Publications by authors named "Adrian Bot"

96 Publications

KTE-X19 anti-CD19 CAR T-cell therapy in adult relapsed/refractory acute lymphoblastic leukemia: ZUMA-3 phase 1 results.

Blood 2021 Apr 7. Epub 2021 Apr 7.

University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States.

ZUMA-3 is a phase 1/2 study evaluating KTE-X19, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in adult relapsed/refractory (R/R) B-ALL. We report the phase 1 results. Following fludarabine/cyclophosphamide lymphodepletion, patients received a single infusion of KTE-X19 at 2, 1, or 0.5×106 cells/kg. The rate of dose-limiting toxicities (DLTs) within 28 days following KTE-X19 infusion was the primary endpoint. KTE-X19 was manufactured for 54 enrolled patients and administered to 45 (median age: 46 years [range, 18-77]). No DLTs occurred in the DLT-evaluable cohort. Grade ≥3 cytokine release syndrome (CRS) and neurologic events (NE) occurred in 31% and 38% of patients, respectively. To optimize the benefit-risk ratio, revised adverse event (AE) management for CRS and NE (earlier steroid use for NE and tocilizumab only for CRS) was evaluated at 1×106 cells/kg KTE-X19. In the 9 patients treated under revised AE management, 33% had grade 3 CRS and 11% had grade 3 NE, with no grade 4/5 NE. The overall complete remission rate correlated with CAR T-cell expansion and was 83% in patients treated with 1×106 cells/kg and 69% in all patients. Minimal residual disease was undetectable in all responding patients. At 22.1 months (range, 7.1-36.1) median follow-up, the median duration of remission was 17.6 months (95% CI, 5.8-17.6) in patients treated with 1×106 cells/kg and 14.5 months (95% CI, 5.8-18.1) in all patients. KTE-X19 treatment provided a high response rate and tolerable safety in adults with R/R B-ALL. Phase 2 is ongoing at 1×106 cells/kg with revised AE management.
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http://dx.doi.org/10.1182/blood.2020009098DOI Listing
April 2021

TCR-engineered T cells targeting E7 for patients with metastatic HPV-associated epithelial cancers.

Nat Med 2021 03 8;27(3):419-425. Epub 2021 Feb 8.

Genitourinary Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Genetically engineered T cell therapy can induce remarkable tumor responses in hematologic malignancies. However, it is not known if this type of therapy can be applied effectively to epithelial cancers, which account for 80-90% of human malignancies. We have conducted a first-in-human, phase 1 clinical trial of T cells engineered with a T cell receptor targeting HPV-16 E7 for the treatment of metastatic human papilloma virus-associated epithelial cancers (NCT02858310). The primary endpoint was maximum tolerated dose. Cell dose was not limited by toxicity with a maximum dose of 1 × 10 engineered T cells administered. Tumor responses following treatment were evaluated using RECIST (Response Evaluation Criteria in Solid Tumors) guidelines. Robust tumor regression was observed with objective clinical responses in 6 of 12 patients, including 4 of 8 patients with anti-PD-1 refractory disease. Responses included extensive regression of bulky tumors and complete regression of most tumors in some patients. Genomic studies, which included intra-patient tumors with dichotomous treatment responses, revealed resistance mechanisms from defects in critical components of the antigen presentation and interferon response pathways. These findings demonstrate that engineered T cells can mediate regression of common carcinomas, and they reveal immune editing as a constraint on the curative potential of cellular therapy and possibly other immunotherapies in advanced epithelial cancer.
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http://dx.doi.org/10.1038/s41591-020-01225-1DOI Listing
March 2021

A Critical Role for Fas-Mediated Off-Target Tumor Killing in T-cell Immunotherapy.

Cancer Discov 2021 Mar 17;11(3):599-613. Epub 2020 Dec 17.

Department of Medicine, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York.

T cell-based therapies have induced cancer remissions, though most tumors ultimately progress, reflecting inherent or acquired resistance including antigen escape. Better understanding of how T cells eliminate tumors will help decipher resistance mechanisms. We used a CRISPR/Cas9 screen and identified a necessary role for Fas-FasL in antigen-specific T-cell killing. We also found that Fas-FasL mediated off-target "bystander" killing of antigen-negative tumor cells. This localized bystander cytotoxicity enhanced clearance of antigen-heterogeneous tumors , a finding that has not been shown previously. Fas-mediated on-target and bystander killing was reproduced in chimeric antigen receptor (CAR-T) and bispecific antibody T-cell models and was augmented by inhibiting regulators of Fas signaling. Tumoral expression alone predicted survival of CAR-T-treated patients in a large clinical trial (NCT02348216). These data suggest strategies to prevent immune escape by targeting both the antigen expression of most tumor cells and the geography of antigen-loss variants. SIGNIFICANCE: This study demonstrates the first report of Fas-dependent bystander killing of antigen-negative tumors by T cells, a phenomenon that may be contributing to the high response rates of antigen-directed immunotherapies despite tumoral heterogeneity. Small molecules that target the Fas pathway may potentiate this mechanism to prevent cancer relapse..
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http://dx.doi.org/10.1158/2159-8290.CD-20-0756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933082PMC
March 2021

Tumor burden, inflammation, and product attributes determine outcomes of axicabtagene ciloleucel in large B-cell lymphoma.

