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1.
Cell ; 167(2): 405-418.e13, 2016 Oct 06.
Artículo en Inglés | MEDLINE | ID: mdl-27693350

RESUMEN

The HVEM (TNFRSF14) receptor gene is among the most frequently mutated genes in germinal center lymphomas. We report that loss of HVEM leads to cell-autonomous activation of B cell proliferation and drives the development of GC lymphomas in vivo. HVEM-deficient lymphoma B cells also induce a tumor-supportive microenvironment marked by exacerbated lymphoid stroma activation and increased recruitment of T follicular helper (TFH) cells. These changes result from the disruption of inhibitory cell-cell interactions between the HVEM and BTLA (B and T lymphocyte attenuator) receptors. Accordingly, administration of the HVEM ectodomain protein (solHVEM(P37-V202)) binds BTLA and restores tumor suppression. To deliver solHVEM to lymphomas in vivo, we engineered CD19-targeted chimeric antigen receptor (CAR) T cells that produce solHVEM locally and continuously. These modified CAR-T cells show enhanced therapeutic activity against xenografted lymphomas. Hence, the HVEM-BTLA axis opposes lymphoma development, and our study illustrates the use of CAR-T cells as "micro-pharmacies" able to deliver an anti-cancer protein.


Asunto(s)
Traslado Adoptivo/métodos , Linfoma Folicular/terapia , Receptores Inmunológicos/metabolismo , Miembro 14 de Receptores del Factor de Necrosis Tumoral/genética , Linfocitos T/inmunología , Proteínas Supresoras de Tumor/genética , Animales , Antígenos CD19/inmunología , Linfocitos B/inmunología , Proliferación Celular , Humanos , Activación de Linfocitos , Linfoma Folicular/genética , Ratones , Neoplasias Experimentales/genética , Neoplasias Experimentales/terapia , Dominios Proteicos , Ingeniería de Proteínas , Miembro 14 de Receptores del Factor de Necrosis Tumoral/química , Miembro 14 de Receptores del Factor de Necrosis Tumoral/metabolismo , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Microambiente Tumoral , Proteínas Supresoras de Tumor/química , Proteínas Supresoras de Tumor/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
2.
N Engl J Med ; 387(13): 1196-1206, 2022 09 29.
Artículo en Inglés | MEDLINE | ID: mdl-36170501

RESUMEN

BACKGROUND: B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapies have generated responses in patients with advanced myeloma, but relapses are common. G protein-coupled receptor, class C, group 5, member D (GPRC5D) has been identified as an immunotherapeutic target in multiple myeloma. Preclinical studies have shown the efficacy of GPRC5D-targeted CAR T cells, including activity in a BCMA antigen escape model. METHODS: In this phase 1 dose-escalation study, we administered a GPRC5D-targeted CAR T-cell therapy (MCARH109) at four dose levels to patients with heavily pretreated multiple myeloma, including patients with relapse after BCMA CAR T-cell therapy. RESULTS: A total of 17 patients were enrolled and received MCARH109 therapy. The maximum tolerated dose was identified at 150×106 CAR T cells. At the 450×106 CAR T-cell dose, 1 patient had grade 4 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS), and 2 patients had a grade 3 cerebellar disorder of unclear cause. No cerebellar disorder, ICANS of any grade, or cytokine release syndrome of grade 3 or higher occurred in the 12 patients who received doses of 25×106 to 150×106 cells. A response was reported in 71% of the patients in the entire cohort and in 58% of those who received doses of 25×106 to 150×106 cells. The patients who had a response included those who had received previous BCMA therapies; responses were observed in 7 of 10 such patients in the entire cohort and in 3 of 6 such patients who received 25×106 to 150×106 cells. CONCLUSIONS: The results of this study of a GPRC5D-targeted CAR T-cell therapy (MCARH109) confirm that GPRC5D is an active immunotherapeutic target in multiple myeloma. (Funded by Juno Therapeutics/Bristol Myers Squibb; ClinicalTrials.gov number, NCT04555551.).


