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Chimeric Antigen Receptor (CAR) immunotherapy utilizes genetically-engineered immune cells that express a unique cell surface receptor that combines tumor antigen specificity with immune cell activation. In recent clinical trials, the adoptive transfer of CAR-modified immune cells (including CAR-T and CAR-NK cells) into patients has been remarkably successful in treating multiple refractory blood cancers. To improve safety and efficacy, and expand potential applicability to other cancer types, CARs with different target specificities and sequence modifications are being developed and tested by many laboratories. Despite the overall progress in CAR immunotherapy, conventional tools to design and evaluate the efficacy and safety of CAR immunotherapies can be inaccurate, time-consuming, costly, and labor-intensive. Furthermore, existing tools cannot always determine how responsive individual patients will be to a particular CAR immunotherapy. Recent work in our laboratory suggests that the quality of the immunological synapse (IS) can accurately predict CAR-modified cell efficacy (and toxicity) that can correlate with clinical outcomes. Here we review current efforts to develop a Synapse Predicts Efficacy (SPE) system for easy, rapid and cost-effective evaluation of CAR-modified immune cell immunotherapy. Ultimately, we hypothesize the conceptual basis and clinical application of SPE will serve as an important parameter in evaluating CAR immunotherapy and significantly advance precision cancer immunotherapy. Video abstract Graphic abstract for manuscript CCAS-D-20-00136 by Liu, D., et al., 'The Role of Immunological Synapse in Predicting the Efficacy of Chimeric Antigen Receptor (CAR) Immunotherapy". The various branches of evaluating cancer immunotherapy metaphorically represented as a Rubik's cube. The development of a novel approach to predict the effectiveness of Chimeric Antigen Receptor (CAR)-modified cells by quantifying the quality of CAR IS will introduce a new parameter to the rapidly expanding field of cancer immunotherapy. Currently, no single parameter can predict the clinical outcome or efficacy of a specific type of CAR-modified cell. IS quality will serve as a quantifiable measure to evaluate CAR products and can be used in conjunction with other conventional parameters to form a composite clinical predictor. Much like a Rubik's cube has countless configurations, several methods and combinations of clinical metrics have arisen for evaluating the ability of a given immunotherapeutic strategy to treat cancer. The quality of IS depicting cancer immunotherapy is metaphorically expressed as a Rubik's cube. Each face/color represents one aspect of cancer therapy. Each grid in one face indicates one factor within that aspect of cancer therapy. For example, the green color represents the tumor microenvironment, and one out of the nine grids in the green color indicates suppressor cells (suppressors in green). Changes in one factor may completely alter the entire strategy of cancer therapy. However, the quality of IS (illuminated center red grid) makes the effectiveness of CAR immunotherapy predictable.
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Sinapses Imunológicas/metabolismo , Imunoterapia , Receptores de Antígenos Quiméricos/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Ensaios Clínicos como Assunto , Humanos , Resultado do TratamentoRESUMO
Wolf-Hirschhorn syndrome (WHS) is a contiguous gene deletion condition. The WHS core phenotype includes developmental delays, intellectual disabilities, seizures, and distinctive facial features. Various other comorbidities have also been reported, such as hearing loss, heart defects, as well as eye problems and kidney problems. In this report, we present a case of WHS accompanied by hyperparathyroidism and hypercalcemia, which has not been previously reported. A girl was born at 37 weeks of gestation by vaginal delivery. She was small for the gestational age (2,045 g) and admitted to neonatal intensive care unit. She had typical WHS facial features and was found to have bilateral small kidneys associated with transient metabolic acidosis and renal insufficiency. She had right-sided sensorineural hearing loss, a small atrial septal defect, and colpocephaly and hypoplasia of corpus callosum. She had a single seizure which was well controlled with an oral antiepileptic medication. Cytogenetic studies demonstrated a large terminal chromosome 4p deletion (21.4 Mb) and 4p duplication (2.1 Mb) adjacent to the deletion. A unique finding in this patient is her consistently elevated levels of parathyroid hormone and serum calcium, suggesting hyperparathyroidism. We present this rare case along with a review of the literature and hope to draw an attention to a potential relationship between WHS and hyperparathyroidism.