Blood Adv 2020 10;4(19):4898-4911

Kite, a Gilead Company, Santa Monica, CA.

ZUMA-1 demonstrated a high rate of durable response and a manageable safety profile with axicabtagene ciloleucel (axi-cel), an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in patients with refractory large B-cell lymphoma. As previously reported, prespecified clinical covariates for secondary end point analysis were not clearly predictive of efficacy; these included Eastern Cooperative Oncology Group performance status (0 vs 1), age, disease subtype, disease stage, and International Prognostic Index score. We interrogated covariates included in the statistical analysis plan and an extensive panel of biomarkers according to an expanded translational biomarker plan. Univariable and multivariable analyses indicated that rapid CAR T-cell expansion commensurate with pretreatment tumor burden (influenced by product T-cell fitness), the number of CD8 and CCR7+CD45RA+ T cells infused, and host systemic inflammation, were the most significant determining factors for durable response. Key parameters differentially associated with clinical efficacy and toxicities, with both theoretical and practical implications for optimizing CAR T-cell therapy. This trial was registered at www.clinicaltrials.gov as #NCT02348216.
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http://dx.doi.org/10.1182/bloodadvances.2020002394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556133PMC
October 2020

A Phase I, Open-label, Dose-escalation, and Cohort Expansion Study to Evaluate the Safety and Immune Response to Autologous Dendritic Cells Transduced With AdGMCA9 (DC-AdGMCAIX) in Patients With Metastatic Renal Cell Carcinoma.

J Immunother 2020 Nov/Dec;43(9):273-282

Department of Urology, Institute of Urologic Oncology.

Expression of carbonic-anhydrase IX (CAIX) in clear cell renal cell carcinoma (RCC) makes it an attractive vaccine target. We developed a fusion-gene construct, granulocyte-macrophage (GM) colony-stimulating factor+CAIX, delivered by an adenoviral vector (Ad) into autologous dendritic cells (DCs) in this phase 1 study. The injected immature DCs were expected to stimulate an antigen-specific immune response against CAIX expressing RCC. Three dose-escalation cohorts (5, 15, and 50×10 cells/administration) were injected intradermally q2wk×3 doses based on a 3+3 design. The primary objective was the safety of the injections. Secondary objectives were immune responses using enzyme-linked immunosorbent spot, a serum biomarker panel, and clinical response. Fifteen patients with metastatic RCC were enrolled, and 9 patients received all 3 doses. No serious adverse events were seen. There were 3 (33%) patients with grade 1 fatigue, 1 of whom subsequently experienced grade 2 fatigue. One patient (11%) experienced grade 1-2 leukopenia. Only 1 patient (11%) experienced grade 2 flu-like symptoms. Of the 9 patients who received treatment, 1 expired of progressive disease, 2 patients were lost to follow-up and 6 patients are alive. Of the 6 patients, 5 have progressive disease, and 1 has completed treatment with stable disease at 27 months follow-up. Immune response measurements appeared more robust in higher dose cohorts, which appeared to be related to patients with stable disease at 3 months. These early data show that autologous immature DC-AdGMCAIX can be safely given to metastatic RCC patients without any serious adverse events with CAIX-specific immune response elicited by the treatment. These preliminary data support further study of Ad-GMCAIX, particularly with combination therapies that may enhance clinical activity.
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http://dx.doi.org/10.1097/CJI.0000000000000336DOI Listing
September 2020

Activation of CAR and non-CAR T cells within the tumor microenvironment following CAR T cell therapy.

JCI Insight 2020 06 18;5(12). Epub 2020 Jun 18.

Center for Immuno-Oncology and.

Mechanisms of chimeric antigen receptor (CAR) T cell-mediated antitumor immunity and toxicity remain poorly characterized because few studies examine the intact tumor microenvironment (TME) following CAR T cell infusion. Axicabtagene ciloleucel is an autologous anti-CD19 CAR T cell therapy approved for patients with large B cell lymphoma. We devised multiplex immunostaining and ISH assays to interrogate CAR T cells and other immune cell infiltrates in biopsies of diffuse large B cell lymphoma following axicabtagene ciloleucel infusion. We found that a majority of intratumoral CAR T cells expressed markers of T cell activation but, unexpectedly, constituted ≤5% of all T cells within the TME 5 days or more after therapy. Large numbers of T cells without CAR were also activated within the TME after axicabtagene ciloleucel infusion; these cells were positive for Ki-67, IFN-γ, granzyme B (GzmB), and/or PD-1 and were found at the highest levels in biopsies with CAR T cells. Additionally, non-CAR immune cells were the exclusive source of IL-6, a cytokine associated with cytokine release syndrome, and were found at their highest numbers in biopsies with CAR T cells. These data suggest that intratumoral CAR T cells are associated with non-CAR immune cell activation within the TME with both beneficial and pathological effects.
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http://dx.doi.org/10.1172/jci.insight.134612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406247PMC
June 2020

Author Correction: Safety and feasibility of anti-CD19 CAR T cells with fully human binding domains in patients with B-cell lymphoma.