Asunto(s)
Inmunoterapia Adoptiva , Mieloma Múltiple , Receptores Quiméricos de Antígenos , Receptores Acoplados a Proteínas G , Antígeno de Maduración de Linfocitos B/uso terapéutico , Síndrome de Liberación de Citoquinas/etiología , Humanos , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Mieloma Múltiple/tratamiento farmacológico , Recurrencia Local de Neoplasia/etiología , Receptores Quiméricos de Antígenos/uso terapéutico , Receptores Acoplados a Proteínas G/uso terapéutico , Linfocitos T
3.
Nat Chem Biol ; 18(2): 216-225, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34969970

RESUMEN

Chimeric antigen receptor (CAR)-T cells represent a major breakthrough in cancer therapy, wherein a patient's own T cells are engineered to recognize a tumor antigen, resulting in activation of a local cytotoxic immune response. However, CAR-T cell therapies are currently limited to the treatment of B cell cancers and their effectiveness is hindered by resistance from antigen-negative tumor cells, immunosuppression in the tumor microenvironment, eventual exhaustion of T cell immunologic functions and frequent severe toxicities. To overcome these problems, we have developed a novel class of CAR-T cells engineered to express an enzyme that activates a systemically administered small-molecule prodrug in situ at a tumor site. We show that these synthetic enzyme-armed killer (SEAKER) cells exhibit enhanced anticancer activity with small-molecule prodrugs, both in vitro and in vivo in mouse tumor models. This modular platform enables combined targeting of cellular and small-molecule therapies to treat cancers and potentially a variety of other diseases.


Asunto(s)
Antineoplásicos/uso terapéutico , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Sistemas de Liberación de Medicamentos , Femenino , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Neoplasias/terapia , Neoplasias Experimentales , Profármacos , Receptores Quiméricos de Antígenos , Linfocitos T , Microambiente Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto
4.
J Transl Med ; 21(1): 275, 2023 04 22.
Artículo en Inglés | MEDLINE | ID: mdl-37087493

RESUMEN

The 2022 Immunotherapy Bridge congress (November 30-December 1, Naples, Italy) featured a Great Debate session which addressed three contemporary topics in the field of immunotherapy. The debates included counterpoint views from leading experts and considered whether adoptive cell therapy (ACT) has a role in the treatment of solid tumors, the use of peripheral/blood biomarkers versus tumor microenvironment biomarkers for cancer immunotherapy and the role of chimeric antigen receptor T cell versus natural killer cell therapy. As is the tradition in the Immunotherapy Bridge Great Debates, speakers are invited by the meeting Chairs to express one side of the assigned debate and the opinions given may not fully reflect their own personal views. Audiences voted in favour of either side of the topic both before and after each debate.


Asunto(s)
Inmunoterapia , Neoplasias , Humanos , Neoplasias/terapia , Inmunoterapia Adoptiva , Linfocitos T , Biomarcadores de Tumor , Microambiente Tumoral
5.
Blood ; 138(7): 531-543, 2021 08 19.
Artículo en Inglés | MEDLINE | ID: mdl-33851211

RESUMEN

CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has become a breakthrough treatment of patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, despite the high initial response rate, the majority of adult patients with B-ALL progress after CD19 CAR T-cell therapy. Data on the natural history, management, and outcome of adult B-ALL progressing after CD19 CAR T cells have not been described in detail. Herein, we report comprehensive data of 38 adult patients with B-ALL who progressed after CD19 CAR T therapy at our institution. The median time to progression after CAR T-cell therapy was 5.5 months. Median survival after post-CAR T progression was 7.5 months. A high disease burden at the time of CAR T-cell infusion was significantly associated with risk of post-CAR T progression. Thirty patients (79%) received salvage treatment of post-CAR T disease progression, and 13 patients (43%) achieved complete remission (CR), but remission duration was short. Notably, 7 (58.3%) of 12 patients achieved CR after blinatumomab and/or inotuzumab administered following post-CAR T failure. Multivariate analysis revealed that a longer remission duration from CAR T cells was associated with superior survival after progression following CAR T-cell therapy. In summary, overall prognosis of adult B-ALL patients progressing after CD19 CAR T cells was poor, although a subset of patients achieved sustained remissions to salvage treatments, including blinatumomab, inotuzumab, and reinfusion of CAR T cells. Novel therapeutic strategies are needed to reduce risk of progression after CAR T-cell therapy and improve outcomes of these patients.


