Skip to main content
Erschienen in: memo - Magazine of European Medical Oncology 2/2018

Open Access 06.06.2018 | short review

Chimeric antigen receptor T‑cell therapy—a hematological success story

verfasst von: Philipp Wohlfarth, MD, Nina Worel, Georg Hopfinger

Erschienen in: memo - Magazine of European Medical Oncology | Ausgabe 2/2018

download
DOWNLOAD
print
DRUCKEN
insite
SUCHEN

Summary

Chimeric antigen receptor (CAR) T cells are genetically engineered autologous cells that express an activating receptor targeted towards one or more tumoral antigens. After ex vivo production and re-infusion, they are able to proliferate in the host and to recognize and kill tumor cells. Together with checkpoint inhibition, this new therapy is already being celebrated as a major medical breakthrough in recent years, due to the substantial benefit observed in clinical trials with patients with chemotherapy-refractory B‑cell malignancies. These results have led to the recent approval of two CAR T‑cell products by the Food and Drug Administration (FDA) in the United States. The list of targetable antigens and possible indications is continuously being expanded, as are the modifications to the CAR structure and the final cell products currently under investigation. In some patients, CAR T‑cell therapy may lead to substantial toxicity including the cytokine release syndrome (CRS). In summary, CAR T‑cell therapy has already provided clinical benefit to patients with B‑cell malignancies unresponsive to conventional treatment. Yet, the therapy is still in an early stage of development, and the many opportunities for improvement in its various aspects as well as its future role in relation to conventional therapy will set the pace in the field of hematology for the next years or even decades.
Abkürzungen
ALL
Acute lymphoblastic leukemia
CAR
Chimeric antigen receptor
CD19
Cluster of differentiation 19
CLL
Chronic lymphocytic leukemia
CR
Complete remission
CRS
Cytokine release syndrome
DLBCL
Diffuse large B‑cell lymphoma
EMA
European Medicines Agency
FDA
Food and Drug Administration
MHC
Major histocompatibility complex
NHL
Non-Hodgkin lymphoma
PBMCs
Peripheral blood mononuclear cells
scFv
Single-chain variable antibody fragment
TCR
T-cell receptor

Introduction

Advances in cancer immunotherapy, the effort to harness the immune system to battle tumors, are considered a major medical breakthrough of the recent years. Recently, we witnessed the first approvals of a ground-breaking new form of cell-based immunotherapy, chimeric antigen receptor (CAR) T cells, by the Food and Drug Administration (FDA) in the United States. In Europe, CAR T‑cell products from several pharmaceutical companies have been filed and granted access to the European Medicines Agency (EMA) Priority Medicine (PRIME) scheme to facilitate their approval based on promising results from phase I/II trials. In this article, we give an overview about the principles of CAR T‑cell therapy, review the currently available clinical data, and provide a short overview of future perspectives.

