RESUMO
In vitro cancer cultures, including three-dimensional organoids, typically contain exclusively neoplastic epithelium but require artificial reconstitution to recapitulate the tumor microenvironment (TME). The co-culture of primary tumor epithelia with endogenous, syngeneic tumor-infiltrating lymphocytes (TILs) as a cohesive unit has been particularly elusive. Here, an air-liquid interface (ALI) method propagated patient-derived organoids (PDOs) from >100 human biopsies or mouse tumors in syngeneic immunocompetent hosts as tumor epithelia with native embedded immune cells (T, B, NK, macrophages). Robust droplet-based, single-cell simultaneous determination of gene expression and immune repertoire indicated that PDO TILs accurately preserved the original tumor T cell receptor (TCR) spectrum. Crucially, human and murine PDOs successfully modeled immune checkpoint blockade (ICB) with anti-PD-1- and/or anti-PD-L1 expanding and activating tumor antigen-specific TILs and eliciting tumor cytotoxicity. Organoid-based propagation of primary tumor epithelium en bloc with endogenous immune stroma should enable immuno-oncology investigations within the TME and facilitate personalized immunotherapy testing.
Assuntos
Modelos Imunológicos , Neoplasias Experimentais/imunologia , Organoides/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Microambiente Tumoral/imunologia , Animais , Antígeno B7-H1/imunologia , Técnicas de Cocultura , Feminino , Humanos , Imunoterapia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas de Neoplasias/imunologia , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Organoides/patologiaRESUMO
Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal paediatric tumours of the central nervous system1. We have previously shown that the disialoganglioside GD2 is highly expressed on H3K27M-mutated glioma cells and have demonstrated promising preclinical efficacy of GD2-directed chimeric antigen receptor (CAR) T cells2, providing the rationale for a first-in-human phase I clinical trial (NCT04196413). Because CAR T cell-induced brainstem inflammation can result in obstructive hydrocephalus, increased intracranial pressure and dangerous tissue shifts, neurocritical care precautions were incorporated. Here we present the clinical experience from the first four patients with H3K27M-mutated DIPG or spinal cord DMG treated with GD2-CAR T cells at dose level 1 (1 × 106 GD2-CAR T cells per kg administered intravenously). Patients who exhibited clinical benefit were eligible for subsequent GD2-CAR T cell infusions administered intracerebroventricularly3. Toxicity was largely related to the location of the tumour and was reversible with intensive supportive care. On-target, off-tumour toxicity was not observed. Three of four patients exhibited clinical and radiographic improvement. Pro-inflammatory cytokine levels were increased in the plasma and cerebrospinal fluid. Transcriptomic analyses of 65,598 single cells from CAR T cell products and cerebrospinal fluid elucidate heterogeneity in response between participants and administration routes. These early results underscore the promise of this therapeutic approach for patients with H3K27M-mutated DIPG or spinal cord DMG.
Assuntos
Astrocitoma , Neoplasias do Tronco Encefálico , Gangliosídeos , Glioma , Histonas , Imunoterapia Adotiva , Mutação , Receptores de Antígenos Quiméricos , Astrocitoma/genética , Astrocitoma/imunologia , Astrocitoma/patologia , Astrocitoma/terapia , Neoplasias do Tronco Encefálico/genética , Neoplasias do Tronco Encefálico/imunologia , Neoplasias do Tronco Encefálico/patologia , Neoplasias do Tronco Encefálico/terapia , Criança , Gangliosídeos/imunologia , Perfilação da Expressão Gênica , Glioma/genética , Glioma/imunologia , Glioma/patologia , Glioma/terapia , Histonas/genética , Humanos , Imunoterapia Adotiva/métodos , Receptores de Antígenos Quiméricos/imunologia , Neoplasias da Medula Espinal/genética , Neoplasias da Medula Espinal/imunologia , Neoplasias da Medula Espinal/patologia , Neoplasias da Medula Espinal/terapiaRESUMO
Adoptive cellular therapy using chimeric antigen receptors (CARs) has revolutionized our treatment of relapsed B cell malignancies and is currently being integrated into standard therapy. The impact of selecting specific T cell subsets for CAR transduction remains under investigation. Previous studies demonstrated that effector T cells derived from naive, rather than central memory T cells mediate more potent antitumor effects. Here, we investigate a method to skew CAR transduction toward naive T cells without physical cell sorting. Viral-mediated CAR transduction requires ex vivo T cell activation, traditionally achieved using antibody-mediated strategies. CD81 is a T cell costimulatory molecule that when combined with CD3 and CD28 enhances naive T cell activation. We interrogate the effect of CD81 costimulation on resultant CAR transduction. We identify that upon CD81-mediated activation, naive T cells lose their identifying surface phenotype and switch to a memory phenotype. By prelabeling naive T cells and tracking them through T cell activation and CAR transduction, we document that CD81 costimulation enhanced naive T cell activation and resultantly generated a CAR T cell product enriched with naive-derived CAR T cells.