Asunto(s)
Anticuerpos Biespecíficos/administración & dosificación , Inmunoterapia Adoptiva , Inotuzumab Ozogamicina/administración & dosificación , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Terapia Recuperativa , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Tasa de Supervivencia
6.
Mol Ther ; 30(4): 1381-1395, 2022 04 06.
Artículo en Inglés | MEDLINE | ID: mdl-35151842

RESUMEN

T cells genetically engineered to recognize and eliminate tumor cells through synthetic chimeric antigen receptors (CARs) have demonstrated remarkable clinical efficacy against B cell leukemia over the past decade. This therapy is a form of highly personalized medicine that involves genetically modifying a patient's T cells to recognize and kill cancer cells. With the FDA approval of 5 CAR T cell products, this approach has been validated as a powerful new drug in the therapeutic armamentarium against cancer. Researchers are now studying how to expand this technology beyond its use in conventional polyclonal αß T cells to address limitations to the current therapy in cancer and applications beyond it. Considering the specific characteristics of immune cell from diverse lineages, several preclinical and clinical studies are under way to assess the advantages of CAR-redirected function in these cells and apply the lessons learned from CAR T cell therapy in cancer to other diseases.


Asunto(s)
Neoplasias , Receptores Quiméricos de Antígenos , Ingeniería Genética , Humanos , Inmunoterapia Adoptiva , Neoplasias/terapia , Receptores de Antígenos de Linfocitos T/genética , Receptores Quiméricos de Antígenos/genética , Linfocitos T
7.
Wiad Lek ; 76(12): 2543-2555, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38290016

RESUMEN

Marie Sklodowska-Curie Symposia on Cancer Research and Care (MSCS-CRC) promote collaborations between cancer researchers and care providers in the United States, Canada and Central and Eastern European Countries (CEEC), to accelerate the development of new cancer therapies, advance early detection and prevention, increase cancer awareness, and improve cancer care and the quality of life of patients and their families. The third edition of MSCS-CRC, held at Roswell Park Comprehensive Cancer Center, Buffalo, NY, in September 2023, brought together 137 participants from 20 academic institutions in the US, Poland, Ukraine, Lithuania, Croatia and Hungary, together with 16 biotech and pharma entities. The key areas of collaborative opportunity identified during the meeting are a) creating of a database of available collaborative projects in the areas of early-phase clinical trials, preclinical development, and identification of early biomarkers; b) promoting awareness of cancer risks and efforts at cancer prevention; c) laboratory and clinical training; and d) sharing experience in cost-effective delivery of cancer care and improving the quality of life of cancer patients and their families. Examples of ongoing international collaborations in the above areas were discussed. Participation of the representatives of the Warsaw-based Medical Research Agency, National Cancer Institute (NCI) of the United States, National Cancer Research Institutes of Poland and Lithuania, New York State Empire State Development, Ministry of Health of Ukraine and Translational Research Cancer Center Consortium of 13 cancer centers from the US and Canada, facilitated the discussion of available governmental and non-governmental funding initiatives in the above areas.


