Rate of durable complete response in ALL, NHL, and CLL after immunotherapy with optimized lymphodepletion and defined composition CD19 CAR-T cells.

Turtle, Cameron J.; Hanafi, Laïla-Aïcha; Berger, Carolina; Gooley, Theodore A.; Chaney, Colette; Cherian, Sindhu; Soma, Lori; Chen, Xueyan; Yeung, Cecilia C.S.; Loeb, Keith R.; Wood, Brent L.; Hudecek, Michael; Sommermeyer, Daniel; Li, Daniel; Hay, Kevin A.; Heimfeld, Shelly; Riddell, Stanley R.; Maloney, David G.

doi:10.1200/jco.2016.34.15_suppl.102

Cited by 35 publications

(35 citation statements)

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“…We observed that treatment with the same lymphodepletion and CD19 CAR-T cell immunotherapy regimen resulted in lower CR rates in NHL and CLL patients compared to BALL patients (1,25). The reasons for the differences are yet to be determined, but may include differences in CAR-T cell access to tumor antigen and/or immune suppression in the tumor microenvironment in each disease.…”

Section: Discussionmentioning

confidence: 79%

“…This manuscript reports the data from NHL patients in the study. Because of differences in disease characteristics and the response to CAR-T cells, CLL and B-ALL patients are treated in distinct cohorts and reported separately (1,25). The study is available at https://clinicaltrials.gov/ct2/show/NCT01865617, and was conducted with approval of the Fred Hutchinson Cancer Research Center (FHCRC) institutional review board.…”

Section: Methodsmentioning

confidence: 99%

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Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8 ⁺ and CD4 ⁺ CD19-specific chimeric antigen receptor–modified T cells

et al. 2016

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CD19-specific chimeric antigen receptor (CAR)-modified T cells have antitumor activity in B cellmalignancies, but factors that impact toxicity and efficacy have been difficult to define because of differences in lymphodepletion regimens and heterogeneity of CAR-T cells administered to individual patients. We conducted a clinical trial in which CD19 CAR-T cells were manufactured from defined T cell subsets and administered in a 1:1 CD4 + :CD8 + ratio of CAR-T cells to 32 adults with relapsed and/or refractory B cell non-Hodgkin lymphoma after cyclophosphamide (Cy)-based lymphodepletion chemotherapy with or without fludarabine (Flu). Patients who received Cy/Flu lymphodepletion had markedly increased CAR-T cell expansion and persistence, and higher response rates (50% CR, 72% ORR, n=20) than patients who received Cy-based lymphodepletion without Flu (8% CR, 50% ORR, n=12). The complete response (CR) rate in patients treated with Cy/Flu at the maximally tolerated dose was 64% (82% ORR, n=11). Cy/Flu minimized the effects of an immune response to the murine scFv component of the CAR, which limited CAR-T cell expansion, persistence, and clinical efficacy in patients who received Cy-based lymphodepletion without Flu. Severe cytokine release syndrome (sCRS) and grade ≥ 3 neurotoxicity were observed in 13% and 28% of all patients, respectively. Serum biomarkers one # Corresponding author: Cameron J.

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Section: Discussionmentioning

confidence: 79%

Section: Methodsmentioning

confidence: 99%

Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8 ⁺ and CD4 ⁺ CD19-specific chimeric antigen receptor–modified T cells

et al. 2016

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“…Characteristics of patients' intrinsic immune response prior to CAR T cell infusion is likely important in response to this therapy. Studies have demonstrated that lymphodepletion prior to adoptive T cell transfer results in a more favorable environment for expansion of the infused lymphocytes, likely by reducing the population of regulatory T cells and by minimizing the number of lymphocytes available to act as a “cytokine sink.” Although several pediatric ALL patients who received CTL019 in the absence of lymphodepletion developed CRs that were durable, this is less common in CLL and subsequent studies in adult patients have suggested that lymphodepletion prior to CAR T cell infusion can facilitate more robust clinical activity . Clinical trial protocols have generally incorporated lymphodepletion regimens consisting of cyclophosphamide and/or fludarabine.…”

