Clinical development of CAR T cells—challenges and opportunities in translating innovative treatment concepts

doi:10.15252/EMMM.201607485

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Clinical development of CAR T cells—challenges and opportunities in translating innovative treatment concepts

Journal Article•DOI•

Clinical development of CAR T cells—challenges and opportunities in translating innovative treatment concepts

Jessica Hartmann¹, Martina Schüßler-Lenz¹, Attilio Bondanza², Christian J. Buchholz¹•Institutions (2)

Paul Ehrlich Institute¹, Vita-Salute San Raffaele University²

01 Sep 2017-Embo Molecular Medicine (John Wiley & Sons, Ltd)-Vol. 9, Iss: 9, pp 1183-1197

TL;DR: A comprehensive overview of the clinical trials performed so far worldwide and analyze parameters such as targeted antigen and indication, CAR molecular design, CAR T cell manufacturing, anti‐tumor activities, and related toxicities, with a special focus on the European stage.

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Abstract: Chimeric antigen receptor (CAR) T cell therapy, together with checkpoint inhibition, has been celebrated as a breakthrough technology due to the substantial benefit observed in clinical trials with patients suffering from relapsed or refractory B-cell malignancies. In this review, we provide a comprehensive overview of the clinical trials performed so far worldwide and analyze parameters such as targeted antigen and indication, CAR molecular design, CAR T cell manufacturing, anti-tumor activities, and related toxicities. More than 200 CAR T cell clinical trials have been initiated so far, most of which aim to treat lymphoma or leukemia patients using CD19-specific CARs. An increasing number of studies address solid tumors as well. Notably, not all clinical trials conducted so far have shown promising results. Indeed, in a few patients CAR T cell therapy resulted in severe adverse events with fatal outcome. Of note, less than 10% of the ongoing CAR T cell clinical trials are performed in Europe. Taking lead from our analysis, we discuss the problems and general hurdles preventing efficient clinical development of CAR T cells as well as opportunities, with a special focus on the European stage.

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Journal Article•DOI•

Cytokine release syndrome

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Alexander Shimabukuro-Vornhagen, Philipp Gödel¹, Marion Subklewe, Hans Joachim Stemmler², Hans A. Schlößer³, Max Schlaak, M. Kochanek¹, B. Böll¹, Michael von Bergwelt-Baildon - Show less +5 more•Institutions (3)

University of Bonn¹, Ludwig Maximilian University of Munich², University of Cologne³

15 Jun 2018-Journal for ImmunoTherapy of Cancer

TL;DR: This review provides a comprehensive overview of the mechanisms underlying CRS pathophysiology, risk factors, clinical presentation, differential diagnoses, and prognostic factors and gives practical guidance to the management of the cytokine release syndrome.

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Abstract: During the last decade the field of cancer immunotherapy has witnessed impressive progress. Highly effective immunotherapies such as immune checkpoint inhibition, and T-cell engaging therapies like bispecific T-cell engaging (BiTE) single-chain antibody constructs and chimeric antigen receptor (CAR) T cells have shown remarkable efficacy in clinical trials and some of these agents have already received regulatory approval. However, along with growing experience in the clinical application of these potent immunotherapeutic agents comes the increasing awareness of their inherent and potentially fatal adverse effects, most notably the cytokine release syndrome (CRS). This review provides a comprehensive overview of the mechanisms underlying CRS pathophysiology, risk factors, clinical presentation, differential diagnoses, and prognostic factors. In addition, based on the current evidence we give practical guidance to the management of the cytokine release syndrome.

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1,056 citations

Cites background from "Clinical development of CAR T cells..."

...Another promising line of research that will certainly help to improve the safety of T cell-engaging immunotherapy focuses on the optimization of the design of the compounds themselves [84]....
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Journal Article•DOI•

Advances in cancer immunotherapy 2019 – latest trends

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Stephan Kruger¹, Stephan Kruger², Matthias Ilmer¹, Matthias Ilmer³, Sebastian Kobold², Bruno L. Cadilha², Stefan Endres², Steffen Ormanns¹, Gesa Schuebbe¹, Bernhard W. Renz¹, Bernhard W. Renz³, Jan G. D’Haese¹, Hans Anton Schloesser, Volker Heinemann¹, Volker Heinemann³, Marion Subklewe¹, Marion Subklewe³, Stefan Boeck¹, Stefan Boeck³, Jens Werner¹, Michael von Bergwelt-Baildon - Show less +17 more•Institutions (3)

Ludwig Maximilian University of Munich¹, Protein Sciences², German Cancer Research Center³

19 Jun 2019-Journal of Experimental & Clinical Cancer Research

TL;DR: This review summarizes seminal findings from clinical and translational studies recently presented or published at important meetings or in top-tier journals, respectively, regarding cellular immunotherapy and checkpoint blockade.