Asunto(s)
Investigación Biomédica , Neoplasias , Humanos , Estados Unidos , New York , Calidad de Vida , Neoplasias/terapia , Polonia
8.
N Engl J Med ; 378(5): 449-459, 2018 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-29385376

RESUMEN

BACKGROUND: CD19-specific chimeric antigen receptor (CAR) T cells induce high rates of initial response among patients with relapsed B-cell acute lymphoblastic leukemia (ALL) and long-term remissions in a subgroup of patients. METHODS: We conducted a phase 1 trial involving adults with relapsed B-cell ALL who received an infusion of autologous T cells expressing the 19-28z CAR at the Memorial Sloan Kettering Cancer Center (MSKCC). Safety and long-term outcomes were assessed, as were their associations with demographic, clinical, and disease characteristics. RESULTS: A total of 53 adults received 19-28z CAR T cells that were manufactured at MSKCC. After infusion, severe cytokine release syndrome occurred in 14 of 53 patients (26%; 95% confidence interval [CI], 15 to 40); 1 patient died. Complete remission was observed in 83% of the patients. At a median follow-up of 29 months (range, 1 to 65), the median event-free survival was 6.1 months (95% CI, 5.0 to 11.5), and the median overall survival was 12.9 months (95% CI, 8.7 to 23.4). Patients with a low disease burden (<5% bone marrow blasts) before treatment had markedly enhanced remission duration and survival, with a median event-free survival of 10.6 months (95% CI, 5.9 to not reached) and a median overall survival of 20.1 months (95% CI, 8.7 to not reached). Patients with a higher burden of disease (≥5% bone marrow blasts or extramedullary disease) had a greater incidence of the cytokine release syndrome and neurotoxic events and shorter long-term survival than did patients with a low disease burden. CONCLUSIONS: In the entire cohort, the median overall survival was 12.9 months. Among patients with a low disease burden, the median overall survival was 20.1 months and was accompanied by a markedly lower incidence of the cytokine release syndrome and neurotoxic events after 19-28z CAR T-cell infusion than was observed among patients with a higher disease burden. (Funded by the Commonwealth Foundation for Cancer Research and others; ClinicalTrials.gov number, NCT01044069 .).


Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Receptores de Antígenos de Linfocitos T/uso terapéutico , Linfocitos T/inmunología , Adulto , Anciano , Citocinas/metabolismo , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Recurrencia , Inducción de Remisión , Análisis de Supervivencia
9.
Blood ; 134(7): 626-635, 2019 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-31262783

RESUMEN

High-dose chemotherapy and autologous stem cell transplantation (HDT-ASCT) is the standard of care for relapsed or primary refractory (rel/ref) chemorefractory diffuse large B-cell lymphoma. Only 50% of patients are cured with this approach. We investigated safety and efficacy of CD19-specific chimeric antigen receptor (CAR) T cells administered following HDT-ASCT. Eligibility for this study includes poor-risk rel/ref aggressive B-cell non-Hodgkin lymphoma chemosensitive to salvage therapy with: (1) positron emission tomography-positive disease or (2) bone marrow involvement. Patients underwent standard HDT-ASCT followed by 19-28z CAR T cells on days +2 and +3. Of 15 subjects treated on study, dose-limiting toxicity was observed at both dose levels (5 × 106 and 1 × 107 19-28z CAR T per kilogram). Ten of 15 subjects experienced CAR T-cell-induced neurotoxicity and/or cytokine release syndrome (CRS), which were associated with greater CAR T-cell persistence (P = .05) but not peak CAR T-cell expansion. Serum interferon-γ elevation (P < .001) and possibly interleukin-10 (P = .07) were associated with toxicity. The 2-year progression-free survival (PFS) is 30% (95% confidence interval, 20% to 70%).  Subjects given decreased naive-like (CD45RA+CCR7+) CD4+ and CD8+ CAR T cells experienced superior PFS (P = .02 and .04, respectively). There was no association between CAR T-cell peak expansion, persistence, or cytokine changes and PFS. 19-28z CAR T cells following HDT-ASCT were associated with a high incidence of reversible neurotoxicity and CRS. Following HDT-ASCT, effector CD4+ and CD8+ immunophenotypes may improve disease control. This trial was registered at www.clinicaltrials.gov as #NCT01840566.


