Durable Molecular Remissions in Chronic Lymphocytic Leukemia Treated With CD19-Specific Chimeric Antigen Receptor–Modified T Cells After Failure of Ibrutinib

Turtle, Cameron J.; Hay, Kevin A.; Hanafi, Laïla-Aïcha; Li, Daniel; Cherian, Sindhu; Chen, Xueyan; Wood, Brent L.; Lozanski, Arletta; Byrd, John C.; Heimfeld, Shelly; Riddell, Stanley R.; Maloney, David G.

doi:10.1200/jco.2017.72.8519

Cited by 575 publications

(548 citation statements)

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“…21 in published clinical trials. [1][2][3][4][5][6][7][8][9][10][11][12][13]30,[37][38][39][40][41][42][43][44] By administering diminishing doses of CAR19 T cell products with similar phenotype, including CD4:CD8 ratios, we found 4-1BB co-stimulation led to greater potency and control of repeat doses of B-ALL. These results are most likely a product of 4-1BB co-stimulation promoting longer CAR19 T cell persistence than CD28, a finding consistent with other pre-clinical studies [45][46][47] and clinical trials.…”

Section: Discussionmentioning

confidence: 90%

“…These results are most likely a product of 4-1BB co-stimulation promoting longer CAR19 T cell persistence than CD28, a finding consistent with other pre-clinical studies [45][46][47] and clinical trials. [2][3][4][5][6][7][8][9][10][11][12][13]37,40,44 Regardless of co-stimulatory domain, our final piggy-Bac-generated CAR19 T cell products all displayed a predominantly differentiated phenotype with elevated immuno-inhibitory markers. This may result from ex vivo expansion via repeated CAR stimulation.…”

Section: Discussionmentioning

confidence: 93%

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PiggyBac-Engineered T Cells Expressing CD19-Specific CARs that Lack IgG1 Fc Spacers Have Potent Activity against B-ALL Xenografts

Bishop

Tse

et al. 2018

Molecular Therapy

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Clinical trials of CD19-specific chimeric antigen receptor (CAR19) T cells have demonstrated remarkable efficacy against relapsed and refractory B cell malignancies. The piggyBac transposon system offers a less complex and more economical means for generating CAR19 T cells compared to viral vectors. We have previously optimized a protocol for the generation of CAR19 T cells using the piggyBac system, but we found that CAR19 T cells had poor in vivo efficacy and persistence, probably due to deleterious FcγR interactions with the CAR's IgG1 Fc-containing spacer domain. We therefore designed three CD19-specifc CARs that lacked the IgG1 Fc region, and we incorporated combinations of CD28 or 4-1BB transmembrane and co-stimulatory domains. PiggyBac-generated CAR19 T cells expressing these re-designed constructs all demonstrated reactivity in vitro specifically against CD19 cell lines. However, those combining CD28 transmembrane and co-stimulatory domains showed CD4 predominance and inferior cytotoxicity. At high doses, CAR19 T cells were effective against B-ALL in a xenograft mouse model, regardless of co-stimulatory domain. At diminishing doses, 4-1BB co-stimulation led to greater potency and persistence of CAR19 T cells, and it provided protection against B-ALL re-challenge. Production of potent CAR T cells using piggyBac is simple and cost-effective, and it may enable wider access to CAR T cell therapy.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 93%

PiggyBac-Engineered T Cells Expressing CD19-Specific CARs that Lack IgG1 Fc Spacers Have Potent Activity against B-ALL Xenografts

Bishop

Tse

et al. 2018

Molecular Therapy

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“…This precautionary approach was required in the clinical trials of axi-cel, but we have not found this to be necessary in studies using CAR T cell constructs containing a 4-1BB co-stimulatory domain, including tisagenlecleucel, JCAR014, and JCAR017, in both ALL and NHL populations. Fever is typically the presenting symptom of CAR T cell-associated CRS (at least with 4-1BB CAR T cells), with critical illness arising 12-96 h later, if at all [7][8][9][10][11][12] . Patients can therefore be infused with CAR T cells in the outpatient setting and admitted to hospital at the time of fever development.…”

mentioning

confidence: 99%

“…We believe that this recommendation is not supported by clinical trial data from across the field of CAR T cell research to date, necessitating further studies to establish the comparative effectiveness of these agents. Tocilizumab is now approved by the FDA for the management of severe CRS based on extensive clinical data demonstrating the efficacy of this agent in the majority of patients 8,9,[11][12][13]15 . Siltuximab has not been studied as a first-line therapy for CRS and is not currently FDA-approved for this indication.…”

