RESUMEN
The efficacy of T cell-based immunotherapies is limited by immunosuppressive pressures in the tumor microenvironment. Here we show a predominant role for the interaction between BTLA on effector T cells and HVEM (TNFRSF14) on immunosuppressive tumor microenvironment cells, namely regulatory T cells. High BTLA expression in chimeric antigen receptor (CAR) T cells correlated with poor clinical response to treatment. Therefore, we deleted BTLA in CAR T cells and show improved tumor control and persistence in models of lymphoma and solid malignancies. Mechanistically, BTLA inhibits CAR T cells via recruitment of tyrosine phosphatases SHP-1 and SHP-2, upon trans engagement with HVEM. BTLA knockout thus promotes CAR signaling and subsequently enhances effector function. Overall, these data indicate that the BTLA-HVEM axis is a crucial immune checkpoint in CAR T cell immunotherapy and warrants the use of strategies to overcome this barrier.
Asunto(s)
Inmunoterapia Adoptiva , Receptores Quiméricos de Antígenos , Receptores Inmunológicos , Miembro 14 de Receptores del Factor de Necrosis Tumoral , Microambiente Tumoral , Animales , Humanos , Inmunoterapia Adoptiva/métodos , Miembro 14 de Receptores del Factor de Necrosis Tumoral/metabolismo , Miembro 14 de Receptores del Factor de Necrosis Tumoral/inmunología , Miembro 14 de Receptores del Factor de Necrosis Tumoral/genética , Ratones , Microambiente Tumoral/inmunología , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/metabolismo , Receptores Quiméricos de Antígenos/genética , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/genética , Linfocitos T Reguladores/inmunología , Transducción de Señal , Línea Celular Tumoral , Neoplasias/inmunología , Neoplasias/terapia , Ratones NoqueadosRESUMEN
Splenic marginal zone B-cell lymphoma (SMZL) is a heterogeneous clinico-biological entity. The clinical course is variable, multiple genes are mutated with no unifying mechanism, and essential regulatory pathways and surrounding microenvironments are diverse. We sought to clarify the heterogeneity of SMZL by resolving different subgroups and their underlying genomic abnormalities, pathway signatures, and microenvironment compositions to uncover biomarkers and therapeutic vulnerabilities. We studied 303 SMZL spleen samples collected through the IELSG46 multicenter international study (NCT02945319) by using a multiplatform approach. We carried out genetic and phenotypic analyses, defined self-organized signatures, validated the findings in independent primary tumor metadata and in genetically modified mouse models, and determined correlations with outcome data. We identified 2 prominent genetic clusters in SMZL, termed NNK (58% of cases, harboring NF-κB, NOTCH, and KLF2 modules) and DMT (32% of cases, with DNA-damage response, MAPK, and TLR modules). Genetic aberrations in multiple genes as well as cytogenetic and immunogenetic features distinguished NNK- from DMT-SMZLs. These genetic clusters not only have distinct underpinning biology, as judged by differences in gene-expression signatures, but also different outcomes, with inferior survival in NNK-SMZLs. Digital cytometry and in situ profiling segregated 2 basic types of SMZL immune microenvironments termed immune-suppressive SMZL (50% of cases, associated with inflammatory cells and immune checkpoint activation) and immune-silent SMZL (50% of cases, associated with an immune-excluded phenotype) with distinct mutational and clinical connotations. In summary, we propose a nosology of SMZL that can implement its classification and also aid in the development of rationally targeted treatments.
Asunto(s)
Linfoma de Células B de la Zona Marginal , Neoplasias del Bazo , Anciano , Animales , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Aberraciones Cromosómicas , Inmunofenotipificación , Linfoma de Células B de la Zona Marginal/diagnóstico , Linfoma de Células B de la Zona Marginal/genética , Familia de Multigenes , Mutación , Bazo/patología , Neoplasias del Bazo/diagnóstico , Neoplasias del Bazo/genética , Transcriptoma , Microambiente TumoralRESUMEN
Several studies have shown the influence of commensal microbes on T cell function, specifically in the setting of checkpoint immunotherapy for cancer. In this study, we investigated how vancomycin-induced gut microbiota dysbiosis affects chimeric antigen receptor (CAR) T immunotherapy using multiple preclinical models as well as clinical correlates. In two murine tumor models, hematopoietic CD19+-A20 lymphoma and CD19+-B16 melanoma, mice receiving vancomycin in combination with CD19-directed CAR T cell (CART-19) therapy displayed increased tumor control and tumor-associated antigens (TAAs) cross-presentation compared with CART-19 alone. Fecal microbiota transplant from human healthy donors to pre-conditioned mice recapitulated the results obtained in naive gut microbiota mice. Last, B cell acute lymphoblastic leukemia patients treated with CART-19 and exposed to oral vancomycin showed higher CART-19 peak expansion compared with unexposed patients. These results substantiate the role of the gut microbiota on CAR T cell therapy and suggest that modulation of the gut microbiota using vancomycin may improve outcomes after CAR T cell therapy across tumor types.