Asunto(s)
Inmunoterapia Adoptiva/métodos , Linfoma de Células B Grandes Difuso/terapia , Receptores de Antígenos de Linfocitos T/uso terapéutico , Trasplante de Células Madre/métodos , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/terapia , Trasplante Autólogo/métodos , Resultado del Tratamiento
10.
Blood ; 134(26): 2361-2368, 2019 12 26.
Artículo en Inglés | MEDLINE | ID: mdl-31650176

RESUMEN

Chimeric antigen receptor (CAR) T cells have demonstrated clinical benefit in patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We undertook a multicenter clinical trial to determine toxicity, feasibility, and response for this therapy. A total of 25 pediatric/young adult patients (age, 1-22.5 years) with R/R B-ALL were treated with 19-28z CAR T cells. Conditioning chemotherapy included high-dose (3 g/m2) cyclophosphamide (HD-Cy) for 17 patients and low-dose (≤1.5 g/m2) cyclophosphamide (LD-Cy) for 8 patients. Fifteen patients had pretreatment minimal residual disease (MRD; <5% blasts in bone marrow), and 10 patients had pretreatment morphologic evidence of disease (≥5% blasts in bone marrow). All toxicities were reversible, including severe cytokine release syndrome in 16% (4 of 25) and severe neurotoxicity in 28% (7 of 25) of patients. Treated patients were assessed for response, and, among the evaluable patients (n = 24), response and peak CAR T-cell expansion were superior in the HD-Cy/MRD cohorts, as compared with the LD-Cy/morphologic cohorts without an increase in toxicity. Our data support the safety of CD19-specific CAR T-cell therapy for R/R B-ALL. Our data also suggest that dose intensity of conditioning chemotherapy and minimal pretreatment disease burden have a positive impact on response without a negative effect on toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01860937.


Asunto(s)
Antígenos CD19/metabolismo , Resistencia a Antineoplásicos , Recurrencia Local de Neoplasia/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Receptores de Antígenos de Linfocitos T/inmunología , Receptores Quiméricos de Antígenos/inmunología , Linfocitos T/trasplante , Adolescente , Adulto , Niño , Preescolar , Síndrome de Liberación de Citoquinas/etiología , Síndrome de Liberación de Citoquinas/patología , Síndrome de Liberación de Citoquinas/prevención & control , Femenino , Humanos , Lactante , Masculino , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/metabolismo , Neoplasia Residual/etiología , Neoplasia Residual/patología , Neoplasia Residual/prevención & control , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/patología , Síndromes de Neurotoxicidad/prevención & control , Leucemia-Linfoma Linfoblástico de Células Precursoras B/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Terapia Recuperativa , Tasa de Supervivencia , Linfocitos T/inmunología , Resultado del Tratamiento , Adulto Joven
11.
Br J Haematol ; 190(1): 45-51, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32135029

RESUMEN

Radiotherapy is potentially an important salvage strategy post-chimeric antigen receptor T cell therapy (CART), but limited data exist. We reviewed 14 patients treated with salvage radiation post-CART progression (SRT). Most received SRT for first post-CART relapse (71%) to sites previously PET-avid pre-CART (79%). Median overall survival (OS) post-SRT was 10 months. Post-SRT, six localized relapses achieved 100% response (3 = complete, 3 = partial), with improved freedom from subsequent relapse (P = 0·001) and OS (P = 0·004) compared to advanced stage relapses. Three were bridged to allogeneic transplantation; at analysis, all were alive/NED. SRT has diverse utility and can integrate with novel agents or transplantation to attempt durable remissions.