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confidence: 99%

Toxicity management after chimeric antigen receptor T cell therapy: one size does not fit 'ALL'

et al. 2018

Self Cite

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“…Adoptive T-cell therapy involves the isolation of a patient's T cells, followed by, in certain cases, manipulation of the T cell to target a specific tumor antigen, expansion and re-infusion following lymphodepleting chemotherapy [23]. The excitement in the field is largely due to the remarkable responses seen in patients with refractory hematology malignancies to CD19-targeted chimeric antigen receptor-modified T cells [24][25][26]. In solid tumor oncology, there are several studies of chimeric antigen receptor-modified T cells currently enrolling patients in various malignancies (e.g., NCT02706392, NCT03089203 and NCT02208362).…”

mentioning

confidence: 99%

Immuno-Oncology in Urothelial Carcinoma: Who or What Will Ultimately Sit on the Iron Throne?

Ramos

2017

Immunotherapy

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" only a minority of patients will respond to immune checkpoint inhibitors. Therefore, clinical trials using immune checkpoint inhibitors in earlier disease settings, novel combinations and other immuno-oncology agents (e.g., ADCs and adoptive T-cell therapy) are ongoing. These treatment strategies will add to the framework of knowledge of the interaction between tumors and the host immune system " First draft submitted: 10 August 2017; Accepted for publication: 23 August 2017; Published online: 3 October 2017Platinum-based chemotherapy has been the mainstay of treatment for metastatic urothelial carcinoma for over 25 years [1][2][3]. Response rates with first-line cisplatin-based chemotherapy are approximately 50%, however, responses are often brief and prognosis is dismal, with a median overall survival (OS) of 15 months [2,3]. Furthermore, until recently, there were no US FDA-approved agents for patients who progressed on platinum-based chemotherapy. In Europe, vinflunine has regulatory approval after platinum-based chemotherapy despite not demonstrating an OS benefit in the intention-to-treat analysis [4]. Monoclonal antibodies targeting immune checkpoints, such as PD-1 or PD-L1, have been developed based on the growing recognition of the importance of the immune checkpoint pathway in tumor evasion of the adaptive immune response [5]. In metastatic urothelial carcinoma, patients treated with immune checkpoint inhibitors have been shown to have durable clinical responses [6][7][8][9][10][11]. The success of these agents has resulted in FDA approval of 5 PD-1/PD-L1 inhibitors (i.e., atezolizumab, avelumab, durvalumab, nivolumab and pembrolizumab) in platinum-refractory metastatic urothelial carcinoma, providing an essential new option for patients. Furthermore, this newfound understanding of the interplay between a tumor and our immune system establishes the framework for further development of other immuno-oncology agents for urothelial carcinoma. Herein, we discuss the current role of PD-1/PD-L1 inhibitors in urothelial carcinoma and potential opportunities for advancing the field.Atezolizumab, a PD-L1 inhibitor, was the first immune checkpoint inhibitor to demonstrate clinical efficacy in urothelial carcinoma. In the Phase I study, metastatic urothelial carcinoma patients treated with atezolizumab had an objective response rate (ORR) of 26.2% [12]. Subsequently, in the Phase II IMvigor 210 study, platinumrefractory metastatic urothelial carcinoma patients had an ORR of 15% to atezolizumab [9]. More importantly, 71% of patients had an ongoing response at a median follow-up of 17.5 months. Thereafter, several PD-1/PD-L1 inhibitors have demonstrated similar clinical efficacy in early phase studies, with ORRs generally in the 18-31% range [6,8,10,11,13].Recently, pembrolizumab and atezolizumab were compared with investigator's choice of single-agent chemotherapy with docetaxel, paclitaxel or vinflunine in the post-platinum setting in the Phase III KEYNOTE-045 and IMvigor 211 studies, respectively. In KEYNOTE-04...

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Durable Molecular Remissions in Chronic Lymphocytic Leukemia Treated With CD19-Specific Chimeric Antigen Receptor–Modified T Cells After Failure of Ibrutinib

Cited by 575 publications

References 25 publications

PiggyBac-Engineered T Cells Expressing CD19-Specific CARs that Lack IgG1 Fc Spacers Have Potent Activity against B-ALL Xenografts

PiggyBac-Engineered T Cells Expressing CD19-Specific CARs that Lack IgG1 Fc Spacers Have Potent Activity against B-ALL Xenografts

Toxicity management after chimeric antigen receptor T cell therapy: one size does not fit 'ALL'

Immuno-Oncology in Urothelial Carcinoma: Who or What Will Ultimately Sit on the Iron Throne?

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