Asunto(s)
Microbioma Gastrointestinal , Receptores Quiméricos de Antígenos , Humanos , Ratones , Animales , Receptores de Antígenos de Linfocitos T/genética , Reactividad Cruzada , Vancomicina/farmacología , Inmunoterapia , Linfocitos T , Inmunoterapia Adoptiva/métodos , Receptores Quiméricos de Antígenos/genética , Antígenos CD19RESUMEN
BACKGROUND: Commercial anti-CD19 chimeric antigen receptor T-cell therapies (CART19) are efficacious against advanced B-cell non-Hodgkin lymphoma (NHL); however, most patients ultimately relapse. Several mechanisms contribute to this failure, including CD19-negative escape and CAR T dysfunction. All four commercial CART19 products utilize the FMC63 single-chain variable fragment (scFv) specific to a CD19 membrane-distal epitope and characterized by slow association (on) and dissociation (off) rates. We hypothesized that a novel anti-CD19 scFv that engages an alternative CD19 membrane-proximal epitope independent of FMC63 and that is characterized by faster on- and off-rates could mitigate CART19 failure and improve clinical efficacy. METHODS: We developed an autologous CART19 product with 4-1BB co-stimulation using a novel humanized chicken antibody (h1218). This antibody is specific to a membrane-proximal CD19 epitope and harbors faster on/off rates compared to FMC63. We tested h1218-CART19 in vitro and in vivo using FMC63-CART19-resistant models. We conducted a first-in-human multi-center phase I clinical trial to test AT101 (clinical-grade h1218-CART19) in patients with relapsed or refractory (r/r) NHL. RESULTS: Preclinically, h1218- but not FMC63-CART19 were able to effectively eradicate lymphomas expressing CD19 point mutations (L174V and R163L) or co-expressing FMC63-CAR19 as found in patients relapsing after FMC63-CART19. Furthermore, h1218-CART19 exhibited enhanced killing of B-cell malignancies in vitro and in vivo compared with FMC63-CART19. Mechanistically, we found that h1218-CART19 had reduced activation-induced cell death (AICD) and enhanced expansion compared to FMC63-CART19 owing to faster on- and off-rates. Based on these preclinical results, we performed a phase I dose-escalation trial, testing three dose levels (DL) of AT101 (the GMP version of h1218) using a 3 + 3 design. In 12 treated patients (7 DLBCL, 3 FL, 1 MCL, and 1 MZL), AT101 showed a promising safety profile with 8.3% grade 3 CRS (n = 1) and 8.3% grade 4 ICANS (n = 1). In the whole cohort, the overall response rate was 91.7%, with a complete response rate of 75.0%, which improved to 100% in DL-2 and -3. AT101 expansion correlates with CR and B-cell aplasia. CONCLUSIONS: We developed a novel, safe, and potent CART19 product that recognizes a membrane-proximal domain of CD19 with fast on- and off-rates and showed significant efficacy and promising safety in patients with relapsed B-cell NHL. TRIAL REGISTRATION: NCT05338931; Date: 2022-04-01.