Asunto(s)
Linfoma no Hodgkin/radioterapia , Receptores Quiméricos de Antígenos/uso terapéutico , Terapia Recuperativa/métodos , Adulto , Anciano , Antígenos CD19 , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Adulto Joven
13.
Clin Nephrol ; 93(1): 42-46, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31670650

RESUMEN

BACKGROUND: Various studies have demonstrated that interleukin-6 (IL-6) activates the central magnocellular arginine vasopressin (AVP)-secreting neurons in the brain to produce non-osmotic, non-volume-mediated increases in AVP. The most common toxicity of CD19+ chimeric antigen receptor (CAR) T-cells is cytokine release syndrome, which is related to increased levels of IL-6. This study will evaluate the correlation of IL-6 levels with hyponatremia in patients receiving CD19+ CAR T-cells. MATERIALS AND METHODS: This is a single-center retrospective analysis of adult patients who received CD19+ CAR T-cells for the treatment of relapsed/refractory acute lymphoblastic leukemia (ALL). RESULTS: Hyponatremia, defined as a serum sodium (Na) ≤ 135 mEq/L, occurred in 31 (61%) patients. A change in Na > 7 mEq occurred in 32 (63%) patients, and the median lowest Na was 133 mEq/L (interquartile range (IQR): 131 - 136)). There was an inverse linear relationship between IL-6 levels and lowest Na (p = 0.001). Overall, per 10-fold increase in IL-6, Na decreased by an average of 2.68 mEq/L. CONCLUSION: Hyponatremia is common in patients who received CD19+ CAR T-cells. There is an inverse linear relationship between IL-6 levels and nadir Na (p = 0.001). Further studies will be needed to confirm a causative relationship between IL-6 levels and hyponatremia following CD19+ CAR T-cell infusion.


Asunto(s)
Hiponatremia/sangre , Hiponatremia/etiología , Inmunoterapia Adoptiva/efectos adversos , Interleucina-6/sangre , Sodio/sangre , Adulto , Anciano , Antígenos CD19/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores Quiméricos de Antígenos , Estudios Retrospectivos , Linfocitos T/metabolismo , Adulto Joven
14.
Hematol Oncol ; 37 Suppl 1: 95-100, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-31187533

RESUMEN

Chimeric antigen receptor (CAR) T-cell therapy has dramatically shifted the landscape of treatment for lymphoid malignancies, especially diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL). However, there continue to be significant limitations of this therapy, such as incomplete or nonsustained responses and severe toxicities in a subset of patients. Furthermore, expanding the role of CAR T-cell therapy to new disease types is an important next step. In this review, we will highlight landmark trials for anti-CD19 CAR T cells and first-in-human trials of novel CARs, as well as discuss promising innovative CAR designs that are still undergoing preclinical development. Lastly, we will discuss toxicity and mechanisms of CAR T-cell resistance and failure, as well as potential future treatment approaches to these common issues.


Asunto(s)
Inmunoterapia Adoptiva , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores Quiméricos de Antígenos/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Animales , Antígenos CD19 , Antígenos de Neoplasias/inmunología , Ensayos Clínicos como Asunto , Ingeniería Genética , Humanos , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Neoplasias/diagnóstico , Neoplasias/inmunología , Neoplasias/terapia , Receptores de Antígenos de Linfocitos T/genética , Receptores Quiméricos de Antígenos/genética , Investigación , Resultado del Tratamiento
15.
Am J Hematol ; 94(S1): S55-S58, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30680777

RESUMEN

CAR T cells have revolutionized the treatment of relapsed and refractory CD19-positive leukemia and lymphoma. Unfortunately, the majority of patients treated will not achieve durable remissions. Reasons for these suboptimal clinical outcomes can be tied back to intrinsic CAR T cell design and manufacturing processes, factors that are highly amenable to modification and improvement. As CAR T cell therapy is being deployed in spaces outside of CD19-positive disease, these limitations, complications, and setbacks need to be overcome, allowing for the full potential of this novel therapy to be realized. Preclinical work has begun tackling these major roadblocks, paving the way for potentially off-the-shelf products that are safer and more potent. In time, a number of these advances will be translated to the clinic and usher in an era of CARs of the future.