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Hamartomas are primary, benign neoplastic lesions that most commonly derive from a single variably differentiated cell lineage. Here, we report an unusual case of a cardiac hamartoma. A 62-year-old woman presented with chest pain and palpitations. Serial imaging revealed a large slowly growing and highly vascularized left ventricular mass, which required surgical resection. Microscopically, the lesion was composed of nodular fibrovascular proliferation with haphazardly embedded muscle bundles and peripheral calcifications. Immunohistochemical studies revealed prominent muscle-specific actin positive and smooth muscle actin positive muscle fiber bundles within a disorganized fibrovascular stroma. This characterization is most consistent with cardiac mesenchymal hamartoma. Relevant differential diagnoses for this lesion include hamartoma of mature cardiac myocytes (HMCMs) and intramuscular hemangioma. The prominent smooth muscle differentiation of muscle bundles was incompatible with defining features of HMCM. Absence of S100-positive nerve and mature adipose cells distinguished this lesion from the recently defined, heterogeneous cardiac mesenchymal hamartoma. Forty-seven cases of cardiac hamartoma reported from 1970 to 2020 were reviewed to provide histopathologic context.
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Dor no Peito/etiologia , Hamartoma/diagnóstico , Cardiopatias/diagnóstico , Ventrículos do Coração/patologia , Dor no Peito/cirurgia , Angiografia por Tomografia Computadorizada , Angiografia Coronária , Diagnóstico Diferencial , Feminino , Hamartoma/complicações , Hamartoma/patologia , Hamartoma/cirurgia , Cardiopatias/complicações , Cardiopatias/patologia , Cardiopatias/cirurgia , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/cirurgia , Humanos , Pessoa de Meia-IdadeRESUMO
The challenge for treating breast cancer (BC) is partly due to long-term dormancy driven by cancer stem cells (CSCs) capable of evading immune response and resist chemotherapy. BC cells show preference for the BM, resulting in poor prognosis. CSCs use connexin 43 (Cx43) to form gap junctional intercellular communication with BM niche cells, fibroblasts, and mesenchymal stem cells (MSCs). However, Cx43 is an unlikely target to reverse BC dormancy because of its role as a hematopoietic regulator. We found N-cadherin (CDH2) and its associated pathways as potential drug targets. CDH2, highly expressed in CSCs, interacts intracellularly with Cx43, colocalizes with Cx43 in BC cells within BM biopsies of patients, and is required for Cx43-mediated gap junctional intercellular communication with BM niche cells. Notably, CDH2 and anti-apoptotic pathways maintained BC dormancy. We thereby propose these pathways as potential pharmacological targets to prevent dormancy and chemosensitize resistant CSCs.
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Antígenos CD/metabolismo , Neoplasias da Mama/metabolismo , Caderinas/metabolismo , Conexina 43/metabolismo , Antígenos CD/genética , Medula Óssea/metabolismo , Caderinas/genética , Caderinas/fisiologia , Conexina 43/genética , Resistencia a Medicamentos Antineoplásicos/fisiologia , Feminino , Junções Comunicantes/metabolismo , Junções Comunicantes/patologia , Humanos , Células-Tronco Mesenquimais/metabolismo , Metástase Neoplásica/patologia , Células-Tronco Neoplásicas/metabolismo , Evasão Tumoral/fisiologiaRESUMO
Autoimmune hepatitis (AIH) and Langerhans cell histiocytosis (LCH) are two independently rare disease processes that can have similar presentations. We present a unique, complex case that required a multidisciplinary approach to ultimately diagnose and treat the patient. A 20-year-old male with no significant history presented with worsening jaundice, diffuse, pruritic rash, and abdominal pain over one month. On admission, the patient's labs showed significantly elevated liver function tests (LFTs), eosinophilia, and anemia. The exam was notable for diffuse lymphadenopathy (LAD), hepatosplenomegaly, and a diffuse, non-blanching, morbilliform rash. Interdisciplinary workup was notable for positive anti-smooth muscle antibody (ASMA) and anti-neutrophilic antibody (ANA). A liver biopsy showed severe inflammation with interface activity, consistent with AIH. A lymph node (LN) biopsy showed findings consistent with LCH, including histiocyte clusters. He was started on high-dose steroids with LAD/LFT improvement; yet, his course was complicated by a gastrointestinal (GI) bleed requiring a hemicolectomy. The patient was transferred to a larger referral center where he continued to improve with steroids and was ultimately discharged. This case was notable for an LN biopsy showing histiocyte clusters with reniform nuclei, nuclear grooves, and eosinophils with immunohistochemical stains positive for S-100, CD1a, fascin, langerin, CD45, and CD68, consistent with LCH. The resected colon showed atypical histiocyte proliferation positive for fascin, CD4, and CD68. Other findings, including elevated LFTs, ASMA, and a liver biopsy showing inflammation with interface activity, eosinophils, plasma cells, and characteristic fibrosis, supported a diagnosis of AIH. In either case, steroids were indicated.