Nat Med 2020 05;26(5):803

Experimental Transplantation and Immunotherapy Branch, Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41591-020-0864-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819238PMC
May 2020

Advanced Cell Mapping Visualizations for Single Cell Functional Proteomics Enabling Patient Stratification.

Proteomics 2020 07;20(13):e1900270

IsoPlexis Corporation, Branford, CT, 06405, USA.

Highly multiplexed single-cell functional proteomics has emerged as one of the next-generation toolkits for a deeper understanding of functional heterogeneity in cell. Different from the conventional population-based bulk and single-cell RNA-Seq assays, the microchip-based proteomics at the single-cell resolution enables a unique identification of highly polyfunctional cell subsets that co-secrete many proteins from live single cells and most importantly correlate with patient response to a therapy. The 32-plex IsoCode chip technology has defined a polyfunctional strength index (PSI) of pre-infusion anti-CD19 chimeric antigen receptor (CAR)-T products, that is significantly associated with patient response to the CAR-T cell therapy. To complement the clinical relevance of the PSI, a comprehensive visualization toolkit of 3D uniform manifold approximation and projection (UMAP) and t-distributed stochastic neighbor embedding (t-SNE) in a proteomic analysis pipeline is developed, providing more advanced analytical algorithms for more intuitive data visualizations. The UMAP and t-SNE of anti-CD19 CAR-T products reveal distinct cytokine profiles between nonresponders and responders and demonstrate a marked upregulation of antitumor-associated cytokine signatures in CAR-T cells from responding patients. Using this powerful while user-friendly analytical tool, the multi-dimensional single-cell data can be dissected from complex immune responses and uncover underlying mechanisms, which can promote correlative biomarker discovery, improved bioprocessing, and personalized treatment development.
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http://dx.doi.org/10.1002/pmic.201900270DOI Listing
July 2020

Safety and feasibility of anti-CD19 CAR T cells with fully human binding domains in patients with B-cell lymphoma.

Nat Med 2020 02 20;26(2):270-280. Epub 2020 Jan 20.

Experimental Transplantation and Immunotherapy Branch, Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA.

Anti-CD19 chimeric antigen receptor (CAR)-expressing T cells are an effective treatment for B-cell lymphoma, but often cause neurologic toxicity. We treated 20 patients with B-cell lymphoma on a phase I, first-in-human clinical trial of T cells expressing the new anti-CD19 CAR Hu19-CD828Z (NCT02659943). The primary objective was to assess safety and feasibility of Hu19-CD828Z T-cell therapy. Secondary objectives included assessments of blood levels of CAR T cells, anti-lymphoma activity, second infusions and immunogenicity. All objectives were met. Fifty-five percent of patients who received Hu19-CD828Z T cells obtained complete remission. Hu19-CD828Z T cells had clinical anti-lymphoma activity similar to that of T cells expressing FMC63-28Z, an anti-CD19 CAR tested previously by our group, which contains murine binding domains and is used in axicabtagene ciloleucel. However, severe neurologic toxicity occurred in only 5% of patients who received Hu19-CD828Z T cells, whereas 50% of patients who received FMC63-28Z T cells experienced this degree of toxicity (P = 0.0017). T cells expressing Hu19-CD828Z released lower levels of cytokines than T cells expressing FMC63-28Z. Lower levels of cytokines were detected in blood from patients who received Hu19-CD828Z T cells than in blood from those who received FMC63-28Z T cells, which could explain the lower level of neurologic toxicity associated with Hu19-CD828Z. Levels of cytokines released by CAR-expressing T cells particularly depended on the hinge and transmembrane domains included in the CAR design.
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http://dx.doi.org/10.1038/s41591-019-0737-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781235PMC
February 2020

Toward a comprehensive view of cancer immune responsiveness: a synopsis from the SITC workshop.

J Immunother Cancer 2019 05 22;7(1):131. Epub 2019 May 22.

Rutgers University, New Brunswick, NJ, USA.