CAR T‑cell therapy—principles and specifications

T cells can be genetically engineered ex vivo to express a chimeric antigen receptor (CAR) in addition to their natural T‑cell receptor (TCR). When one or more tumor-specific antigens are targeted, T cells harboring the CAR are able to proliferate and kill tumor cells upon antigen recognition. In contrast to the natural T‑cell response, this process is not major histocompatibility complex (MHC) restricted but only dependent on the presence of the targeted surface antigen, thus, eliminating MHC downregulation as a major mechanism of cancer immune evasion [1].
CARs are fusion proteins that are composed of an extracellular binding domain, a hinge region, a transmembrane domain, and one or more intracellular signaling domains (Fig. 1; [2]). The antigen-recognition moiety is commonly a single-chain variable fragment (scFv) derived from a tumor-antigen reactive monoclonal antibody. Targeting of B‑cell antigen CD19 to treat acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) has so far produced the most considerable clinical success rates [3], but a variety of other antigens are currently under consideration for targeting of malignant hematologic diseases (Table 1).
Table 1
List of selected target antigens with available trial results or currently under investigation
Antigen
Disease
Trial/Product and clinical results
CD19
B-cell malignancies
KTE-C19/Axicabtagene ciloleucel (NHL) a : 82% ORR, 54% CR, 42% with ongoing response after median follow-up of 15.4 months (ZUMA-1, n = 111) [7]
CTL-019/Tisagenlecleucel (ALL <21y) b : 81% CR, all MRD negative, RFS 80% and 59% at 6 and 12 months, respectively (ELIANA, n = 75) [11]
CTL-019/Tisagenlecleucel (DLBCL) b : 53% ORR, 40% CR, RFS 74% at 6 months (JULIET, n = 99) [14]
Park et al. (ALL ≥18y): 83% CR, median EFS 6 months (n = 53) [25]
JCAR017 (NHL): 75% ORR, 56% CR, 37% with CR at 6 months (results only reported for DLBCL cohort, n = 69) [15]
CD30
Hodgkin lymphoma, T‑cell lymphoma
Wang et al. (HL, ALCL): 0/18 CR, 7/18 PR, 1/18 SD, 10/18 NR [26]
Ramos et al. (HL, ALCL): 3/9 CR, 3/9 SD, 3/9 NR [27]
CD22
B-cell malignancies
Fry et al. (ALL): 73% CR; CR also in 5/5 pts. with CD19 or CD19dim B‑ALL (n = 21) [28]
CD20
B-cell malignancies
Zhang et al. (NHL): 82% ORR, 55% CR (n = 11) [29]
BCMA
Multiple myeloma
Bb2121 (MM): 89% ORR; 100% ORR in pts. with >150 × 10^6 CAR T cells, 3/15 sCR, 1/15 CR, 7/15 VGPR, 4/15 PR [30]
Either the designated CAR T‑cell product reference (italic) or, if not applicable, the name of the first-author of the respective publication is shown
ALCL anaplastic large cell lymphoma, BCMA B-cell maturation antigen, CR complete remission, DLBCL diffuse large B‑cell lymphoma, EFS event-free survival, HL Hodgkin lymphoma, MRD minimal residual disease, NHL non-Hodgkin lymphoma, NR no response, ORR overall response rate, PR partial remission, RFS relapse-free survival, SD stable disease, sCR stringent complete remission, VGPR very good partial remission
aMarketed as “Yescarta” in the United States
bMarketed as “Kymriah” in the United States
CAR T cells are infused intravenously either at a single dose or as split doses in multiple injections. Importantly, CAR T‑cell infusion should be preceded by a lymphocyte-depleting conditioning regimen (e. g., fludarabine in combination with cyclophosphamide), as this was shown to enhance their efficacy by elevating cytokine levels and possibly by reducing the number of inhibitory regulatory T cells (Tregs) in the host [4, 5]. Following infusion and in vivo expansion, CAR T cells have been shown to be able to persist and remain functionally active for several years in some patients [6].
Autologous unselected peripheral blood mononuclear cells (PBMCs) are most commonly used as the starting material for CAR T‑cell generation. T cells are isolated from the apheresis product and usually transfected with the CAR construct by using replication incompetent gamma-retroviruses or lentiviruses. In the final steps, the CAR T cells are expanded and the product is formulated. As CAR T‑cell generation is a delicate process, it is so far only possible in a handful of GMP-certified facilities worldwide. Still, a recently published landmark trial (ZUMA-1) involving 22 centers demonstrated the feasibility of CAR T‑cell generation as a centralized process with a 99% production success rate and a median time from apheresis to delivery of the product to the administration facility of only 17 days [7]. Currently, several pharmaceutical companies pursue CAR-cell therapies (Table 1).
CAR T‑cell therapy may come with significant side effects, some of which can be fatal. Most prominently, a “cytokine release syndrome” (CRS), characterized by fever, tachycardia and hypotension and associated with excessive cytokine release by the CAR T cells in response to tumor recognition has been described already in the first CAR T‑cell trials [8]. Some mild form of CRS can be observed almost universally (up to 90% of patients), but around 15–40% of the patients will experience grade 3/4 CRS and thus require vasopressors and/or respiratory support. While mild cases of CRS may be managed with supportive care, tocilizumab (interleukin-6 antibody) is the drug of choice for the treatment of severe CRS followed by corticosteroids. However, the latter have been shown to lead to CAR T‑cell ablation at least in some patients and are thus considered only second-line therapy [9].
Neurological toxicities such as confusion, tremors, ataxia, and aphasia are another frequently observed complication with reported 30–40% incidence rates, and may occur alone or as part of the CRS. The complications are usually self-limited, but cases of fatal cerebral edemas have also been described. Their pathophysiology is so far not understood. Other toxicities of CAR T‑cell therapy may include “on target, off tumor recognition”, for example, leading to B‑cell aplasia and hypogammaglobulinemia with CD19 CAR T cells, and cytopenia due to the conditioning regimen [10].