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Clinical success of chimeric antigen receptor (CAR) T cell immunotherapy requires the engineering of autologous T cells, which limits the broader implementation of CAR cell therapy. The development of allogeneic and universal cell products will significantly broaden their application and reduce costs. Allogeneic natural killer (NK) cells can be used for universal CAR immunotherapy. Here, we develop an alternative approach for the rapid expansion of primary NK and CAR-NK cells with superior expansion capability and in vivo cytotoxicity from various sources (including peripheral blood, cord blood, and tumor tissue). We apply a human B-lymphoblastoid cell-line 721.221 (hereinafter, 221)-based artificial feeder cell system with membrane-bound interleukin 21 (mIL-21) to propagate NK and CAR-NK cells. The expansion capability, purity, and cytotoxicity of NK cells expanded with 221-mIL-21 feeder cells are superior to that of conventional K562-mIL-21 feeder cells. RNA sequencing (RNA-seq) data show that 221-mIL-21 feeder cell-expanded NK cells display a less differentiated, non-exhausted, limited fratricidal, memory-like phenotype correlated with enriched metabolic pathways, which explains underlying mechanisms. Thus, "off-the-shelf" NK and CAR-NK cells with superior functionalities and expansion using a genetically modified 221-mIL-21 feeder cell expansion system will greatly support clinical use of NK immunotherapy.
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Targeted therapy has changed the paradigm of advanced NSCLC management by improving the survival rate of patients carrying actionable gene alterations using specific inhibitors. The epidemiologic features of these alterations vary among races. Understanding the racial differences benefits drug development, clinical trial design, and health resource allocation. Compared to Caucasian and Asian populations, current knowledge on Hispanic patients is less and no data of Hispanic patients from Puerto Rico have been reported. We retrieved and analyzed the demographic, clinical, and molecular data of Hispanic NSCLC patients from Puerto Rico with molecular tests performed in the Genoptix Medical Laboratory in Carlsbad, CA, USA between 2011 and 2018. The majority of the NSCLC patients in our study had either adenocarcinoma (75.4%) or squamous cell carcinoma (15.1%). The incidence of EGFR mutations was 24%. They were more common in female and younger patients (<60 years). The deletion of Exon 19 and Exon 21 L858R comprised 55.1% and 31.0% of all EGFR mutations, respectively. The frequency of the T790M mutation was lower compared to that of Hispanic patients reported in the literature (0.5% vs. 2.1%). In addition, 18.7% of the patients were positive for KRAS mutations, which was at the high end of that reported in Hispanic patients. Other driver gene alterations, ALK, MET, RET, ROS1, KRAS, ERBB2, etc., demonstrated similar incidences, as well as gender and age distributions to those previously reported. The KRAS/TP53 and KRAS/STK11 co-mutations were of very low frequencies (3.6%), which could potentially affect the responsiveness to PD1/PD-L1 immunotherapy. Our study demonstrated that the prevalence of NSCLC gene alterations in Hispanic patients from Puerto Rico was comparable to the reported average prevalence in Latin American countries, supporting the intermediate NSCLC gene alteration rate of Hispanic patients between Asian and Caucasian patients. Novel information of the frequencies of KRAS mutation subtypes, driver gene alterations in ROS1, BRAF, and ERBB2, and passenger gene alterations including a rare case with the FGFR2-TACC2 translocation in Hispanic NSCLC patients from Puerto Rico were also described.