Assuntos
Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/metabolismo , Tetraspanina 28/farmacologia , Bioengenharia/métodos , Antígenos CD28/imunologia , Complexo CD3/imunologia , Linhagem Celular Tumoral , Voluntários Saudáveis , Humanos , Imunoterapia Adotiva/métodos , Ativação Linfocitária/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/genética , Transdução de Sinais/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Linfócitos T/efeitos dos fármacos , Tetraspanina 28/imunologia , Tetraspanina 28/metabolismoRESUMO
The prognosis of patients with large B-cell lymphoma (LBCL) that progresses after treatment with chimeric antigen receptor (CAR) T-cell therapy targeting CD19 (CAR19) is poor. We report on the first 3 consecutive patients with autologous CAR19-refractory LBCL who were treated with a single infusion of autologous 1 × 106 CAR+ T cells per kilogram targeting CD22 (CAR22) as part of a phase 1 dose-escalation study. CAR22 therapy was relatively well tolerated, without any observed nonhematologic adverse events higher than grade 2. After infusion, all 3 patients achieved complete remission, with all responses continuing at the time of last follow-up (mean, 7.8 months; range, 6-9.3). Circulating CAR22 cells demonstrated robust expansion (peak range, 85.4-350 cells per microliter), and persisted beyond 3 months in all patients with continued radiographic responses and corresponding decreases in circulating tumor DNA beyond 6 months after infusion. Further accrual at a higher dose level in this phase 1 dose-escalation study is ongoing and will explore the role of this therapy in patients in whom prior CAR T-cell therapies have failed. This trial is registered on clinicaltrials.gov as #NCT04088890.
Assuntos
Antígenos CD19/imunologia , Imunoterapia Adotiva/métodos , Linfoma Difuso de Grandes Células B/terapia , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Ensaios Clínicos Fase I como Assunto , Humanos , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/patologia , Prognóstico , Indução de RemissãoRESUMO
PURPOSE OF REVIEW: Lymphodepleting chemotherapy (LD) has emerged as a key determinant of chimeric antigen receptor T cell (CAR) efficacy across pediatric/adult B cell malignancies. Clinical trials demonstrate the superiority of fludarabine/cyclophosphamide (Flu/Cy) regimens, resulting in the adoption of Flu/Cy as the pre-CAR LD standard. In the context of a global fludarabine shortage, consideration of alternative regimens is timely, yet limited clinical data exists, specifically in the pediatric B-ALL CAR setting. RECENT FINDINGS: Bendamustine has been used as an effective LD prior to CD19-CAR in adult lymphoma. Although use in the pediatric CAR setting is limited, tolerability has been established in pediatric Hodgkin's lymphoma. Clofarabine is a purine nucleoside analog with mechanistic overlap with fludarabine; however, toxicity is high in the upfront leukemia setting, and thus use as an LD pre-CAR should be pursued with caution. We review the experience using bendamustine and clofarabine to serve as a resource when considering LD regimens as an alternative to fludarabine for pediatric B-ALL.