Asunto(s)
Linfoma no Hodgkin , Receptores de Antígenos de Linfocitos T , Receptores Quiméricos de Antígenos , Humanos , Anticuerpos , Antígenos CD19 , Epítopos/metabolismo , Inmunoterapia Adoptiva/efectos adversos , Linfoma no Hodgkin/terapia , Linfoma no Hodgkin/metabolismo , Recurrencia Local de Neoplasia/metabolismo , Receptores Quiméricos de Antígenos/metabolismo , Receptores de Antígenos de Linfocitos T/antagonistas & inhibidoresRESUMEN
Chimeric antigen receptor (CAR) T cells (CART) therapies have changed and continue to change the treatment paradigms for B-cell malignancies because they can achieve durable complete remission in patients in whom multiple lines of treatment have failed. These unprecedented results have led to the widespread use of anti-CD19 CART therapy for patients with relapsed and refractory aggressive large B-cell lymphomas. While long-term follow-up data show that about one-third of patients achieve prolonged complete remission and are potentially cured, the majority of patients either do not respond to CD19 CART therapy or eventually relapse after CD19 CART therapy. These results are, on the one hand, driving intense research into identifying mechanisms of relapse and, on the other hand, inspiring the development of novel strategies to overcome resistance. This review summarizes current clinical outcomes of CART immunotherapy in B-cell non-Hodgkin lymphomas, describes the most up-to-date understanding of mechanisms of relapse and discusses novel strategies to address resistance to CART therapy. We are indeed at the beginning of a scientific trek to explore the mechanisms of resistance, seek out new, more effective treatment approaches based on these discoveries and to boldly go where no other therapy has gone before!
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Inmunoterapia Adoptiva , Linfoma de Células B Grandes Difuso/terapia , Receptores Quiméricos de Antígenos/uso terapéutico , Humanos , Linfoma de Células B Grandes Difuso/sangreRESUMEN
Daratumumab, an anti-CD38 antibody, is effective in AL amyloidosis with low tumor burden. Data of daratumumab treatment in patients with AL amyloidosis but high tumor burden (≥10% bone marrow plasma cells) are limited. We report retrospective data of 10 consecutive patients with high tumor burden treated with daratumumab for relapsed/refractory AL amyloidosis. The median age at diagnosis was 62.3 years; all patients had cardiac involvement, and six (60%) patients had renal involvement. Median bone marrow plasma cell infiltration was 15% (range 10%-40%), and the median difference between involved and noninvolved free light-chains (dFLC) was 446 mg/L (range 102-1392 mg/L). Patients had a median of three prior lines of therapy, including bortezomib in all patients and lenalidomide in seven (70%) patients. The median time to first hematological response was 14 days (range 7-28 days), and the median time to best hematological response was 64 days (range 7-301 days). The hematological overall response was 90%, with high-quality response (≥ very good partial remission [VGPR]) in 70% of the patients. Fifty percent of the patients had a cardiac response after a median of 3.8 months (range 0.7-9.1). Infusion-related adverse events ≤ grade 2 occurred in seven (70%) patients and grade 3 adverse events in one patient. After a median follow-up time of 10 months, eight (80%) patients continued to receive daratumumab. We conclude that daratumumab is a very effective and safe treatment option in AL patients with relapsed/refractory disease and high disease burden at diagnosis. Daratumumab leads to rapid disease control and improvement of organ function.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/diagnóstico , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/tratamiento farmacológico , Recuento de Linfocitos , Células Plasmáticas/patología , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Médula Ósea/metabolismo , Médula Ósea/patología , Resistencia a Antineoplásicos , Femenino , Humanos , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/mortalidad , Infecciones/etiología , Infecciones/terapia , Masculino , Persona de Mediana Edad , Recurrencia , Retratamiento , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Fludarabine, cyclophosphamide, and rituximab (FCR) has represented a significant treatment advancement in chronic lymphocytic leukemia (CLL). In the new scenario of targeted agents, there is an increasing interest in identifying patients who gain the maximum benefit from FCR. In this observational multicenter retrospective analysis of 404 CLL patients receiving frontline FCR, the combination of three biomarkers that are widely