Asunto(s)
Inmunoterapia Adoptiva/tendencias , Receptores Quiméricos de Antígenos/uso terapéutico , Predicción , Humanos , Inmunoterapia Adoptiva/métodos , Resultado del Tratamiento
16.
Mol Ther ; 26(6): 1447-1456, 2018 06 06.
Artículo en Inglés | MEDLINE | ID: mdl-29678657

RESUMEN

B cell maturation antigen (BCMA) has recently been identified as an important multiple myeloma (MM)-specific target for chimeric antigen receptor (CAR) T cell therapy. In CAR T cell therapy targeting CD19 for lymphoma, host immune anti-murine CAR responses limited the efficacy of repeat dosing and possibly long-term persistence. This clinically relevant concern can be addressed by generating a CAR incorporating a human single-chain variable fragment (scFv). We screened a human B cell-derived scFv phage display library and identified a panel of BCMA-specific clones from which human CARs were engineered. Despite a narrow range of affinity for BCMA, dramatic differences in CAR T cell expansion were observed between unique scFvs in a repeat antigen stimulation assay. These results were confirmed by screening in a MM xenograft model, where only the top preforming CARs from the repeat antigen stimulation assay eradicated disease and prolonged survival. The results of this screening identified a highly effective CAR T cell therapy with properties, including rapid in vivo expansion (>10,000-fold, day 6), eradication of large tumor burden, and durable protection to tumor re-challenge. We generated a bicistronic construct including a second-generation CAR and a truncated-epithelial growth factor receptor marker. CAR T cell vectors stemming from this work are under clinical investigation.


Asunto(s)
Antígeno de Maduración de Linfocitos B/metabolismo , Inmunoterapia Adoptiva/métodos , Anticuerpos de Cadena Única/inmunología , Inmunidad Adaptativa/fisiología , Linfocitos T CD4-Positivos/metabolismo , Herpesvirus Humano 4/inmunología , Humanos , Receptores de Antígenos de Linfocitos T/metabolismo
17.
Mol Ther ; 26(8): 1896-1905, 2018 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-29910179

RESUMEN

Patients with residual chronic lymphocytic leukemia (CLL) following initial purine analog-based chemoimmunotherapy exhibit a shorter duration of response and may benefit from novel therapeutic strategies. We and others have previously described the safety and efficacy of autologous T cells modified to express anti-CD19 chimeric antigen receptors (CARs) in patients with relapsed or refractory B cell acute lymphoblastic leukemia and CLL. Here we report the use of CD19-targeted CAR T cells incorporating the intracellular signaling domain of CD28 (19-28z) as a consolidative therapy in 8 patients with residual CLL following first-line chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab. Outpatients received low-dose conditioning therapy with cyclophosphamide (600 mg/m2), followed by escalating doses of 3 × 106, 1 × 107, or 3 × 107 19-28z CAR T cells/kg. An objective response was observed in 3 of 8 patients (38%), with a clinically complete response lasting more than 28 months observed in two patients. Self-limited fevers were observed post-CAR T cell infusion in 4 patients, contemporaneous with elevations in interleukin-6 (IL-6), IL-10, IL-2, and TGF-α. None developed severe cytokine release syndrome or neurotoxicity. CAR T cells were detectable post-infusion in 4 patients, with a longest observed persistence of 48 days by qPCR. Further strategies to enhance CAR T cell efficacy in CLL are under investigation.


Asunto(s)
Antígenos CD19/metabolismo , Ciclofosfamida/administración & dosificación , Inmunoterapia Adoptiva/efectos adversos , Leucemia Linfocítica Crónica de Células B/terapia , Linfocitos T/trasplante , Anciano , Terapia Conductista , Ciclofosfamida/uso terapéutico , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/inmunología , Masculino , Persona de Mediana Edad , Neoplasia Residual , Pentostatina/uso terapéutico , Rituximab/uso terapéutico , Linfocitos T/inmunología , Trasplante Autólogo/efectos adversos , Resultado del Tratamiento
18.
Clin Infect Dis ; 67(4): 533-540, 2018 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-29481659