Assuntos
Linfoma de Burkitt , Receptores de Antígenos Quiméricos , Humanos , Criança , Adulto Jovem , Receptores de Antígenos de Linfócitos T , Cloridrato de Bendamustina , Clofarabina , Linfoma de Burkitt/tratamento farmacológico , Ciclofosfamida/uso terapêutico , Imunoterapia Adotiva/métodosRESUMO
The use of radiotherapy as bridging therapy to chimeric antigen receptor T-cell therapy (CAR-T) in pre-B acute lymphoblastic leukemia (B-ALL) has been minimally explored. Here, we present a boy with B-ALL who relapsed after allogeneic bone marrow transplant with disseminated disease, including significant symptomatic cardiovascular and gastrointestinal (GI) involvement. The cardiac and GI leukemic infiltrates were successfully treated with bridging radiation therapy (BRT) prior to CAR-T infusion. Using this approach, he successfully tolerated CAR-T with no evidence of disease or sequelae on 3-month follow-up. This is the first reported case of safe and effective delivery of cardiac BRT in B-ALL.
Assuntos
Doenças Cardiovasculares/radioterapia , Gastroenteropatias/radioterapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Recidiva Local de Neoplasia/radioterapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Radioterapia/métodos , Adolescente , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/terapia , Terapia Combinada , Gastroenteropatias/etiologia , Gastroenteropatias/patologia , Gastroenteropatias/terapia , Humanos , Imunoterapia Adotiva/métodos , Infiltração Leucêmica/etiologia , Infiltração Leucêmica/patologia , Infiltração Leucêmica/radioterapia , Infiltração Leucêmica/terapia , Masculino , Recidiva Local de Neoplasia/etiologia , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , PrognósticoRESUMO
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.
Assuntos
Biomarcadores/análise , Epitopos/metabolismo , Antígenos HLA/metabolismo , Fragmentos de Peptídeos/metabolismo , Linfócitos T/classificação , Linfócitos T/metabolismo , Apresentação de Antígeno/imunologia , Epitopos/imunologia , Antígenos HLA/análise , Antígenos HLA/imunologia , Humanos , Imunoterapia , Fragmentos de Peptídeos/análise , Fragmentos de Peptídeos/imunologia , Linfócitos T/imunologia , Doadores de TecidosAssuntos
Antineoplásicos Imunológicos/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos de Linfócitos T/uso terapêutico , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Imunoterapia Adotiva , Lactente , Masculino , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE OF REVIEW: Building upon preclinical advances, we are uncovering immunotherapy strategies that are translating into improved outcomes in tumor subsets. Advanced pediatric solid tumors carry poor prognoses and resultant robust efforts to apply immunotherapy advances to pediatric solid tumors are in progress. Here, we discuss recent developments in the field using mAb and mAb-based therapies including checkpoint blockade and chimeric antigen receptors (CARs). RECENT FINDINGS: The pediatric solid tumor mAb experience targeting the diganglioside, GD2, for patients with neuroblastoma has been the most compelling to date. GD2 and alternative antigen-specific mAbs are now being incorporated into antibody-drug conjugates, bispecific antibodies and CARs for treatment of solid tumors. CARs in pediatric solid tumors have not yet achieved comparative responses to the hematologic CAR experience; however, novel strategies such as bispecific targeting, intratumoral administration and improved understanding of T-cell biology may yield enhanced CAR-efficacy. Therapeutic effect using single-agent checkpoint blocking antibodies in pediatric solid tumors also remains limited to date. Combinatorial strategies continue to hold promise and the clinical effect in tumor subsets with high antigenic burden is being explored. SUMMARY: Pediatric immunotherapy remains at early stages of translation, yet we anticipate that with advanced technology, we will achieve widespread, efficacious use of immunotherapy for pediatric solid tumors.