Tumor immunology has changed the landscape of cancer treatment. Yet, not all patients benefit as cancer immune responsiveness (CIR) remains a limitation in a considerable proportion of cases. The multifactorial determinants of CIR include the genetic makeup of the patient, the genomic instability central to cancer development, the evolutionary emergence of cancer phenotypes under the influence of immune editing, and external modifiers such as demographics, environment, treatment potency, co-morbidities and cancer-independent alterations including immune homeostasis and polymorphisms in the major and minor histocompatibility molecules, cytokines, and chemokines. Based on the premise that cancer is fundamentally a disorder of the genes arising within a cell biologic process, whose deviations from normality determine the rules of engagement with the host's response, the Society for Immunotherapy of Cancer (SITC) convened a task force of experts from various disciplines including, immunology, oncology, biophysics, structural biology, molecular and cellular biology, genetics, and bioinformatics to address the complexity of CIR from a holistic view. The task force was launched by a workshop held in San Francisco on May 14-15, 2018 aimed at two preeminent goals: 1) to identify the fundamental questions related to CIR and 2) to create an interactive community of experts that could guide scientific and research priorities by forming a logical progression supported by multiple perspectives to uncover mechanisms of CIR. This workshop was a first step toward a second meeting where the focus would be to address the actionability of some of the questions identified by working groups. In this event, five working groups aimed at defining a path to test hypotheses according to their relevance to human cancer and identifying experimental models closest to human biology, which include: 1) Germline-Genetic, 2) Somatic-Genetic and 3) Genomic-Transcriptional contributions to CIR, 4) Determinant(s) of Immunogenic Cell Death that modulate CIR, and 5) Experimental Models that best represent CIR and its conversion to an immune responsive state. This manuscript summarizes the contributions from each group and should be considered as a first milestone in the path toward a more contemporary understanding of CIR. We appreciate that this effort is far from comprehensive and that other relevant aspects related to CIR such as the microbiome, the individual's recombined T cell and B cell receptors, and the metabolic status of cancer and immune cells were not fully included. These and other important factors will be included in future activities of the taskforce. The taskforce will focus on prioritization and specific actionable approach to answer the identified questions and implementing the collaborations in the follow-up workshop, which will be held in Houston on September 4-5, 2019.
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http://dx.doi.org/10.1186/s40425-019-0602-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529999PMC
May 2019

Melanoma-associated antigen-A and programmed death-ligand 1 expression are associated with advanced urothelial carcinoma.

Cancer Immunol Immunother 2019 May 21;68(5):743-751. Epub 2019 Feb 21.

Department of Urology, Institute of Urologic Oncology, David Geffen School of Medicine at University of California, 300 Stein Plaza, Suite 348, Los Angeles, CA, 90095, USA.

Background: Melanoma-associated antigen-A (MAGE-A) and programmed-death ligand 1 (PD-L1) are present in urothelial carcinoma (UC). We assessed survival outcomes in patients with MAGE-A and PD-L1 expression.

Methods: MAGE-A and PD-L1 expression on neoplastic cells was analyzed using tissue microarrays from patients with UC. We compared differential expression between disease stage and grade. MAGE-A and PD-L1 co-expression was subcategorized. Fisher's exact test was done for categorical variables followed by univariable and multivariable analysis of recurrence-free survival (RFS) and progression-free survival (PFS).

Results: Co-expression of MAGE+/PD-L1+ was higher in advanced disease; however, only MAGE+/PD-L1- was associated with shorter RFS [hazard ratio (HR) 1.89; 95% confidence interval (CI) 1.19-2.99; p = .006]. MAGE+/PD-L1+ was associated with the worst PFS (HR 17.1; 95% CI 5.96-49.4; p ≤ .001). MAGE-A expression was more prevalent with high-grade (p = .015), and higher-stage ≥ pT2 (p = .001) disease. The 5-year RFS was 44% for MAGE+ versus 58% for MAGE- patients. On multivariable analysis, MAGE+ was also associated with shorter RFS (HR 1.55; 95% CI 1.05-2.30; p = .03). Similarly, MAGE+ was associated with shorter PFS (HR 3.12; 95% CI 1.12-8.68; p = .03).

Conclusion: MAGE-A and PD-L1 expression is increased in advanced disease and associated with shorter PFS. Furthermore, MAGE-A expression was significantly associated with higher-grade and -stage disease and associated with shorter RFS and PFS. The worse prognosis associated with MAGE-A+/PD-L1+ provides evidence that a combinatorial treatment strategy co-targeting MAGE/PD-L1 might be feasible. Further studies are needed to validate these findings.
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http://dx.doi.org/10.1007/s00262-019-02316-wDOI Listing
May 2019

Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial.

Lancet Oncol 2019 01 2;20(1):31-42. Epub 2018 Dec 2.

Kite, Santa Monica, CA, USA.

Background: Axicabtagene ciloleucel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. In the previous analysis of the ZUMA-1 registrational study, with a median follow-up of 15·4 months (IQR 13·7-17·3), 89 (82%) of 108 assessable patients with refractory large B-cell lymphoma treated with axicabtagene ciloleucel achieved an objective response, and complete responses were noted in 63 (58%) patients. Here we report long-term activity and safety outcomes of the ZUMA-1 study.