RESUMEN

Background: Chimeric antigen receptor (CAR)-modified T cells that target the CD19 antigen present a novel promising therapy for the treatment of relapsed B-cell acute lymphoblastic leukemia (B-ALL). Although cytokine release syndrome (CRS) and neurotoxicity have emerged as predominant noninfectious complications of CD19 CAR T-cell therapy, infections associated with this treatment modality have not been well documented. Methods: We analyzed infectious complications that followed CD19 CAR T-cell therapy in 53 adult patients with relapsed B-ALL enrolled in a phase I clinical trial at Memorial Sloan Kettering Cancer Center (NCT01044069). Results: Overall, 22 patients (42%) experienced 26 infections (17 bacterial, 4 fungal, and 5 viral) within the first 30 days of CAR T-cell infusion. In 10 of 32 (31%) patients in whom complete remission was achieved, 15 infections developed between days 31 and 180; the majority of these late infections were due to respiratory viruses. In general, bacterial, fungal, and viral infections were detected at a median of 18, 23, and 48 days, respectively, after CAR T-cell infusion. CRS grade 3 or higher was independently associated with increased risk of subsequent infection (adjusted hazard ratio [HR], 2.67; P = .05) and in particular with bloodstream infection (adjusted HR, 19.97; P < .001). Three of 53 patients (6%) died of an infection-related cause. Conclusions: Infections in adult patients with relapsed B-ALL are common after CD19 CAR T-cell therapy. Understanding the infectious complications that are temporally coincident with CD19 CAR T-cell therapy is critical for developing effective prophylactic and other supportive care measures to improve clinical outcomes. Clinical Trials Registration: NCT01044069.


Asunto(s)
Infecciones Bacterianas/complicaciones , Citocinas/sangre , Inmunoterapia Adoptiva/efectos adversos , Micosis/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Virosis/complicaciones , Adulto , Anciano , Antígenos CD19/inmunología , Biomarcadores/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Receptores Quiméricos de Antígenos/uso terapéutico , Recurrencia
19.
Biol Blood Marrow Transplant ; 24(6): 1135-1141, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29499327

RESUMEN

Two commercial chimeric antigen receptor (CAR) T cell therapies for CD19-expressing B cell malignancies, Kymriah and Yescarta, have recently been approved by the Food and Drug Administration. The administration of CAR T cells is a complex endeavor involving cell manufacture, tracking and shipping of apheresis products, and management of novel and severe toxicities. At Memorial Sloan Kettering Cancer Center, we have identified 8 essential tasks that define the CAR T cell workflow. In this review, we discuss practical aspects of CAR T cell program development, including clinical, administrative, and regulatory challenges for successful implementation.


Asunto(s)
Instituciones Oncológicas/organización & administración , Inmunoterapia Adoptiva/métodos , Receptores Quiméricos de Antígenos , Flujo de Trabajo , Antígenos CD19/uso terapéutico , Productos Biológicos , Humanos , Leucemia de Células B/terapia , Linfoma de Células B/terapia , Receptores de Antígenos de Linfocitos T/uso terapéutico , Receptores Quiméricos de Antígenos/uso terapéutico
20.
Blood ; 127(26): 3312-20, 2016 06 30.
Artículo en Inglés | MEDLINE | ID: mdl-27207800

RESUMEN

Adoptive transfer of T cells genetically modified to express chimeric antigen receptors (CARs) targeting CD19 has produced impressive results in treating patients with B-cell malignancies. Although these CAR-modified T cells target the same antigen, the designs of CARs vary as well as several key aspects of the clinical trials in which these CARs have been studied. It is unclear whether these differences have any impact on clinical outcome and treatment-related toxicities. Herein, we review clinical results reflecting the investigational use of CD19-targeted CAR T-cell therapeutics in patients with B-cell hematologic malignancies, in light of differences in CAR design and production, and outline the limitations inherent in comparing outcomes between studies.


Asunto(s)
Traslado Adoptivo , Antígenos CD19 , Neoplasias Hematológicas/terapia , Receptores de Antígenos de Linfocitos T/genética , Linfocitos T/trasplante , Animales , Linfocitos B/metabolismo , Linfocitos B/patología , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/metabolismo , Humanos
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