Assuntos
Imunoterapia/métodos , Neoplasias/terapia , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Criança , Humanos , Imunoterapia/tendências , Imunoterapia Adotiva , Neoplasias/imunologia , PediatriaRESUMO
Treatment with tisagenlecleucel (tisa-cel) achieves excellent complete remission rates in children and young adults with relapsed or refractory B cell acute lymphoblastic leukemia (B-ALL), but approximately 50% maintain long-term remission. Consolidative hematopoietic stem cell transplantation (cHSCT) is a potential strategy to reduce relapse risk, but it carries substantial short- and long-term toxicities. Additionally, several strategies for management of B cell recovery (BCR) and next-generation sequencing (NGS) positivity post-tisa-cel exist, without an accepted standard. We hypothesized that practice preferences surrounding cHSCT, as well as management of BCR and NGS positivity, varies across tisa-cel-prescribing physicians and sought to characterize current practice preferences. A survey focusing on preferences regarding the use of cHSCT, management of BCR, and NGS positivity was distributed to physicians who prescribe tisa-cel for children and young adults with B-ALL. Responses were collected from August 2022 to April 2023. Fifty-nine unique responses were collected across 43 institutions. All respondents prescribed tisa-cel for children and young adults. The clinical focus of respondents was HSCT in 71%, followed by leukemia/lymphoma in 24%. For HSCT-naive patients receiving tisa-cel, 57% of respondents indicated they made individualized decisions for cHSCT based on patient factors, whereas 22% indicated they would avoid cHSCT and 21% indicated they would pursue cHSCT when feasible. Certain factors influenced >50% of respondents towards recommending cHSCT (either an increased likelihood of recommending or always recommending), including preinfusion disease burden >25%, primary refractory B-ALL, M3 bone marrow following reinduction for relapse, KMT2A-rearranged B-ALL, history of blinatumomab nonresponse, and HSCT-naive status. Most respondents indicated they would pursue HSCT for HSCT-naive, total body irradiation (TBI) recipients with BCR before 6 months post-tisa-cel or with NGS positivity at 1 or 3 months post-tisa-cel, although there was variability in responses regarding whether to proceed to HSCT directly or provide intervening therapy prior to HSCT. Fewer respondents recommended HSCT for BCR or NGS positivity in patients with a history of HSCT, in noncandidates for TBI, and in patients with trisomy 21. The results of this survey indicate there exists significant practice variability regarding the use of cHSCT, as well as interventions for post-tisa-cel BCR or NGS positivity. These results highlight areas in which ongoing clinical trials could inform more standardized practice.
Assuntos
Linfoma de Burkitt , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Humanos , Adulto Jovem , Transplante de Células-Tronco Hematopoéticas/métodos , Receptores de Antígenos de Linfócitos T/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , RecidivaRESUMO
Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of B cell malignancies, with multiple CAR T cell products approved for numerous indications by regulatory agencies worldwide. However, significant work remains to be done to enhance these treatments. In March 2023, a group of experts in CAR T cell therapy assembled at the National Institutes of Health in Bethesda, Maryland at the Insights in Pediatric CAR T Cell Immunotherapy: Recent Advances and Future Directions (INSPIRED) Symposium to identify key areas for research for the coming years. In session 4B, correlative studies to be incorporated into future clinical trials and real-world settings were discussed. Active areas of research identified included (1) optimizing CAR T cell product manufacturing; (2) ensuring adequate lymphodepletion prior to CAR T cell administration; (3) overcoming immunoregulatory cells and tumor stroma present in the tumor microenvironment, particularly in solid tumors; (4) understanding tumor intrinsic properties that lead to CAR T cell immunotherapy resistance; and (5) uncovering biomarkers predictive of treatment resistance, treatment durability, or immune-related adverse events. Here we review the results of previously published clinical trials and real-world studies to summarize what is currently known about each of these topics. We then outline priorities for future research that we believe will be important for improving our understanding of CAR T cell therapy and ultimately leading to better outcomes for patients.
Assuntos
Neoplasias , Receptores de Antígenos Quiméricos , Estados Unidos , Humanos , Criança , Receptores de Antígenos Quiméricos/genética , Linfócitos T , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/uso terapêutico , Neoplasias/terapia , Imunoterapia Adotiva/efeitos adversos , Microambiente TumoralRESUMO
Chimeric antigen receptor (CAR) T cells targeting CD22 (CD22-CAR) provide a therapeutic option for patients with CD22+ malignancies with progression after CD19-directed therapies. Using on-site, automated, closed-loop manufacturing, we conducted parallel Phase 1b clinical trials investigating a humanized CD22-CAR with 41BB costimulatory domain in children and adults with heavily treated, relapsed/refractory (r/r) B-ALL. Of 19 patients enrolled, 18 had successful CD22-CAR manufacturing, and 16 patients were infused. High grade (3-4) cytokine release syndrome (CRS) and immune effector-cell-associated neurotoxicity syndrome (ICANS) each occurred in only one patient; however, three patients experienced immune-effector-cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS). Twelve of 16 patients (75%) achieved CR with an overall 56% MRD-negative CR rate. Duration of response was overall limited (median 77 days), and CD22 expression was downregulated in 4/12 (33%) available samples at relapse. In summary, we demonstrate that closed-loop manufacturing of CD22-CAR T cells is feasible and is associated with a favorable safety profile and high CR rates in pediatric and adult r/r B-ALL, a cohort with limited CD22-CAR reporting.