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Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic neoplasm that exhibits myelodysplastic and myeloproliferative characteristics with heterogeneous clinical and pathological features. There are limited publications on the ethnic and racial disparity of cytogenetics and genomics in CMML patients. This study aims to define the cytogenetic and molecular landscape in Hispanic CMML patients from Puerto Rico and explore its possible clinical significance. One hundred and eleven (111) Hispanic CMML patients from Puerto Rico were diagnosed in our institute from 2009 to 2018. Karyotypes were available in one hundred and seven (107) patients. Seventeen (17) patients had abnormal karyotypes (17/107, 16%). Compared to previously published data, Hispanic CMML patients in this study had significantly lower rates of overall cytogenetic abnormalities (16% vs 27-28%, p < 0.05) and trisomy 8 (2% vs 7%, p < 0.05). Among one hundred and eleven (111) Hispanic CMML patients, 40-gene myeloid molecular profile tests were performed in fifty-six (56) CMML patients. Gene mutations were identified in fifty-four (54) patients (96%). The most frequent mutated genes were: TET2, SRSF2, ASXL1, ZRSR2, DNMT3A, NRAS, CBL, and RUNX1. Twenty-nine (29) out of fifty-six (56) patients (29/56, 52%) had mutated TET2/wild type ASXL1 (muTET2/wtASXL1). Previous studies indicated that mutated ASXL1, DNMT3A, NRAS, RUNX1, and SETBP1 may associate with an unfavorable prognosis and muTET2/wtASXL1 may associate with a favorable prognosis in CMML patients. Compared to previously published data, Hispanic CMML patients from Puerto Rico in this study had significantly lower mutation rates in ASXL1 and SETBP1, and a higher rate of muTET2/wtASXL1. The findings raise the possibility of a favorable prognosis in Hispanic CMML patients.
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Chimeric antigen receptor (CAR) therapy is a promising immunotherapeutic strategy for treating multiple refractory blood cancers, but further advances are required for solid tumor CAR therapy. One challenge is identifying a safe and effective tumor antigen. Here, we devise a strategy for targeting hepatocellular carcinoma (HCC, one of the deadliest malignancies). We report that T and NK cells transduced with a CAR that recognizes the surface marker, CD147, also known as Basigin, can effectively kill various malignant HCC cell lines in vitro, and HCC tumors in xenograft and patient-derived xenograft mouse models. To minimize any on-target/off-tumor toxicity, we use logic-gated (log) GPC3-synNotch-inducible CD147-CAR to target HCC. LogCD147-CAR selectively kills dual antigen (GPC3+CD147+), but not single antigen (GPC3-CD147+) positive HCC cells and does not cause severe on-target/off-tumor toxicity in a human CD147 transgenic mouse model. In conclusion, these findings support the therapeutic potential of CD147-CAR-modified immune cells for HCC patients.
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Basigina/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Imunoterapia Adotiva/métodos , Neoplasias Hepáticas/tratamento farmacológico , Receptores de Antígenos Quiméricos/efeitos dos fármacos , Animais , Basigina/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Células Hep G2 , Humanos , Células Matadoras Naturais , Fígado/patologia , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Emergence of clonal chromosomal abnormalities in Philadelphia chromosome-negative (CCA/Ph-) cells in chronic myeloid leukemia (CML) patients during the treatment with tyrosine kinase inhibitors (TKIs) is an interesting phenomenon. Although previous studies revealed some potential impact of CCA/Ph- on CML patients' outcome, clinical significance of CCA/Ph- in CML patients remains to be further elucidated. We retrospectively reviewed the patients with CML evaluated at Genoptix Medical Laboratory in Carlsbad, California from 2005 to 2015. Twenty-four CML patients with CCA/Ph- cells were identified. These include 18 patients with single chromosomal abnormality, 4 patients with double chromosomal abnormalities, and two patients with complex cytogenetic abnormalities. In addition to trisomy 8 and monosomy 7, we identified that 20q- was also a common abnormality in CCA/Ph- cells. Most of the patients with CCA/Ph- cells demonstrated no significant dysplasia or increased blasts with two exceptions: one patient with persistent 7q- exhibiting mild dysmegakaryopoiesis, suggestive of an early evolving myelodysplastic syndrome, and another patient with complex cytogenetic abnormalities who developed acute myeloid leukemia after gained MLL amplification. One patient with complex cytogenetic abnormalities showed optimal response to TKI treatment, no overt dysplasia, and no disease progression during almost 4-years of follow-up. More interestingly, FISH tests could identify more cases with double chromosomal abnormalities and these cases showed suboptimal responses to TKI treatments. Our observation indicates that 20q- was also a common abnormality in CCA/Ph- cells, further FISH tests revealed additional CCA/Ph-, and the majority of CML patients with two or more chromosomal abnormalities in Ph- cells showed inferior response to TKI treatments. The results of our study suggest that CML cases with CCA/Ph- may represent a group of patients with heterogeneous genetic alterations.