tested before treatment (IGHV mutation status, 11q deletion and 17p deletion; available in 80% of the study cohort) allowed to identify a very low-risk category of patients carrying mutated IGHV genes but neither 11q or 17p deletion that accounted for 28% of all cases. The majority of very low-risk patients (71%) remained free of progression after treatment and their hazard of relapse decreased after 4 years from FCR. The life expectancy of very low-risk patients (91% at 5 years) was superimposable to that observed in the matched normal general population, indicating that neither the disease nor complications of its treatment affected survival in this favorable CLL group. These findings need a prospective validation and may be helpful for the design of clinical trials aimed at comparing FCR to new targeted treatments of CLL, and, possibly, for optimized disease management.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Deleción Cromosómica , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 17/genética , Leucemia Linfocítica Crónica de Células B , Síndrome de Smith-Magenis , Anciano , Ciclofosfamida/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Persona de Mediana Edad , Rituximab/administración & dosificación , Tasa de Supervivencia , Vidarabina/administración & dosificación , Vidarabina/análogos & derivadosRESUMEN
Bendamustine has been retrospectively shown to be an effective and safe lymphodepletion regimen prior to the anti-CD19 chimeric antigen receptor T cell (CART) products tisagenlecleucel and axicabtagene ciloleucel, as well as the anti-BCMA CART products idecabtagene vicleucel and ciltacabtagene autoleucel. However, bendamustine as lymphodepletion prior to lisocabtagene maraleucel (liso-cel), a 4-1BB co-stimulated, fixed CD4:CD8 ratio anti-CD19 CART product, has not been described yet. Thus, we studied a cohort of sequentially-treated patients with large B-cell lymphomas who received bendamustine lymphodepletion before liso-cel at the University of Pennsylvania between 5/2021 and 12/2023 (n = 31). Patients were evaluated for toxicities and responses. Of note, 7 patients (22.6%) would have dnot met the inclusion criteria for the registrational liso-cel clinical trials, mostly due to older age. Overall and complete response rates were 76.9% and 73.1%, respectively. At a median follow-up of 6.3 months, the 6-month progression-free and overall survival were 59.9% and 91.1%, respectively. Rates of cytokine-release syndrome (CRS) and neurotoxicity (ICANS) of any grade were 9.7% and 9.7%, respectively, with no grade ≥ 3 events. No infections were reported during the first 30 days following liso-cel infusion. Neutropenia ≥ grade 3 was observed in 29.0% of patients; thrombocytopenia ≥ grade 3 occurred in 9.7%. In conclusion, bendamustine lymphodepletion before liso-cel appears to be a strategy that can drive tumor responses while ensuring a mild toxicity profile.
Asunto(s)
Clorhidrato de Bendamustina , Inmunoterapia Adoptiva , Humanos , Clorhidrato de Bendamustina/uso terapéutico , Persona de Mediana Edad , Masculino , Femenino , Anciano , Inmunoterapia Adoptiva/métodos , Inmunoterapia Adoptiva/efectos adversos , Estudios Retrospectivos , Adulto , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Antineoplásicos Alquilantes/uso terapéutico , Antineoplásicos Alquilantes/efectos adversos , Productos Biológicos/uso terapéutico , Productos Biológicos/efectos adversos , Anciano de 80 o más Años , Resultado del TratamientoRESUMEN
Chimeric antigen receptor (CAR) T cell therapy targeting CD19 elicits remarkable clinical efficacy in B-cell malignancies, but many patients relapse due to failed expansion and/or progressive loss of CAR-T cells. We recently reported a strategy to potently restimulate CAR-T cells in vivo, enhancing their functionality by administration of a vaccine-like stimulus comprised of surrogate peptide ligands for a CAR linked to a lymph node-targeting amphiphilic PEG-lipid (termed CAR-T-vax). Here, we demonstrate a general strategy to generate and optimize peptide mimotopes enabling CAR-T-vax generation for any CAR. Using the clinical CD19 CAR FMC63 as a test case, we employed yeast surface display to identify peptide binders to soluble IgG versions of FMC63, which were subsequently affinity matured by directed evolution. CAR-T vaccines using these optimized mimotopes triggered marked expansion of both murine CD19 CAR-T cells in a syngeneic model and human CAR-T cells in a humanized mouse model of B cell acute lymphoblastic leukemia (B-ALL), and enhanced control of leukemia progression. This approach thus enables vaccine boosting to be applied to any clinically-relevant CAR-T cell product.