Assuntos
Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Receptores de Antígenos Quiméricos , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico , Humanos , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Criança , Adulto , Feminino , Masculino , Adolescente , Imunoterapia Adotiva/métodos , Imunoterapia Adotiva/efeitos adversos , Adulto Jovem , Receptores de Antígenos Quiméricos/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Pré-Escolar , Pessoa de Meia-Idade , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
H3K27M-mutant diffuse midline gliomas (DMGs) express high levels of the GD2 disialoganglioside and chimeric antigen receptor modified T-cells targeting GD2 (GD2-CART) eradicate DMGs in preclinical models. Arm A of the Phase I trial NCT04196413 administered one IV dose of autologous GD2-CART to patients with H3K27M-mutant pontine (DIPG) or spinal (sDMG) diffuse midline glioma at two dose levels (DL1=1e6/kg; DL2=3e6/kg) following lymphodepleting (LD) chemotherapy. Patients with clinical or imaging benefit were eligible for subsequent intracerebroventricular (ICV) GD2-CART infusions (10-30e6 GD2-CART). Primary objectives were manufacturing feasibility, tolerability, and identification of a maximally tolerated dose of IV GD2-CART. Secondary objectives included preliminary assessments of benefit. Thirteen patients enrolled and 11 received IV GD2-CART on study [n=3 DL1(3 DIPG); n=8 DL2(6 DIPG/2 sDMG). GD2-CART manufacturing was successful for all patients. No dose-limiting toxicities (DLTs) occurred on DL1, but three patients experienced DLT on DL2 due to grade 4 cytokine release syndrome (CRS). Nine patients received ICV infusions, which were not associated with DLTs. All patients exhibited tumor inflammation-associated neurotoxicity (TIAN). Four patients demonstrated major volumetric tumor reductions (52%, 54%, 91% and 100%). One patient exhibited a complete response ongoing for >30 months since enrollment. Eight patients demonstrated neurological benefit based upon a protocol-directed Clinical Improvement Score. Sequential IV followed by ICV GD2-CART induced tumor regressions and neurological improvements in patients with DIPG and sDMG. DL1 was established as the maximally tolerated IV GD2-CART dose. Neurotoxicity was safely managed with intensive monitoring and close adherence to a management algorithm.
RESUMO
INTRODUCTION: Antigen downregulation and early chimeric antigen receptor (CAR) T-cell loss have emerged as two major challenges threatening outcomes following CD19-specific CAR T-cell therapy for children and young adults with B-cell acute lymphoblastic leukemia (B-ALL). In addressing the future of CAR T-cell therapy for B-ALL, innovative strategies to avert antigen downregulation and enhance CAR persistence warrant prioritized focus. AREAS COVERED: We describe promising engineering strategies to refine CAR constructs to reverse exhaustion, develop regulatable CARs, optimize manufacturing, enrich for immune memory, and disrupt immune inhibition. We additionally focus on alternative targeting to CD19-monospecific targeting and contextualize possibilities for expanded CAR utilization. EXPERT OPINION: We describe research advances as they are independently reported, however, anticipate an integrative strategy incorporating complementary modifications will be required to effectively address CAR loss, overcome antigen downregulation, and enhance reliability and durability of CAR T-cell responses for B-ALL.