Methods: ZUMA-1 is a single-arm, multicentre, registrational trial at 22 sites in the USA and Israel. Eligible patients were aged 18 years or older, and had histologically confirmed large B-cell lymphoma-including diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and transformed follicular lymphoma-according to the 2008 WHO Classification of Tumors of Hematopoietic and Lymphoid Tissue; refractory disease or relapsed after autologous stem-cell transplantation; an Eastern Cooperative Oncology Group performance status of 0 or 1; and had previously received an anti-CD20 monoclonal antibody containing-regimen and an anthracycline-containing chemotherapy. Participants received one dose of axicabtagene ciloleucel on day 0 at a target dose of 2 × 10 CAR T cells per kg of bodyweight after conditioning chemotherapy with intravenous fludarabine (30 mg/m body-surface area) and cyclophosphamide (500 mg/m body-surface area) on days -5, -4, and -3. The primary endpoints were safety for phase 1 and the proportion of patients achieving an objective response for phase 2, and key secondary endpoints were overall survival, progression-free survival, and duration of response. Pre-planned activity and safety analyses were done per protocol. ZUMA-1 is registered with ClinicalTrials.gov, number NCT02348216. Although the registrational cohorts are closed, the trial remains open, and recruitment to extension cohorts with alternative endpoints is underway.

Findings: Between May 19, 2015, and Sept 15, 2016, 119 patients were enrolled and 108 received axicabtagene ciloleucel across phases 1 and 2. As of the cutoff date of Aug 11, 2018, 101 patients assessable for activity in phase 2 were followed up for a median of 27·1 months (IQR 25·7-28·8), 84 (83%) had an objective response, and 59 (58%) had a complete response. The median duration of response was 11·1 months (4·2-not estimable). The median overall survival was not reached (12·8-not estimable), and the median progression-free survival was 5·9 months (95% CI 3·3-15·0). 52 (48%) of 108 patients assessable for safety in phases 1 and 2 had grade 3 or worse serious adverse events. Grade 3 or worse cytokine release syndrome occurred in 12 (11%) patients, and grade 3 or worse neurological events in 35 (32%). Since the previous analysis at 1 year, additional serious adverse events were reported in four patients (grade 3 mental status changes, grade 4 myelodysplastic syndrome, grade 3 lung infection, and two episodes of grade 3 bacteraemia), none of which were judged to be treatment related. Two treatment-related deaths (due to haemophagocytic lymphohistiocytosis and cardiac arrest) were previously reported, but no new treatment-related deaths occurred during the additional follow-up.

Interpretation: These 2-year follow-up data from ZUMA-1 suggest that axicabtagene ciloleucel can induce durable responses and a median overall survival of greater than 2 years, and has a manageable long-term safety profile in patients with relapsed or refractory large B-cell lymphoma.

Funding: Kite and the Leukemia & Lymphoma Society Therapy Acceleration Program.
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http://dx.doi.org/10.1016/S1470-2045(18)30864-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733402PMC
January 2019

In this issue: Antibodies and T Cell subtypes in diseases and therapy.

Int Rev Immunol 2018 ;37(4):175-176

b International Reviews of Immunology, Translational Sciences , Kite Pharma Inc. , Santa Monica , CA , USA.

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http://dx.doi.org/10.1080/08830185.2018.1499488DOI Listing
April 2019

Preinfusion polyfunctional anti-CD19 chimeric antigen receptor T cells are associated with clinical outcomes in NHL.

Blood 2018 08 12;132(8):804-814. Epub 2018 Jun 12.

Kite, a Gilead Company, Santa Monica, CA.

After treatment with chimeric antigen receptor (CAR) T cells, interleukin-15 (IL-15) elevation and CAR T-cell expansion are associated with non-Hodgkin lymphoma (NHL) outcomes. However, the association of preinfusion CAR product T-cell functionality with clinical outcomes has not been reported. A single-cell analysis of the preinfusion CD19 CAR product from patients with NHL demonstrated that CAR products contain polyfunctional T-cell subsets capable of deploying multiple immune programs represented by cytokines and chemokines, including interferon-γ, IL-17A, IL-8, and macrophage inflammatory protein 1α. A prespecified T-cell polyfunctionality strength index (PSI) applied to preinfusion CAR product was significantly associated with clinical response, and PSI combined with CAR T-cell expansion or pretreatment serum IL-15 levels conferred additional significance. Within the total product cell population, associations with clinical outcomes were greater with polyfunctional CD4 T cells compared with CD8 cells. Grade ≥3 cytokine release syndrome was associated with polyfunctional T cells, and both grade ≥3 neurologic toxicity and antitumor efficacy were associated with polyfunctional IL-17A-producing T cells. The findings in this exploratory study show that a preinfusion CAR product T-cell subset with a definable polyfunctional profile has a major association with clinical outcomes of CAR T-cell therapy. This trial was registered at www.clinicaltrials.gov as #NCT00924326.
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http://dx.doi.org/10.1182/blood-2018-01-828343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107882PMC
August 2018

In this issue: Role of immune cells and molecules in rheumatoid arthritis pathogenesis and cancer immunotherapy.

Int Rev Immunol 2018 05;37(3):127-128

b International Reviews of Immunology and Vice President, Translational Sciences , Kite Pharma Inc. , Santa Monica , CA , USA.

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http://dx.doi.org/10.1080/08830185.2018.1469353DOI Listing
May 2018

In this issue: Effect of gut microbiome on mucosal immunity and enteric diseases.