RESUMEN
Brexucabtagene autoleucel (brexu-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for treatment of relapsed/refractory mantle cell lymphoma (MCL). During a fludarabine shortage, we used bendamustine as an alternative to standard cyclophosphamide/fludarabine (cy/flu) lymphodepletion (LD) prior to brexu-cel. We assessed MCL patient outcomes as well as CAR T-cell expansion and persistence after brexu-cel following bendamustine or cy/flu LD at our center. This was a retrospective single institution study that utilized prospectively banked blood and tissue samples. Clinical efficacy was assessed by 2014 Lugano guidelines. CAR T-cell expansion and persistence in peripheral blood were assessed on day 7 and at ≥month 6 for patients with available samples. Seventeen patients received bendamustine and 5 received cy/flu. For the bendamustine cohort, 14 (82%) received bridging therapy and 4 (24%) had CNS involvement. Fifteen patients (88%) developed CRS with 4 (24%) ≥grade 3 events. Six (35%) patients developed ICANS with 4 (24%) events ≥grade 3. No patient had ≥grade 3 cytopenias at day 90. Best objective (BOR) and complete response (CRR) rates were 82% and 65%, respectively. At 24.5 months median follow-up, 12-month progression-free survival (PFS) was 45%, 24-month PFS was 25%, and median duration of response was 19 months. Median OS was not reached. BOR was 25% (1/4) for patients with CNS involvement. CAR transgene expansion after bendamustine LD was observed on day 7 in all (4/4) patients tested and persisted at ≥6 months (2/2), regardless of response. Bendamustine LD before brexu-cel for MCL is feasible and safe with a lower frequency and shorter duration of cytopenias than reported for cy/flu. Both CAR T-cell expansion and persistence were observed after bendamustine LD. Outcomes appear comparable to the real world outcomes reported with cy/flu LD.
Asunto(s)
Clorhidrato de Bendamustina , Inmunoterapia Adoptiva , Linfoma de Células del Manto , Humanos , Clorhidrato de Bendamustina/uso terapéutico , Clorhidrato de Bendamustina/administración & dosificación , Linfoma de Células del Manto/tratamiento farmacológico , Masculino , Femenino , Persona de Mediana Edad , Anciano , Estudios Retrospectivos , Inmunoterapia Adoptiva/métodos , Vidarabina/análogos & derivados , Vidarabina/uso terapéutico , Vidarabina/administración & dosificación , Adulto , Antineoplásicos Alquilantes/uso terapéutico , Antineoplásicos Alquilantes/administración & dosificación , Antígenos CD19/inmunología , Resultado del TratamientoRESUMEN
We report a T cell lymphoma (TCL) occurring 3 months after anti-CD19 chimeric antigen receptor (CAR) T cell immunotherapy for non-Hodgkin B cell lymphoma. The TCL was diagnosed from a thoracic lymph node upon surgery for lung cancer. The TCL exhibited CD8+ cytotoxic phenotype and a JAK3 variant, while the CAR transgene was very low. The T cell clone was identified at low levels in the blood before CAR T infusion and in lung cancer. To assess the overall risk of secondary primary malignancy after commercial CAR T (CD19, BCMA), we analyzed 449 patients treated at the University of Pennsylvania. At a median follow-up of 10.3 months, 16 patients (3.6%) had a secondary primary malignancy. The median onset time was 26.4 and 9.7 months for solid and hematological malignancies, respectively. The projected 5-year cumulative incidence is 15.2% for solid and 2.3% for hematological malignancies. Overall, one case of TCL was observed, suggesting a low risk of TCL after CAR T.
