti-CD19 chimeric antigen receptor (CAR19) T cells relapse. To characterize determinants of resistance, we profiled over 700 longitudinal specimens from two independent cohorts (n = 65 and n = 73) of r/rLBCL patients treated with axicabtagene ciloleucel. A method for simultaneous profiling of circulating tumor DNA (ctDNA), cell-free CAR19 (cfCAR19) retroviral fragments, and cell-free T cell receptor rearrangements (cfTCR) enabled integration of tumor and both engineered and non-engineered T cell effector-mediated factors for assessing treatment failure and predicting outcomes. Alterations in multiple classes of genes are associated with resistance, including B cell identity (PAX5 and IRF8), immune checkpoints (CD274), and those affecting the microenvironment (TMEM30A). Somatic tumor alterations affect CAR19 therapy at multiple levels, including CAR19 T cell expansion, persistence, and tumor microenvironment. Further, CAR19 T cells play a reciprocal role in shaping tumor genotype and phenotype. We envision these findings will facilitate improved chimeric antigen receptor (CAR) T cells and personalized therapeutic approaches.
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Linfoma de Células B Grandes Difuso , Receptores Quiméricos de Antígenos , Humanos , Receptores Quiméricos de Antígenos/genética , Recurrencia Local de Neoplasia/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/terapia , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Inmunoterapia Adoptiva/métodos , Linfocitos T , Antígenos CD19/genética , Microambiente TumoralRESUMEN
The PD-1 inhibitor pembrolizumab is effective in treating Sézary syndrome, a leukemic variant of cutaneous T-cell lymphoma. Our purpose was to investigate the effects of pembrolizumab on healthy and malignant T cells in Sézary syndrome and to discover characteristics that predict pembrolizumab response. Samples were analyzed before and after 3 weeks of pembrolizumab treatment using single-cell RNA-sequencing of 118,961 peripheral blood T cells isolated from six Sézary syndrome patients. T-cell receptor clonotyping, bulk RNA-seq signatures, and whole-exome data were integrated to classify malignant T-cells and their underlying subclonal heterogeneity. We found that responses to pembrolizumab were associated with lower KIR3DL2 expression within Sézary T cells. Pembrolizumab modulated Sézary cell gene expression of T-cell activation associated genes. The CD8 effector populations included clonally expanded populations with a strong cytotoxic profile. Expansions of CD8 terminal effector and CD8 effector memory T-cell populations were observed in responding patients after treatment. We observed intrapatient Sézary cell heterogeneity including subclonal segregation of a coding mutation and copy number variation. Our study reveals differential effects of pembrolizumab in both malignant and healthy T cells. These data support further study of KIR3DL2 expression and CD8 immune populations as predictive biomarkers of pembrolizumab response in Sézary syndrome.
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Síndrome de Sézary , Neoplasias Cutáneas , Anticuerpos Monoclonales Humanizados , Variaciones en el Número de Copia de ADN , Humanos , ARN , Receptores KIR3DL2/genética , Síndrome de Sézary/tratamiento farmacológico , Síndrome de Sézary/genética , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/genéticaRESUMEN
To obtain a deeper understanding of poor responses to COVID-19 vaccination in patients with lymphoma, we assessed blocking antibodies, total anti-spike IgG, and spike-specific memory B cells in the peripheral blood of 126 patients with lymphoma and 20 age-matched healthy controls 1 and 4 months after COVID-19 vaccination. Fifty-five percent of patients developed blocking antibodies postvaccination, compared with 100% of controls. When evaluating patients last treated from days to nearly 18 years prior to vaccination, time since last anti-CD20 was a significant independent predictor of vaccine response. None of 31 patients who had received anti-CD20 treatment within 6 months prior to vaccination developed blocking antibodies. In contrast, patients who initiated anti-CD20 treatment shortly after achieving a vaccine-induced antibody response tended to retain that response during treatment, suggesting a policy of immunizing prior to treatment whenever possible. SIGNIFICANCE: In a large cohort of patients with B-cell lymphoma, time since anti-CD20 treatment was an independent predictor of neutralizing antibody response to COVID-19 vaccination. Comparing patients who received anti-CD20 treatment before or after vaccination, we demonstrate that vaccinating first can generate an antibody response that endures through anti-CD20-containing treatment. This article is highlighted in the In This Issue feature, p. 85.
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Vacunas contra la COVID-19 , COVID-19 , Formación de Anticuerpos , Vacunas contra la COVID-19/uso terapéutico , Humanos , Lactante , SARS-CoV-2 , VacunaciónRESUMEN
Immunotherapies are revolutionizing cancer treatment by boosting the natural ability of the immune system. In addition to antibodies against traditional checkpoint molecules or their ligands (i.e., CTLA-4, PD-1, and PD-L1), therapies targeting molecules such as ICOS, IDO-1, LAG-3, OX40, TIM-3, and VISTA are currently in clinical trials. To better inform clinical care and the design of therapeutic combination strategies, the co-expression of immunoregulatory proteins on individual immune cells within the tumor microenvironment must be robustly characterized. Highly multiplexed tissue imaging platforms, such as CO-Detection by indEXing (CODEX), are primed to meet this need by enabling >50 markers to be simultaneously analyzed in single-cells on formalin-fixed paraffin-embedded (FFPE) tissue sections. Assembly and validation of antibody panels is particularly challenging, with respect to the specificity of antigen detection and robustness of signal over background. Herein, we report the design, development, optimization, and application of a 56-marker CODEX antibody panel to eight cutaneous T cell lymphoma (CTCL) patient samples. This panel is comprised of structural, tumor, and immune cell markers, including eight immunoregulatory proteins that are approved or currently undergoing clinical trials as immunotherapy targets. Here we provide a resource to enable extensive high-dimensional, spatially resolved characterization of the tissue microenvironment across tumor types and imaging modalities. This framework provides researchers with a readily applicable blueprint to study tumor immunology, tissue architecture, and enable mechanistic insights into immunotherapeutic targets.
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Biomarcadores de Tumor/análisis , Técnica del Anticuerpo Fluorescente , Proteínas de Punto de Control Inmunitario/análisis , Linfoma Cutáneo de Células T/inmunología , Análisis de la Célula Individual , Neoplasias Cutáneas/inmunología , Análisis de Matrices Tisulares , Microambiente Tumoral , Toma de Decisiones Clínicas , Ensayos Analíticos de Alto Rendimiento , Humanos , Procesamiento de Imagen Asistido por Computador , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoterapia , Linfoma Cutáneo de Células T/tratamiento farmacológico , Linfoma Cutáneo de Células T/patología , Microscopía Fluorescente , Valor Predictivo de las Pruebas , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patologíaRESUMEN
We describe a case of a 48-year-old woman with a refractory cutaneous CD30 positive lymphoproliferative disorder treated successfully with total skin electron beam radiotherapy (TSEBT).