Int Rev Immunol 2018 03;37(2):77-78

b Editor in Chief, International Reviews of Immunology and Vice President , Translational Sciences, Kite Pharma Inc. , Santa Monica , CA , USA.

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http://dx.doi.org/10.1080/08830185.2018.1450947DOI Listing
March 2018

In this issue: Role of specific and non-specific immunity in disease.

Int Rev Immunol 2018 01;37(1):1-2

b Editor in Chief, International Reviews of Immunology and Vice President, Translational Sciences, Kite Pharma Inc. , Santa Monica , CA , USA.

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http://dx.doi.org/10.1080/08830185.2018.1432192DOI Listing
January 2018

Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma.

N Engl J Med 2017 12 10;377(26):2531-2544. Epub 2017 Dec 10.

From the University of Texas M.D. Anderson Cancer Center, Houston (S.S.N., J.R.W.); H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL (F.L.L., J.C.C.); Washington University and Siteman Cancer Center, St. Louis (N.L.B., A. Ghobadi); University of Miami, Miami (L.J.L., K.V.K.); Stanford University, Stanford (D.B.M., R.L.), City of Hope National Medical Center, Duarte (T.S.), University of California at Los Angeles, Los Angeles (J.M.T.), University of California at San Diego, San Diego (J.E.C.), and Kite Pharma, Santa Monica (A.B., J.R., L.N., Y.J., J.A., M.E., D.C., J.W., W.Y.G.) - all in California; Dana-Farber Cancer Institute, Boston (C.A.J., E.D.J.); Montefiore Medical Center, Bronx (I.B.), and the University of Rochester School of Medicine, Rochester (J.W.F., P.R.) - both in New York; Vanderbilt University Medical Center (O.O.O.) and the Sarah Cannon Research Institute and Tennessee Oncology (I.W.F.), Nashville; Mayo Clinic, Rochester, MN (Y.L., T.E.W.); Loyola University Medical Center, Maywood, IL (P.J.S.); John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ (A. Goy); Cleveland Clinic, Cleveland (B.T.H., M.R.S.); Karmanos Cancer Center, Wayne State University, Detroit (A.D.); University of Iowa Carver College of Medicine, Iowa City (U.F.); Colorado Blood Cancer Institute, Denver (P.M.S.); Banner M.D. Anderson Cancer Center, Gilbert, AZ (J.M.); and Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel (I.A.).

Background: In a phase 1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, showed efficacy in patients with refractory large B-cell lymphoma after the failure of conventional therapy.

Methods: In this multicenter, phase 2 trial, we enrolled 111 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma who had refractory disease despite undergoing recommended prior therapy. Patients received a target dose of 2×10 anti-CD19 CAR T cells per kilogram of body weight after receiving a conditioning regimen of low-dose cyclophosphamide and fludarabine. The primary end point was the rate of objective response (calculated as the combined rates of complete response and partial response). Secondary end points included overall survival, safety, and biomarker assessments.

Results: Among the 111 patients who were enrolled, axi-cel was successfully manufactured for 110 (99%) and administered to 101 (91%). The objective response rate was 82%, and the complete response rate was 54%.With a median follow-up of 15.4 months, 42% of the patients continued to have a response, with 40% continuing to have a complete response. The overall rate of survival at 18 months was 52%. The most common adverse events of grade 3 or higher during treatment were neutropenia (in 78% of the patients), anemia (in 43%), and thrombocytopenia (in 38%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 13% and 28% of the patients, respectively. Three of the patients died during treatment. Higher CAR T-cell levels in blood were associated with response.

Conclusions: In this multicenter study, patients with refractory large B-cell lymphoma who received CAR T-cell therapy with axi-cel had high levels of durable response, with a safety profile that included myelosuppression, the cytokine release syndrome, and neurologic events. (Funded by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program; ZUMA-1 ClinicalTrials.gov number, NCT02348216 .).
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http://dx.doi.org/10.1056/NEJMoa1707447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882485PMC
December 2017

In this issue: Cancer immunity and immunotherapy.

Int Rev Immunol 2017 11;36(6):313-314

b Editor in Chief, International Reviews of Immunology and Vice President , Translational Sciences, Kite Pharma Inc. , Santa Monica , CA , USA.

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http://dx.doi.org/10.1080/08830185.2017.1398539DOI Listing
November 2017

In this issue: Fine tuners of immunity and their role in infectious and non-infectious diseases.

Int Rev Immunol 2017 09;36(5):257-258

b Editor in Chief, International Reviews of Immunology and Vice President, Translational Sciences , Kite Pharma Inc. , Santa Monica , CA , USA.

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http://dx.doi.org/10.1080/08830185.2017.1399712DOI Listing
September 2017

Axicabtagene ciloleucel, a first-in-class CAR T cell therapy for aggressive NHL.

Leuk Lymphoma 2018 08 23;59(8):1785-1796. Epub 2017 Oct 23.

b Department of Medicine , University of California at Los Angeles Jonsson Comprehensive Cancer Center , Los Angeles , CA , USA.