Section: The Importance Of Lymphodepletionmentioning

confidence: 99%

Accelerating chimeric antigen receptor therapy in chronic lymphocytic leukemia: The development and challenges of chimeric antigen receptor T‐cell therapy for chronic lymphocytic leukemia

Bair

Porter

2019

American J Hematol

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Studies of chimeric antigen receptor (CAR) T‐cell therapy in chronic lymphocytic leukemia (CLL) have demonstrated the potential to produce deep remissions—and possibly cures—in some patients with heavily pretreated, high‐risk, relapsed, and refractory disease. Unfortunately, most clinical trials of CAR T cells in CLL report complete responses only in the minority of patients, although recent studies have begun to elucidate the factors most predictive of response. These studies have suggested strategies for optimizing CAR T‐cell fitness as well as the pre‐existing host immune response, approaches that will likely lead to improvements in the efficacy of CAR T cells in CLL. Treating patients earlier in the course of their disease or using combination therapies with CAR T cells may further enhance efficacy. In this review, we summarize the existing literature on CAR T cell therapy in CLL, discuss mechanisms of response and resistance, and describe challenges facing the field.

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“…[35] All patients had previously received ibrutinib. Of the 12 restaged patients, 10 (83%) achieved clearance of the marrow by flow cytometry and 6 (50%) achieved CR by CT+/−PET imaging.…”

Section: Cd19 Car-t Cell Clinical Trials In B-cell Malignanciesmentioning

confidence: 99%

Chimeric Antigen Receptor (CAR) T Cells: Lessons Learned from Targeting of CD19 in B-Cell Malignancies

Hay

Turtle

2017

Drugs

125

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Adoptive immunotherapy with chimeric antigen receptor-modified T (CAR-T) cells is a rapidly growing therapeutic approach to treating patients with refractory cancer, with over 100 clinical trials in various malignancies in progress. The enthusiasm for CAR-T cells has been driven by the clinical success of CD19-targeted CAR-T therapy in B-cell acute lymphoblastic leukemia, and the promising data in B-cell non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. Despite the success of targeting CD19 with CAR-T cells in early clinical studies, many challenges remain to improve outcomes, reduce toxicity, and determine the appropriate settings for CAR-T cell immunotherapy. Reviewing the lessons learned thus far in CD19 CAR-T cell trials and how some of these challenges may be overcome will help guide the development of CAR-T cell therapy for malignancies of B-cell origin, as well as for other hematopoietic and non-hematopoietic cancers.

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Rate of durable complete response in ALL, NHL, and CLL after immunotherapy with optimized lymphodepletion and defined composition CD19 CAR-T cells.

Cited by 35 publications

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Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8 ⁺ and CD4 ⁺ CD19-specific chimeric antigen receptor–modified T cells

Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8 ⁺ and CD4 ⁺ CD19-specific chimeric antigen receptor–modified T cells

Accelerating chimeric antigen receptor therapy in chronic lymphocytic leukemia: The development and challenges of chimeric antigen receptor T‐cell therapy for chronic lymphocytic leukemia

Chimeric Antigen Receptor (CAR) T Cells: Lessons Learned from Targeting of CD19 in B-Cell Malignancies

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Rate of durable complete response in ALL, NHL, and CLL after immunotherapy with optimized lymphodepletion and defined composition CD19 CAR-T cells.

Cited by 35 publications

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Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8 + and CD4 + CD19-specific chimeric antigen receptor–modified T cells

Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8 + and CD4 + CD19-specific chimeric antigen receptor–modified T cells

Accelerating chimeric antigen receptor therapy in chronic lymphocytic leukemia: The development and challenges of chimeric antigen receptor T‐cell therapy for chronic lymphocytic leukemia

Chimeric Antigen Receptor (CAR) T Cells: Lessons Learned from Targeting of CD19 in B-Cell Malignancies

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Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8 ⁺ and CD4 ⁺ CD19-specific chimeric antigen receptor–modified T cells

Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8 ⁺ and CD4 ⁺ CD19-specific chimeric antigen receptor–modified T cells