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Abstract: Immunotherapy has become an established pillar of cancer treatment improving the prognosis of many patients with a broad variety of hematological and solid malignancies. The two main drivers behind this success are checkpoint inhibitors (CPIs) and chimeric antigen receptor (CAR) T cells. This review summarizes seminal findings from clinical and translational studies recently presented or published at important meetings or in top-tier journals, respectively. For checkpoint blockade, current studies focus on combinational approaches, perioperative use, new tumor entities, response prediction, toxicity management and use in special patient populations. Regarding cellular immunotherapy, recent studies confirmed safety and efficacy of CAR T cells in larger cohorts of patients with acute lymphoblastic leukemia or diffuse large B cell lymphoma. Different strategies to translate the striking success of CAR T cells in B cell malignancies to other hematological and solid cancer types are currently under clinical investigation. Regarding the regional distribution of registered clinical immunotherapy trials a shift from PD-1 / PD-L1 trials (mainly performed in the US and Europe) to CAR T cell trials (majority of trials performed in the US and China) can be noted.

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366 citations

Journal Article•DOI•

Translating gammadelta (γδ) T cells and their receptors into cancer cell therapies

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Zsolt Sebestyén¹, Immo Prinz², Julie Déchanet-Merville³, Bruno Silva-Santos⁴, Jürgen Kuball¹ - Show less +1 more•Institutions (4)

University Medical Center Utrecht¹, Hannover Medical School², University of Bordeaux³, Instituto de Medicina Molecular⁴

01 Mar 2020-Nature Reviews Drug Discovery

TL;DR: The challenges and opportunities for the clinical implementation of cancer immunotherapies based on γδT cells and their receptors are discussed, which display potent cytotoxicity towards a large array of haematological and solid tumours while preserving normal tissues.

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Abstract: Clinical responses to checkpoint inhibitors used for cancer immunotherapy seemingly require the presence of αβT cells that recognize tumour neoantigens, and are therefore primarily restricted to tumours with high mutational load. Approaches that could address this limitation by engineering αβT cells, such as chimeric antigen receptor T (CAR T) cells, are being investigated intensively, but these approaches have other issues, such as a scarcity of appropriate targets for CAR T cells in solid tumours. Consequently, there is renewed interest among translational researchers and commercial partners in the therapeutic use of γδT cells and their receptors. Overall, γδT cells display potent cytotoxicity, which usually does not depend on tumour-associated (neo)antigens, towards a large array of haematological and solid tumours, while preserving normal tissues. However, the precise mechanisms of tumour-specific γδT cells, as well as the mechanisms for self-recognition, remain poorly understood. In this Review, we discuss the challenges and opportunities for the clinical implementation of cancer immunotherapies based on γδT cells and their receptors.

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233 citations

Journal Article•DOI•

B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches.

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Nina Shah¹, Ajai Chari², Emma C. Scott³, Khalid Mezzi⁴, Saad Z. Usmani - Show less +1 more•Institutions (4)

University of California, San Francisco¹, Mount Sinai Hospital², GlaxoSmithKline³, Amgen⁴

13 Feb 2020-Leukemia

TL;DR: Clinical data outline the potential for BCMA-targeted therapies to improve the treatment landscape for MM and suggest that these therapies may hold promise for deep and durable responses and support further investigation in earlier lines of treatment, including newly diagnosed MM.

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Abstract: Despite considerable advances in the treatment of multiple myeloma (MM) in the last decade, a substantial proportion of patients do not respond to current therapies or have a short duration of response. Furthermore, these treatments can have notable morbidity and are not uniformly tolerated in all patients. As there is no cure for MM, patients eventually become resistant to therapies, leading to development of relapsed/refractory MM. Therefore, an unmet need exists for MM treatments with novel mechanisms of action that can provide durable responses, evade resistance to prior therapies, and/or are better tolerated. B-cell maturation antigen (BCMA) is preferentially expressed by mature B lymphocytes, and its overexpression and activation are associated with MM in preclinical models and humans, supporting its potential utility as a therapeutic target for MM. Moreover, the use of BCMA as a biomarker for MM is supported by its prognostic value, correlation with clinical status, and its ability to be used in traditionally difficult-to-monitor patient populations. Here, we review three common treatment modalities used to target BCMA in the treatment of MM: bispecific antibody constructs, antibody–drug conjugates, and chimeric antigen receptor (CAR)-modified T-cell therapy. We provide an overview of preliminary clinical data from trials using these therapies, including the BiTE® (bispecific T-cell engager) immuno-oncology therapy AMG 420, the antibody–drug conjugate GSK2857916, and several CAR T-cell therapeutic agents including bb2121, NIH CAR-BCMA, and LCAR-B38M. Notable antimyeloma activity and high minimal residual disease negativity rates have been observed with several of these treatments. These clinical data outline the potential for BCMA-targeted therapies to improve the treatment landscape for MM. Importantly, clinical results to date suggest that these therapies may hold promise for deep and durable responses and support further investigation in earlier lines of treatment, including newly diagnosed MM.