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Aberrações Cromossômicas , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/tratamento farmacológico , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/genética , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Masculino , Pessoa de Meia-IdadeRESUMO
Plasma cell myeloma is a clonal proliferation of neoplastic plasma cells and typically expresses a monoclonal heavy and/or light chain immunoglobulin. Plasma cell myeloma with dual expression of kappa and lambda light chains in a single clone is extremely rare. Here we report three cases of plasma cell myeloma with a co-expression of both kappa and lambda light chains. All three cases were confirmed by comprehensive workup including IHC, ISH and flow cytometry analysis to detect light chain expression patterns at the mRNA and protein levels. We also reviewed three cases so far published in the literature. Our study suggests that plasma cell myeloma with dual light chain expression may be more likely to be light chain only myeloma. It may have a high frequency of complex cytogenetic and/or FISH abnormalities, associated with a high-risk disease.
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Congenital acute leukemia is a rare form of childhood leukemia, in which lineage conversion at relapse is very rarely reported. Here we describe a case of congenital B-cell acute lymphoblastic leukemia (B-ALL) with t(4;11) and t(1;6) translocations, which at relapse underwent a switch to monocytic lineage with persistence of the original cytogenetic translocations and clonal rearrangement of the JH gene. Similar to the other described cases of congenital acute leukemia with lineage conversion, our case had a MLL gene rearrangement and followed an aggressive clinical course.
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Linfoma de Burkitt/genética , Leucemia Mieloide Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocação Genética , Linfoma de Burkitt/congênito , Linfoma de Burkitt/diagnóstico , Linhagem da Célula , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 4/genética , Cromossomos Humanos Par 6/genética , Análise Citogenética , Progressão da Doença , Evolução Fatal , Feminino , Histona-Lisina N-Metiltransferase , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Cadeias J de Imunoglobulina/genética , Imunofenotipagem , Recém-Nascido , Leucemia Mieloide Aguda/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/congênito , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Prognóstico , RecidivaRESUMO
Maternal floor infarction (also known as massive perivillous fibrin/fibrinoid deposition) is a rare and devastating pregnancy disorder associated with prematurity, fetal growth restriction, spontaneous abortion, and long-term neurologic impairment. Recurrence in multiple pregnancies is common. Little is known regarding either the pathophysiology or the management and treatment of patients at risk for recurrence in subsequent pregnancies. Most authors have emphasized maternal risk factors believed to act in a dominant fashion irrespective of fetal genotype. We report on dizygotic twins discordant for the development of placental maternal floor infarction and fetal growth restriction. The mother was a poorly controlled class C diabetic, and the onset of disease was coincident with the clinical onset of preeclampsia. This case demonstrates that fetal genotype, or some other factor specific to an individual fetoplacental unit, can lead to the differential expression of maternal floor infarction in dizygotic twins gestating in the same intrauterine environment.
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Infarto/patologia , Doenças Placentárias/patologia , Placenta/patologia , Gêmeos Dizigóticos , Adulto , Cesárea , Feminino , Retardo do Crescimento Fetal/etiologia , Humanos , Infarto/complicações , Masculino , Placenta/irrigação sanguínea , Doenças Placentárias/complicações , Gravidez , Resultado da Gravidez , Gravidez em DiabéticasAssuntos
Amplificação de Genes , Histona-Lisina N-Metiltransferase/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/complicações , Leucemia Mieloide Aguda/etiologia , Proteína de Leucina Linfoide-Mieloide/genética , Cromossomo Filadélfia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Células Cultivadas , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
Haematogones are precursor B cells commonly detected in small numbers in the bone marrow. Morphologically, haematogones can mimic lymphoblasts and are best distinguished using multicolour flow cytometry with antibody combinations. Haematogones show characteristic and reproducible patterns of antigen expression representing the B-cell maturation sequence. CD43 expression, widely seen in haematopoietic elements, has not been well characterized in haematogones. We demonstrate that CD43 is consistently expressed in haematogones in a reproducible pattern similar to that of CD10 when combined with CD20. We propose that in combination with other markers, CD43 can be useful in the identification of haematogones.