Asunto(s)
Neoplasias Hematológicas , Neoplasias Pulmonares , Linfoma de Células B , Linfoma de Células T , Receptores Quiméricos de Antígenos , Humanos , Inmunoterapia Adoptiva/efectos adversos , Receptores Quiméricos de Antígenos/genética , Receptores de Antígenos de Linfocitos T/genética , Antígenos CD19RESUMEN
BACKGROUND: Administration of anti-CD19 chimeric antigen receptor T-cell (CART19) immunotherapy for large B-cell lymphomas (LBCLs), a subset of non-Hodgkin lymphoma (NHL), involves high costs and access to specialized tertiary care centers. We investigated whether minority health populations (MHPs) have equal access to CART19 and whether their outcomes are similar to those of non-MHPs. METHODS: We analyzed the prevalence and clinical outcomes of patients treated with commercial CART19 at two geographically and socioeconomically different institutions: the Abramson Cancer Center (ACC, Philadelphia, Pennsylvania) and the Knight Cancer Institute (KCI, Portland, Oregon). RESULTS: In the ACC catchment area, 8956 patients were diagnosed with NHL between 2015 and 2019 (latest available data from the state registry), including 17.9% MHPs. In the ACC, between 2018 and 2022 (CART became available in 2018), 1492 patients with LBCL were treated, and 194 received CART19. The proportion of MHPs was 15.7% for the entire LBCL cohort but only 6.7% for the CART19 cohort. During the same time, in the KCI catchment area, 4568 patients were diagnosed with NHL, including 4.2% MHPs. In the KCI, 396 patients with LBCL were treated, and 47 received CART19. The proportion of MHPs was 6.6% for the entire LBCL cohort and 4.2% for the CART19 cohort. The 3-month response, survival, and toxicities after CART19 infusion showed similar results, although the number of patients who were treated was limited. CONCLUSIONS: This study shows that the access of MHPs to tertiary centers for LBCL care was preserved but appeared reduced for commercial CART19 immunotherapy. Although clinical outcomes of MHPs seemed similar to those of non-MHPs, the small sample size precludes drawing firm conclusions. Further studies are needed. (Funded by the Laffey McHugh Foundation and others.).
Asunto(s)
Inmunoterapia Adoptiva , Humanos , Masculino , Femenino , Persona de Mediana Edad , Inmunoterapia Adoptiva/efectos adversos , Anciano , Adulto , Grupos Minoritarios/estadística & datos numéricos , Receptores Quiméricos de Antígenos/inmunología , Antígenos CD19/inmunología , Antígenos CD19/uso terapéuticoRESUMEN
ABSTRACT: Lymphodepletion (LD) is an integral component of chimeric antigen receptor T-cell (CART) immunotherapies. In this study, we compared the safety and efficacy of bendamustine (Benda) to standard fludarabine/cyclophosphamide (Flu/Cy) LD before CD19-directed, CD28-costimulated CART axicabtagene ciloleucel (axi-cel) for patients with large B-cell lymphoma (LBCL) and follicular lymphoma (FL). We analyzed 59 patients diagnosed with LBCL (n = 48) and FL (n = 11) consecutively treated with axi-cel at the University of Pennsylvania. We also analyzed serum samples for cytokine levels and metabolomic changes before and after LD. Flu/Cy and Benda demonstrated similar efficacy, with complete remission rates of 51.4% and 50.0% (P = .981), respectively, and similar progression-free and overall survivals. Any-grade cytokine-release syndrome occurred in 91.9% of patients receiving Flu/Cy vs 72.7% of patients receiving Benda (P = .048); any-grade neurotoxicity after Flu/Cy occurred in 45.9% of patients and after Benda in 18.2% of patients (P = .031). In addition, Flu/Cy was associated with a higher incidence of grade ≥3 neutropenia (100% vs 54.5%; P < .001), infections (78.4% vs 27.3%; P < .001), and neutropenic fever (78.4% vs 13.6%; P < .001). These results were confirmed both in patients with LBCL and those with FL. Mechanistically, patients with Flu/Cy had a greater increase in inflammatory cytokines associated with neurotoxicity and reduced levels of metabolites critical for redox balance and biosynthesis. This study suggests that Benda LD may be a safe alternative to Flu/Cy for CD28-based CART CD19-directed immunotherapy with similar efficacy and reduced toxicities. Benda is associated with reduced levels of inflammatory cytokines and increased anabolic metabolites.
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Productos Biológicos , Citocinas , Linfoma Folicular , Humanos , Clorhidrato de Bendamustina/efectos adversos , Antígenos CD28 , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , CiclofosfamidaRESUMEN
Most patients treated with US Food and Drug Administration (FDA)-approved chimeric antigen receptor (CAR) T cells eventually experience disease progression. Furthermore, CAR T cells have not been curative against solid cancers and several hematological malignancies such as T cell lymphomas, which have very poor prognoses. One of the main barriers to the clinical success of adoptive T cell immunotherapies is CAR T cell dysfunction and lack of expansion and/or persistence after infusion. In this study, we found that CD5 inhibits CAR T cell activation and that knockout (KO) of CD5 using CRISPR-Cas9 enhances the antitumor effect of CAR T cells in multiple hematological and solid cancer models. Mechanistically, CD5 KO drives increased T cell effector function with enhanced cytotoxicity, in vivo expansion, and persistence, without apparent toxicity in preclinical models. These findings indicate that CD5 is a critical inhibitor of T cell function and a potential clinical target for enhancing T cell therapies.