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220 citations

Cites background from "Clinical development of CAR T cells..."

...Though lymphodepletion is an important part of the CAR T-cell treatment process, reduction of endogenous lymphocyte levels and subsequent CAR T-cell expansion may have implications for salvage therapy after failure of CAR T-cell therapy, as these processes modify the characteristics of patients’ T cells [87]....
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Journal Article•DOI•

Metabolic interventions in the immune response to cancer

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David O’Sullivan¹, David O’Sullivan², David E. Sanin², David E. Sanin¹, Edward J. Pearce², Edward J. Pearce¹, Erika L. Pearce² - Show less +3 more•Institutions (2)

University of Freiburg¹, Max Planck Society²

01 May 2019-Nature Reviews Immunology

TL;DR: How nutrient availability in the tumour microenvironment shapes immune responses and identify areas of intervention to modulate the metabolic constraints placed on immune cells in this setting are explored.

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Abstract: At the centre of the therapeutic dilemma posed by cancer is the question of how to develop more effective treatments that discriminate between normal and cancerous tissues. Decades of research have shown us that universally applicable principles are rare, but two well-accepted concepts have emerged: first, that malignant transformation goes hand in hand with distinct changes in cellular metabolism; second, that the immune system is critical for tumour control and clearance. Unifying our understanding of tumour metabolism with immune cell function may prove to be a powerful approach in the development of more effective cancer therapies. Here, we explore how nutrient availability in the tumour microenvironment shapes immune responses and identify areas of intervention to modulate the metabolic constraints placed on immune cells in this setting. In this Review, Erika Pearce and colleagues detail the metabolic changes that occur in the tumour microenvironment, explaining how these shape immune cell function at these sites. They highlight the potential of targeting these metabolic pathways to treat patients with cancer

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178 citations

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References

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Journal Article•DOI•

Chimeric antigen receptor T cells for sustained remissions in leukemia.

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Shannon L. Maude, Noelle Frey¹, Pamela A. Shaw, Richard Aplenc, David M. Barrett, Nancy Bunin, Anne Chew, Vanessa E. Gonzalez, Zhaohui Zheng, Simon F. Lacey, Yolanda D. Mahnke, J. Joseph Melenhorst, Susan R. Rheingold, Angela Shen, David T. Teachey, Bruce L. Levine, Carl H. June, David L. Porter, Stephan A. Grupp - Show less +15 more•Institutions (1)

Novartis¹

15 Oct 2014-The New England Journal of Medicine

TL;DR: Chimeric antigen receptor-modified T-cell therapy against CD19 was effective in treating relapsed and refractory ALL and was associated with a high remission rate, even among patients for whom stem-cell transplantation had failed, and durable remissions up to 24 months were observed.

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Abstract: A total of 30 children and adults received CTL019. Complete remission was achieved in 27 patients (90%), including 2 patients with blinatumomab-refractory disease and 15 who had undergone stem-cell transplantation. CTL019 cells proliferated in vivo and were detectable in the blood, bone marrow, and cerebrospinal fluid of patients who had a response. Sustained remission was achieved with a 6-month event-free survival rate of 67% (95% confidence interval [CI], 51 to 88) and an overall survival rate of 78% (95% CI, 65 to 95). At 6 months, the probability that a patient would have persistence of CTL019 was 68% (95% CI, 50 to 92) and the probability that a patient would have relapse-free B-cell aplasia was 73% (95% CI, 57 to 94). All the patients had the cytokine-release syndrome. Severe cytokine-release syndrome, which developed in 27% of the patients, was associated with a higher disease burden before infusion and was effectively treated with the anti–interleukin-6 receptor antibody tocilizumab. CONCLUSIONS Chimeric antigen receptor–modified T-cell therapy against CD19 was effective in treating relapsed and refractory ALL. CTL019 was associated with a high remission rate, even among patients for whom stem-cell transplantation had failed, and durable remissions up to 24 months were observed. (Funded by Novartis and others; CART19 ClinicalTrials.gov numbers, NCT01626495 and NCT01029366.)