The development of clinically functional chimeric antigen receptor (CAR) T cell therapy is the culmination of multiple advances over the last three decades. Axicabtagene ciloleucel (formerly KTE-C19) is an anti-CD19 CAR T cell therapy in development for patients with refractory diffuse large B cell lymphoma (DLBCL), including transformed follicular lymphoma (TFL) and primary mediastinal B cell lymphoma (PMBCL). Axicabtagene ciloleucel is manufactured from patients' own peripheral blood mononuclear cells (PBMC) during which T cells are engineered to express a CAR that redirects them to recognize CD19-expressing cells. Clinical trials have demonstrated the feasibility of manufacturing axicabtagene ciloleucel in a centralized facility for use in multicenter clinical trials and have demonstrated potent antitumor activity in patients with refractory DLBCL. Main acute toxicities are cytokine release syndrome and neurologic events. Axicabtagene ciloleucel holds promise for the treatment of patients with CD19-positive malignancies, including refractory DLBCL.
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http://dx.doi.org/10.1080/10428194.2017.1387905DOI Listing
August 2018

Long-Duration Complete Remissions of Diffuse Large B Cell Lymphoma after Anti-CD19 Chimeric Antigen Receptor T Cell Therapy.

Mol Ther 2017 10 13;25(10):2245-2253. Epub 2017 Jul 13.

Surgery Branch, National Cancer Institute, Bethesda, MD 20892, USA.

T cells expressing anti-CD19 chimeric antigen receptors (CARs) can induce complete remissions (CRs) of diffuse large B cell lymphoma (DLBCL). The long-term durability of these remissions is unknown. We administered anti-CD19 CAR T cells preceded by cyclophosphamide and fludarabine conditioning chemotherapy to patients with relapsed DLBCL. Five of the seven evaluable patients obtained CRs. Four of the five CRs had long-term durability with durations of remission of 56, 51, 44, and 38 months; to date, none of these four cases of lymphomas have relapsed. Importantly, CRs continued after recovery of non-malignant polyclonal B cells in three of four patients with long-term complete remissions. In these three patients, recovery of CD19 polyclonal B cells took place 28, 38, and 28 months prior to the last follow-up, and each of these three patients remained in CR at the last follow-up. Non-malignant CD19 B cell recovery with continuing CRs demonstrated that remissions of DLBCL can continue after the disappearance of functionally effective anti-CD19 CAR T cell populations. Patients had a low incidence of severe infections despite long periods of B cell depletion and hypogammaglobulinemia. Only one hospitalization for an infection occurred among the four patients with long-term CRs. Anti-CD19 CAR T cells caused long-term remissions of chemotherapy-refractory DLBCL without substantial chronic toxicities.
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http://dx.doi.org/10.1016/j.ymthe.2017.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5628864PMC
October 2017

Role of MicroRNAs in shaping innate immunity and as therapeutic targets for autoimmune diseases.

Int Rev Immunol 2017 05 10;36(3):123-124. Epub 2017 Jul 10.

b International Reviews of Immunology and Vice President, Translational Sciences , Kite Pharma Inc. , Editor in Chief, Santa Monica , California , USA.

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http://dx.doi.org/10.1080/08830185.2017.1340043DOI Listing
May 2017

New Cancer Immunotherapy Agents in Development: a report from an associated program of the 31Annual Meeting of the Society for Immunotherapy of Cancer, 2016.

J Immunother Cancer 2017 20;5:50. Epub 2017 Jun 20.

Genentech/Roche, 1 DNA Way, South San Francisco, CA 94080 USA.

This report is a summary of 'New Cancer Immunotherapy Agents in Development' program, which took place in association with the 31st Annual Meeting of the Society for Immunotherapy of Cancer (SITC), on November 9, 2016 in National Harbor, Maryland. Presenters gave brief overviews of emerging clinical and pre-clinical immune-based agents and combinations, before participating in an extended panel discussion with multidisciplinary leaders, including members of the FDA, leading academic institutions and industrial drug developers, to consider topics relevant to the future of cancer immunotherapy.
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http://dx.doi.org/10.1186/s40425-017-0253-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477277PMC
April 2018

In this issue: Role of immune cells, immune modulating factors and immunotoxins in cancer immunotherapy.

Int Rev Immunol 2017 07 24;36(4):205-206. Epub 2017 May 24.

b Editor in Chief, International Reviews of Immunology and Vice President, Translational Sciences , Kite Pharma Inc. , Santa Monica , California , USA.

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http://dx.doi.org/10.1080/08830185.2017.1326784DOI Listing
July 2017

In this issue: Innate immunity and infectious diseases-An update.

Int Rev Immunol 2017 03 23;36(2):55-56. Epub 2017 Mar 23.

b Editor in Chief, International Reviews of Immunology and Vice President , Translational Sciences, Kite Pharma Inc. , Santa Monica , California , USA.

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http://dx.doi.org/10.1080/08830185.2017.1307021DOI Listing
March 2017

Lymphoma Remissions Caused by Anti-CD19 Chimeric Antigen Receptor T Cells Are Associated With High Serum Interleukin-15 Levels.