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Antígenos CD5 , Inmunoterapia Adoptiva , Linfocitos T , Animales , Inmunoterapia Adoptiva/métodos , Antígenos CD5/inmunología , Ratones , Humanos , Linfocitos T/inmunología , Linfocitos T/trasplante , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/genética , Línea Celular Tumoral , Sistemas CRISPR-Cas , FemeninoRESUMEN
BACKGROUND: Thrombocytopenia is often considered a risk factor for bleeding, but conversely may be associated with an increased thrombotic risk in several clinical situations. Here we present a patient with arterial thrombosis and chronic disseminated intravascular coagulation caused by metastatic urothelial carcinoma. As the treatment for a disseminated intravascular coagulation caused by a neoplasia is the treatment of the underlying disease itself, our case highlights a new therapeutic approach-immunotherapy-in a patient prone to hematological complications due to conventional chemotherapy. CLINICAL CASE: A 74-year-old Caucasian male patient with a history of urothelial carcinoma of the bladder and moderate thrombocytopenia had multiple arterial thrombotic events despite antiplatelet therapy and anticoagulation. A diagnosis of chronic disseminated intravascular coagulation in the setting of a metastatic bladder urothelial carcinoma was made. The patient was treated with an anti-PD-L1 monoclonal antibody, and achieved a rapid response with subsequent reversal of the disseminated intravascular coagulation. CONCLUSION: Unexplained arterial or venous thrombosis despite adequate thromboprophylaxis should be investigated, especially in the setting of thrombocytopenia. Chronic disseminated intravascular coagulation is a possible, life-threatening reason for this clinical picture, and should prompt rapid identification of the underlying disease. To the best of our knowledge, this is the second case of chronic disseminated intravascular coagulation due to neoplastic disease treated with immunotherapy.
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Carcinoma de Células Transicionales , Coagulación Intravascular Diseminada , Neoplasias de la Vejiga Urinaria , Tromboembolia Venosa , Anciano , Anticuerpos Monoclonales/uso terapéutico , Anticoagulantes/uso terapéutico , Carcinoma de Células Transicionales/complicaciones , Carcinoma de Células Transicionales/tratamiento farmacológico , Coagulación Intravascular Diseminada/tratamiento farmacológico , Coagulación Intravascular Diseminada/etiología , Humanos , Masculino , Neoplasias de la Vejiga Urinaria/complicaciones , Neoplasias de la Vejiga Urinaria/tratamiento farmacológicoRESUMEN
Accurate estimation of the progression risk after first-line therapy represents an unmet clinical need in diffuse large B-cell lymphoma (DLBCL). Baseline (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) parameters, together with genetic analysis of lymphoma cells, could refine the prediction of treatment failure. We evaluated the combined impact of mutation profiling and baseline PET/CT functional parameters on the outcome of DLBCL patients treated with the R-CHOP14 regimen in the SAKK38/07 clinical trial (NCT00544219). The concomitant presence of mutated SOCS1 with wild-type CREBBP and EP300 defined a group of patients with a favorable prognosis and 2-year progression-free survival (PFS) of 100%. Using an unsupervised recursive partitioning approach, we generated a classification-tree algorithm that predicts treatment outcomes. Patients with elevated metabolic tumor volume (MTV) and high metabolic heterogeneity (MH) (15%) had the highest risk of relapse. Patients with low MTV and favorable mutational profile (9%) had the lowest risk, while the remaining patients constituted the intermediate-risk group (76%). The resulting model stratified patients among three groups with 2-year PFS of 100%, 82%, and 42%, respectively (p < 0.001).