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4,208 citations

"Clinical development of CAR T cells..." refers background or result in this paper

...Furthermore, reversible symptoms of neurotoxicity including confusion, delirium, expressive aphasia, encephalopathy, and seizures were reported in several other studies (Brentjens et al, 2011; Maude et al, 2014; Kochenderfer et al, 2015; Lee et al, 2015; Turtle et al, 2016)....
[...]
...Among these, B-cell aplasia is a common adverse event in CAR T cell trials targeting B-cell malignancies (Kochenderfer et al, 2013; Maude et al, 2014; Turtle et al, 2016)....
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...Of note, in trials including pediatric and adult patients, the clinical outcome appeared to be independent from age (Cruz et al, 2013; Maude et al, 2014; Lee et al, 2015; Zhang et al, 2016)....
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...A currently preferred alternative is treatment with tocilizumab, a therapeutic IL-6 receptor blocking antibody, which does not affect CAR T cell persistence (Davila et al, 2014; Maude et al, 2014)....
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...Yet, the reported durable remissions and event-free survival rates following CAR T cell administration are particularly promising, especially since these patient populations included cases refractory to blinatumomab (Maude et al, 2014)....
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Journal Article•DOI•

T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial

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Daniel W. Lee, James N. Kochenderfer, Maryalice Stetler-Stevenson, Yongzhi K Cui, Cindy Delbrook, Steven A. Feldman, Terry J. Fry, Rimas J. Orentas, Marianna Sabatino¹, Nirali N. Shah, Seth M. Steinberg, Dave Stroncek¹, Nick Tschernia², Constance M. Yuan, Hua Zhang, Ling Zhang, Steven A. Rosenberg, Alan S. Wayne³, Crystal L. Mackall - Show less +15 more•Institutions (3)

National Institutes of Health¹, University of Nevada, Reno², University of Southern California³

07 Feb 2015-The Lancet

TL;DR: CD19-CAR T cell therapy is feasible, safe, and mediates potent anti-leukaemic activity in children and young adults with chemotherapy-resistant B-precursor acute lymphoblastic leukaemia and non-Hodgkin lymphoma.

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2,394 citations

"Clinical development of CAR T cells..." refers background or result in this paper

...In some patients, CD19-CAR T cells have been found in cerebrospinal fluid (CSF; Brentjens et al, 2011; Lee et al, 2015)....
[...]
...Furthermore, reversible symptoms of neurotoxicity including confusion, delirium, expressive aphasia, encephalopathy, and seizures were reported in several other studies (Brentjens et al, 2011; Maude et al, 2014; Kochenderfer et al, 2015; Lee et al, 2015; Turtle et al, 2016)....
[...]
...Of note, in trials including pediatric and adult patients, the clinical outcome appeared to be independent from age (Cruz et al, 2013; Maude et al, 2014; Lee et al, 2015; Zhang et al, 2016)....
[...]
...In the ALL studies, the remissions induced by CAR T cells have been variously consolidated with transplantation [three out of 30, 11%; (Maude et al, 2014); seven out of 14, 50% (Davila et al, 2014); 10 out of 14, 71% (Lee et al, 2015); 13 out of 27, 48% (Turtle et al, 2016)]....
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...Systemic corticosteroid administration rapidly reversed symptoms in most cases (Davila et al, 2014; Lee et al, 2015), but, can result in ablation of the infused CAR T cells, thus limiting the anti-tumoral effect (Davila et al, 2014)....
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Journal Article•DOI•

Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2

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Richard A. Morgan¹, James Chih-Hsin Yang¹, Mio Kitano¹, Mark E. Dudley¹, Carolyn M. Laurencot¹, Steven A. Rosenberg¹ - Show less +2 more•Institutions (1)

National Institutes of Health¹

01 Apr 2010-Molecular Therapy

TL;DR: It is speculated that the large number of administered cells localized to the lung immediately following infusion and were triggered to release cytokine by the recognition of low levels of ERBB2 on lung epithelial cells, consistent with a cytokine storm.