Assuntos
Pediatria , Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores de Antígenos Quiméricos , Adulto Jovem , Criança , Humanos , Adolescente , Imunoterapia Adotiva , Receptores de Antígenos de Linfócitos T/genética , Reprodutibilidade dos Testes , Receptores de Antígenos Quiméricos/genética , Antígenos CD19RESUMO
Classic Hodgkin lymphoma (CHL) patients may infrequently present with a prior or recurrent disease with discordant histology resembling non-Hodgkin lymphomas. These include primary mediastinal large B-cell lymphoma (PMBL), diffuse large B-cell lymphoma (DLBCL), or mediastinal gray-zone lymphoma (MGZL). Such patients are often refractory to standard therapy and their diagnosis is hampered by significant morphologic and immunophenotypic overlap and insufficient molecular data. Among 509 CHL patients seen at an academic medical center, 6 patients had a prior or subsequent diagnosis different from CHL. Paired tissue samples were evaluated by targeted mutational analysis using a 164-gene panel. Our findings show multiple shared variants indicative of a clonal relationship between the CHL and the PMBL, DLBCL, or MGZL diagnoses. Most frequent mutated genes included TNFAIP3 (4 of 6, 66.7%), STAT6 (3 or 6, 50%), ARID1A (3 of 6, 50%), and XPO1 (3 of 5, 60%). Three patients showed the same oncogenic variant within the XPO1 gene (E571K), and mutations in TNFAIP3 and B2M were observed in 2 of the 5 patients with shared variants. In addition, differences in the mutation profile between the lymphoma pairs were also observed, which could represent clonal evolution. Mutational profiling could be of benefit in patients with recurrent/refractory disease with discordant histology, where the clonal relationship could be helpful to inform and guide therapeutic decisions. These findings provide further evidence of a true biological continuum surrounding CHL, PMBL, DLBCL, and MGZL and shed light on underlying genetic events and their clinical impact.
Assuntos
Doença de Hodgkin , Linfoma Difuso de Grandes Células B , Neoplasias do Mediastino , Humanos , Neoplasias do Mediastino/genética , Neoplasias do Mediastino/terapia , Neoplasias do Mediastino/diagnóstico , Doença de Hodgkin/diagnóstico , Linfoma Difuso de Grandes Células B/patologia , Imunofenotipagem , MutaçãoRESUMO
BACKGROUND: Chimeric antigen receptor (CAR) T cell therapy is an effective salvage therapy for pediatric relapsed B-cell acute lymphoblastic leukemia (B-ALL), yet is challenged by high rates of post-CAR relapse. Literature describing specific relapse patterns and extramedullary (EM) sites of involvement in the post-CAR setting remains limited, and a clinical standard for post-CAR disease surveillance has yet to be established. We highlight the importance of integrating peripheral blood minimal residual disease (MRD) testing and radiologic imaging into surveillance strategies, to effectively characterize and capture post-CAR relapse. MAIN BODY: Here, we describe the case of a child with multiply relapsed B-ALL who relapsed in the post-CAR setting with gross non-contiguous medullary and EM disease. Interestingly, her relapse was identified first from peripheral blood flow cytometry MRD surveillance, in context of a negative bone marrow aspirate (MRD <0.01%). Positron emission tomography with 18F-fluorodeoxyglucose revealed diffuse leukemia with innumerable bone and lymph node lesions, interestingly sparing her sacrum, the site of her bone marrow aspirate sampling. CONCLUSIONS: We highlight this case as both peripheral blood MRD and 18F-fluorodeoxyglucose positron emission tomography imaging were more sensitive than standard bone marrow aspirate testing in detecting this patient's post-CAR relapse. Clinical/Biologic Insight: In the multiply relapsed B-ALL setting, where relapse patterns may include patchy medullary and/or EM disease, peripheral blood MRD and/or whole body imaging, may carry increased sensitivity at detecting relapse in patient subsets, as compared with standard bone marrow sampling.
Assuntos
Linfoma de Burkitt , Leucemia , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Criança , Feminino , Fluordesoxiglucose F18 , Medula Óssea/diagnóstico por imagem , Neoplasia Residual , Tomografia por Emissão de Pósitrons , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico por imagem , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapiaRESUMO
Chimeric antigen receptor (CAR) T cell therapy (CAR-T) targeting the CD19 antigen on B cell acute lymphoblastic leukemia (B-ALL) has transitioned from a highly investigational therapy with limited access to a commercial therapy with established toxicities, response and survival rates, and access in numerous countries. With more than a decade of clinical study and 5 years of commercial access, data showing associations with success and failure have emerged. To address functional limitations of CAR-T and overcome constrained sample sizes when studying single-trial or single-center data, collaborative groups, including the Pediatric Real World CAR Consortium, the CAR-Multicenter Analysis, the Center for International Blood and Marrow Transplant Research, and the International BFM Study Group, among others, have been retrospectively interrogating the amassed clinical experience. The high patient numbers and varied clinical experiences compiled by these groups have defined clinical variables impacting CAR-T outcomes. Here we review published CAR-T trials and consortium/collaborative outcomes to establish variables associated with optimal response to CAR-T in children and young adults with B-ALL. We focus on findings with clinical relevance that have emerged, including data implicating pretreatment disease burden, presence of extramedullary disease, nonresponse to prior CD19 antigen targeting (blinatumomab therapy), CAR T cell dose, and fludarabine pharmacokinetics as factors impacting post-CAR-T survival. Additionally, we address the role of collaborative efforts going forward in guiding clinical practice evolution and further optimizing post-CAR-T outcomes.