RESUMEN
Chimeric antigen receptor T-cell (CART) immunotherapy led to unprecedented responses in patients with refractory/relapsed B-cell non-Hodgkin lymphoma (NHL); nevertheless, two thirds of patients experience treatment failure. Resistance to apoptosis is a key feature of cancer cells, and it is associated with treatment failure. In 87 patients with NHL treated with anti-CD19 CART, we found that chromosomal alteration of B-cell lymphoma 2 (BCL-2), a critical antiapoptotic regulator, in lymphoma cells was associated with reduced survival. Therefore, we combined CART19 with the FDA-approved BCL-2 inhibitor venetoclax and demonstrated in vivo synergy in venetoclax-sensitive NHL. However, higher venetoclax doses needed for venetoclax-resistant lymphomas resulted in CART toxicity. To overcome this limitation, we developed venetoclax-resistant CART by overexpressing mutated BCL-2(F104L), which is not recognized by venetoclax. Notably, BCL-2(F104L)-CART19 synergized with venetoclax in multiple lymphoma xenograft models. Furthermore, we uncovered that BCL-2 overexpression in T cells intrinsically enhanced CART antitumor activity in preclinical models and in patients by prolonging CART persistence. SIGNIFICANCE: This study highlights the role of BCL-2 in resistance to CART immunotherapy for cancer and introduces a novel concept for combination therapies-the engineering of CART cells to make them resistant to proapoptotic small molecules, thereby enhancing the therapeutic index of these combination therapies. This article is highlighted in the In This Issue feature, p. 2221.
Asunto(s)
Linfoma de Células B , Linfoma , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Receptores Quiméricos de Antígenos , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Humanos , Inmunoterapia , Inmunoterapia Adoptiva/métodos , Linfoma/patología , Proteínas Proto-Oncogénicas c-bcl-2/genética , Receptores de Antígenos de Linfocitos T , Sulfonamidas , Linfocitos TRESUMEN
Anti-CD19 chimeric antigen receptor (CAR) T cell therapy has led to unprecedented responses in patients with high-risk hematologic malignancies. However, up to 60% of patients still experience disease relapse and up to 80% of patients experience CAR-mediated toxicities, such as cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. We investigated the role of the intestinal microbiome on these outcomes in a multicenter study of patients with B cell lymphoma and leukemia. We found in a retrospective cohort (n = 228) that exposure to antibiotics, in particular piperacillin/tazobactam, meropenem and imipenem/cilastatin (P-I-M), in the 4 weeks before therapy was associated with worse survival and increased neurotoxicity. In stool samples from a prospective cohort of CAR T cell recipients (n = 48), the fecal microbiome was altered at baseline compared to healthy controls. Stool sample profiling by 16S ribosomal RNA and metagenomic shotgun sequencing revealed that clinical outcomes were associated with differences in specific bacterial taxa and metabolic pathways. Through both untargeted and hypothesis-driven analysis of 16S sequencing data, we identified species within the class Clostridia that were associated with day 100 complete response. We concluded that changes in the intestinal microbiome are associated with clinical outcomes after anti-CD19 CAR T cell therapy in patients with B cell malignancies.
Asunto(s)
Microbioma Gastrointestinal , Síndromes de Neurotoxicidad , Receptores Quiméricos de Antígenos , Antígenos CD19 , Humanos , Inmunoterapia Adoptiva/efectos adversos , Síndromes de Neurotoxicidad/etiología , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
The optimal melphalan dose prior to autologous stem cell transplantation (ASCT) is not known for elderly multiple myeloma (MM) patients. We analyzed data of all MM patients ≥65 years (n = 388) enrolled in the observational Swiss Blood Stem Cell Transplantation Registry. The median age was 67 years (65-77). Single ASCT was performed in 344 (88.7%) patients, with 259 patients (75.3%) receiving a melphalan dose of 200 mg/m2 (MEL200), and 85 patients (24.7%) receiving lower doses (MELlow) (median 140 mg/m2, range 70-180 mg/m2). MEL200 patients were slightly younger, and had a better renal function, but did not differ with regards to ISS stage, cytogenetic risk, remission status, and KPS. Overall mortality at day 100 was 1.5% without differences between the MEL groups (p = 0.621). Median progression-free survival (PFS) in the MEL200 and the MELlow group was 27.7 and 22.1 months, respectively (p = 0.294). Median overall survival (OS) in the MEL200 and in MELlow group was 91.2 and 61.2 months (p = 0.015). However, multivariate analysis showed no significant association of the melphalan dose and OS (HR 0.734; CI95% 0.264-2.038; p = 0.553). In conclusion, our data reveal no significant differences in safety and PFS for elderly myeloma patients treated with MEL200 or with lower MEL doses.