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2,167 citations

"Clinical development of CAR T cells..." refers background in this paper

...Due to the recognition of ErbB2 on normal lung cells, one patient died from rapid respiratory failure and multi-organ dysfunction (Morgan et al, 2010)....
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Journal Article•DOI•

Efficacy and Toxicity Management of 19-28z CAR T Cell Therapy in B Cell Acute Lymphoblastic Leukemia

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Marco L. Davila¹, Isabelle Riviere, Xiuyan Wang¹, Shirley Bartido¹, Jae H. Park¹, Kevin J. Curran¹, Stephen S. Chung¹, Jolanta Stefanski¹, Oriana Borquez-Ojeda¹, Malgorzata Olszewska¹, Jinrong Qu¹, Teresa Wasielewska¹, Qing He¹, Mitsu Fink¹, Himaly Shinglot¹, Maher Youssif¹, Mark Satter¹, Yongzeng Wang¹, James Hosey¹, Hilda Quintanilla¹, Elizabeth Halton¹, Yvette Bernal¹, Diana C. G. Bouhassira¹, Maria E. Arcila¹, Mithat Gonen¹, Gail J. Roboz², Peter Maslak¹, Dan Douer¹, Mark G. Frattini, Sergio Giralt¹, Michel Sadelain¹, Renier J. Brentjens¹ - Show less +28 more•Institutions (2)

Memorial Sloan Kettering Cancer Center¹, Cornell University²

19 Feb 2014-Science Translational Medicine

TL;DR: Diagnostic criteria for a severe cytokine release syndrome (sCRS) is defined and serum C-reactive protein, a readily available laboratory study, can serve as a reliable indicator for the severity of the CRS.

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Abstract: We report on 16 patients with relapsed or refractory B cell acute lymphoblastic leukemia (B-ALL) that we treated with autologous T cells expressing the 19-28z chimeric antigen receptor (CAR) specific to the CD19 antigen. The overall complete response rate was 88%, which allowed us to transition most of these patients to a standard-of-care allogeneic hematopoietic stem cell transplant (allo-SCT). This therapy was as effective in high-risk patients with Philadelphia chromosome-positive (Ph(+)) disease as in those with relapsed disease after previous allo-SCT. Through systematic analysis of clinical data and serum cytokine levels over the first 21 days after T cell infusion, we have defined diagnostic criteria for a severe cytokine release syndrome (sCRS), with the goal of better identifying the subset of patients who will likely require therapeutic intervention with corticosteroids or interleukin-6 receptor blockade to curb the sCRS. Additionally, we found that serum C-reactive protein, a readily available laboratory study, can serve as a reliable indicator for the severity of the CRS. Together, our data provide strong support for conducting a multicenter phase 2 study to further evaluate 19-28z CAR T cells in B-ALL and a road map for patient management at centers now contemplating the use of CAR T cell therapy.

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2,064 citations

"Clinical development of CAR T cells..." refers background in this paper

...A currently preferred alternative is treatment with tocilizumab, a therapeutic IL-6 receptor blocking antibody, which does not affect CAR T cell persistence (Davila et al, 2014; Maude et al, 2014)....
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...Patients with minimal residual disease (MRD) or morphologic disease, defined by the percentage of blasts in BM, were also included (Dataset EV4)....
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...In the ALL studies, the remissions induced by CAR T cells have been variously consolidated with transplantation [three out of 30, 11%; (Maude et al, 2014); seven out of 14, 50% (Davila et al, 2014); 10 out of 14, 71% (Lee et al, 2015); 13 out of 27, 48% (Turtle et al, 2016)]....
[...]
...Interestingly, there appears to be no major difference in remission rates between patients with morphologic disease and patients with MRD (Davila et al, 2014; Maude et al, 2014; Turtle et al, 2016; Park et al, 2017)....
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...However, patients with MRD lived significantly longer (18-month follow-up) (Park et al, 2017)....
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Journal Article•DOI•

Current concepts in the diagnosis and management of cytokine release syndrome

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Daniel W. Lee, Rebecca Gardner¹, David L. Porter², Chrystal U. Louis³, Nabil Ahmed³, Michael C. Jensen¹, Stephan A. Grupp², Stephan A. Grupp⁴, Crystal L. Mackall - Show less +5 more•Institutions (4)

Seattle Children's¹, University of Pennsylvania², Center for Cell and Gene Therapy³, Children's Hospital of Philadelphia⁴

10 Jul 2014-Blood

TL;DR: A novel system to grade the severity of CRS in individual patients and a treatment algorithm for management of C RS based on severity is presented, to maximize the chance for therapeutic benefit from the immunotherapy while minimizing the risk for life threatening complications of the syndrome.

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2,025 citations

"Clinical development of CAR T cells..." refers background in this paper

...The hallmark of CRS is immune activation resulting in elevated inflammatory cytokines especially IL-6 (Lee et al, 2014)....
[...]
...A currently preferred alternative is treatment with tocilizumab, a therapeutic IL-6 receptor blocking antibody, which does not affect CAR T cell persistence (Davila et al, 2014; Maude et al, 2014)....
[...]