Assuntos
Linfoma de Burkitt , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores de Antígenos Quiméricos , Humanos , Criança , Adulto Jovem , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/uso terapêutico , Antígenos CD19 , Estudos Retrospectivos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Linfoma de Burkitt/tratamento farmacológico , Linfócitos T , Estudos Multicêntricos como AssuntoRESUMO
Background: Tisagenlecleucel was approved by the Food and Drug Administration (FDA) in 2017 for refractory B-cell acute lymphoblastic leukemia (B-ALL) and B-ALL in ≥2nd relapse. Outcomes of patients receiving commercial tisagenlecleucel upon 1st relapse have yet to be established. We aimed to report real-world tisagenlecleucel utilisation patterns and outcomes across indications, specifically including patients treated in 1st relapse, an indication omitted from formal FDA approval. Methods: We conducted a retrospective analysis of real-world tisagenlecleucel utilisation patterns across 185 children and young adults treated between August 30, 2017 and March 6, 2020 from centres participating in the Pediatric Real-World CAR Consortium (PRWCC), within the United States. We described definitions of refractory B-ALL used in the real-world setting and categorised patients by reported Chimeric Antigen Receptor (CAR) T-cell indication, including refractory, 1st relapse and ≥2nd relapse B-ALL. We analysed baseline patient characteristics and post-tisagenlecleucel outcomes across defined cohorts. Findings: Thirty-six percent (n = 67) of our cohort received tisagenlecleucel following 1st relapse. Of 66 evaluable patients, 56 (85%, 95% CI 74-92%) achieved morphologic complete response. Overall-survival (OS) and event-free survival (EFS) at 1-year were 69%, (95% CI 58-82%) and 49%, (95% CI 37-64%), respectively, with survival outcomes statistically comparable to remaining patients (OS; p = 0.14, EFS; p = 0.39). Notably, toxicity was increased in this cohort, warranting further study. Interestingly, of 30 patients treated for upfront refractory disease, 23 (77%, 95% CI 58-90%) had flow cytometry and/or next-generation sequencing (NGS) minimum residual disease (MRD)-only disease at the end of induction, not meeting the historic morphologic definition of refractory. Interpretation: Our findings suggested that tisagenlecleucel response and survival rates overlap across patients treated with upfront refractory B-ALL, B-ALL ≥2nd relapse and B-ALL in 1st relapse. We additionally highlighted that definitions of refractory B-ALL are evolving beyond morphologic measures of residual disease. Funding: St. Baldrick's/Stand Up 2 Cancer, Parker Institute for Cancer Immunotherapy, Virginia and D.K. Ludwig Fund for Cancer Research.
RESUMO
Cancer immunotherapies have unique toxicities. Establishment of grading scales and standardized grade-based treatment algorithms for toxicity syndromes can improve the safety of these treatments, as observed for cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) in patients with B cell malignancies treated with chimeric antigen receptor (CAR) T cell therapy. We have observed a toxicity syndrome, distinct from CRS and ICANS, in patients treated with cell therapies for tumors in the central nervous system (CNS), which we term tumor inflammation-associated neurotoxicity (TIAN). Encompassing the concept of 'pseudoprogression,' but broader than inflammation-induced edema alone, TIAN is relevant not only to cellular therapies, but also to other immunotherapies for CNS tumors. To facilitate the safe administration of cell therapies for patients with CNS tumors, we define TIAN, propose a toxicity grading scale for TIAN syndrome and discuss the potential management of this entity, with the goal of standardizing both reporting and management.