J Clin Oncol 2017 Jun 14;35(16):1803-1813. Epub 2017 Mar 14.

James N. Kochenderfer, Robert P.T. Somerville, Tangying Lu, Victoria Shi, Stephanie L. Goff, James C. Yang, Richard M. Sherry, Christopher A. Klebanoff, Udai S. Kammula, Constance M. Yuan, Mark J. Roschewski, Steven A. Feldman, Lori McIntyre, Mary Ann Toomey, and Steven A. Rosenberg, National Cancer Institute, National Institutes of Health, Bethesda, MD; Adrian Bot, John Rossi, Allen Xue, Marika Sherman, and Arianne Perez, Kite Pharma, Santa Monica, CA; Tatyana Feldman, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ; and Jonathan W. Friedberg, University of Rochester School of Medicine, Rochester, NY.

Purpose T cells genetically modified to express chimeric antigen receptors (CARs) targeting CD19 (CAR-19) have potent activity against acute lymphoblastic leukemia, but fewer results supporting treatment of lymphoma with CAR-19 T cells have been published. Patients with lymphoma that is chemotherapy refractory or relapsed after autologous stem-cell transplantation have a grim prognosis, and new treatments for these patients are clearly needed. Chemotherapy administered before adoptive T-cell transfer has been shown to enhance the antimalignancy activity of adoptively transferred T cells. Patients and Methods We treated 22 patients with advanced-stage lymphoma in a clinical trial of CAR-19 T cells preceded by low-dose chemotherapy. Nineteen patients had diffuse large B-cell lymphoma, two patients had follicular lymphoma, and one patient had mantle cell lymphoma. Patients received a single dose of CAR-19 T cells 2 days after a low-dose chemotherapy conditioning regimen of cyclophosphamide plus fludarabine. Results The overall remission rate was 73% with 55% complete remissions and 18% partial remissions. Eleven of 12 complete remissions are ongoing. Fifty-five percent of patients had grade 3 or 4 neurologic toxicities that completely resolved. The low-dose chemotherapy conditioning regimen depleted blood lymphocytes and increased serum interleukin-15 (IL-15). Patients who achieved a remission had a median peak blood CAR cell level of 98/μL and those who did not achieve a remission had a median peak blood CAR cell level of 15/μL ( P = .027). High serum IL-15 levels were associated with high peak blood CAR cell levels ( P = .001) and remissions of lymphoma ( P < .001). Conclusion CAR-19 T cells preceded by low-dose chemotherapy induced remission of advanced-stage lymphoma, and high serum IL-15 levels were associated with the effectiveness of this treatment regimen. CAR-19 T cells will likely become an important treatment for patients with relapsed lymphoma.
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http://dx.doi.org/10.1200/JCO.2016.71.3024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455597PMC
June 2017

In this issue: Antibodies in pathogenesis and management of diseases.

Int Rev Immunol 2017 01;36(1):1-2

b Editor in Chief, International Reviews of Immunology and Vice President, Translational Sciences , Kite Pharma Inc. , Santa Monica , California , USA.

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http://dx.doi.org/10.1080/08830185.2017.1290936DOI Listing
January 2017

Phase 1 Results of ZUMA-1: A Multicenter Study of KTE-C19 Anti-CD19 CAR T Cell Therapy in Refractory Aggressive Lymphoma.

Mol Ther 2017 Jan 4;25(1):285-295. Epub 2017 Jan 4.

Kite Pharma, Santa Monica, CA 90404, USA.

Outcomes for patients with refractory diffuse large B cell lymphoma (DLBCL) are poor. In the multicenter ZUMA-1 phase 1 study, we evaluated KTE-C19, an autologous CD3ζ/CD28-based chimeric antigen receptor (CAR) T cell therapy, in patients with refractory DLBCL. Patients received low-dose conditioning chemotherapy with concurrent cyclophosphamide (500 mg/m) and fludarabine (30 mg/m) for 3 days followed by KTE-C19 at a target dose of 2 × 10 CAR T cells/kg. The incidence of dose-limiting toxicity (DLT) was the primary endpoint. Seven patients were treated with KTE-C19 and one patient experienced a DLT of grade 4 cytokine release syndrome (CRS) and neurotoxicity. Grade ≥3 CRS and neurotoxicity were observed in 14% (n = 1/7) and 57% (n = 4/7) of patients, respectively. All other KTE-C19-related grade ≥3 events resolved within 1 month. The overall response rate was 71% (n = 5/7) and complete response (CR) rate was 57% (n = 4/7). Three patients have ongoing CR (all at 12+ months). CAR T cells demonstrated peak expansion within 2 weeks and continued to be detectable at 12+ months in patients with ongoing CR. This regimen of KTE-C19 was safe for further study in phase 2 and induced durable remissions in patients with refractory DLBCL.
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http://dx.doi.org/10.1016/j.ymthe.2016.10.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5363293PMC
January 2017