Clinical data

The breakthrough of CAR T cells is closely linked to the use of the B‑lymphocyte differentiation antigen CD19 as a target in B‑cell malignancies. A pooled analysis from CD19 CAR T‑cell trails including 243 patients reported by the end of the year 2016 estimated a 60% response rate with only around 20% of documented non-responders in a relapsed and/or refractory (r/r) or heavy pretreatment setting. Overall, these data suggest that CD19 CAR T cells might be most effective in patients with ALL, less so for B‑NHL and the least for chronic lymphocytic leukemia (CLL) [2]. Consecutive results from multinational phase II studies led to the recent approval of CAR T‑cell products to treat r/r ALL in children and young adults (ELIANA study) [11] and r/r aggressive B‑NHL (ZUMA-1 study) [7] by the FDA.
The ELIANA study is a single-arm multicenter global phase II study investigating the single-infusion of the CTL019 CAR T‑cell product in r/r ALL patients up to 21 years of age. In February 2018, interim data for 92 enrolled patients were published [11]. At that time, 75 out of 92 included patients had been infused with CTL019. Patients in the trial had received a median of three prior lines of therapy and 61% had already received an HSCT. Despite this heavy pretreatment, 81% of the patients attained at least a complete remission (CR) with incomplete blood recovery after a single infusion. Additionally, all of these responding patients had minimal residual-disease negative marrow after treatment. The estimated relapse-free probability at 12 months in responders was 80%. Eight out of the 61 responders (13%) proceeded to allogeneic hematopoietic stem cell transplantation within 6 months while in remission. Grade 3/4 CRS occurred in 46% of the patients, and one associated death was reported.
The ZUMA-1 study is a phase I/II multicenter study enrolling patients with r/r large B‑cell lymphoma (diffuse large B‑cell lymphoma, primary mediastinal B‑cell lymphoma, or transformed follicular lymphoma). Results for 111 patients treated with KTE-C19 CAR T cells as part of the study were recently reported in the New England Journal of Medicine [7]. There was an 82% objective response rate that was consistent across all lymphoma subtypes, with 54% of patients achieving a CR. At a median follow-up of 15 months, 42% had a durable response and 40% continued to have a CR. This resulted in a 52% survival rate at 18 months (median overall survival: not reached), which compares favorably to the expected median overall survival of 6 months in patients with refractory DLBCL (70% of the included patients) [12]. Grade 3/4 CRS occurred in 13% of the patients, and two associated deaths were reported. Mature data in B‑NHL are also available for other CAR T‑cell products (Table 1). As an example, Schuster et al. reported an overall response rate of 64% in a case series of 28 patients with r/r B‑NHL treated with CTL-019 and confirmed the durability of remissions in >80% of the patients after a median follow-up of 29 months [13]. Interim results for 99 patients included in the global extension study (JULIET trial) and infused with CTL-019 for treatment of r/r DLBCL were also recently reported in abstract form at the American Society of Hematology (ASH) Congress (53% overall response rate; 30% CR and 7% PR rate at 6 months, respectively) [14]. Importantly, responses were consistent over all subgroups including double-hit lymphoma. Data for the JCAR017 product from patients participating in the TRANSCEND NHL 001 trial [15] were also presented at the same congress and showed similar results as ZUMA-1 and JULIET.

Perspective

Although already considered a major hematological success, CAR T‑cell therapies are still at an early stage of development and their various facets offer great opportunities for improvements. As examples, modifications in CAR design allow for the creation of armored CAR T cells (Fig. 1) and products with an incorporated suicide gene that would allow their ablation upon stimulation with a pharmacologic agent in cases of life-threatening toxicity. In general, the possible composition and modifications of CAR domains already now give rise to an unlimited number of possible CAR T‑cell products with specific profiles regarding immunogenicity, expansive capabilities, cytokine secretion, cytotoxicity as well as in-host persistence [16]. Hence, it will be a long way to define the ideal CAR construct for each entity and patient. Not all patients respond to CAR T‑cell therapy and relapses rates are significant also with this approach. The latter have in some cases been linked to loss of tumor antigen [17] or immune escape via the PD1-PD-L1 axis [18]. Efforts to overcome primary or secondary resistance thus include multi or tandem CAR T cells targeting two different tumor antigens (e. g., CD19 and CD22) [19], or the use of checkpoint inhibitors [20] or interleukin-15 [21] to reactivate exhausted CAR T cells. Furthermore, several pharmaceutical agents such as ibrutinib have shown to enhance CAR T‑cell efficacy in preclinical models and their supplemental use is currently being investigated [22]. Other possible modifications include the type and intensity of the conditioning regimen, the formulation of the CAR T‑cell product (e. g., selection of T‑cell subsets), the administered cell dose, or their use in earlier disease stages [16]. Finally, advances in genome editing (e. g., CRISPR/Cas9 or TALEN) may allow for the creation of off-the-shelf universal allogeneic CAR T cells with disrupted endogenous TCR expression, thus, diminishing the risk for graft-versus-host reactions [23, 24].

Conclusion

Adoptive CAR T‑cell therapy is a promising new approach to treat chemotherapy-refractory hematologic cancers and has already proven capability to induce durable complete remissions in patients with ALL and B‑NHL. As the list of targeted antigens and thereby the possible indications will be extended, continuous modifications in the production and composition of CAR T‑cell products as well as pre- and post-administration treatments will set the pace to keep researchers and clinicians involved in the future. Ultimately, as many patients as possible have to benefit from CAR T cell therapy. For this, the alleviation of possible toxicities as well as treatment accessibility in the light of its (current) logistic and economic burdens have to be addressed.

Conflict of interest

P. Wohlfarth, N. Worel, and G. Hopfinger declare that they have no competing interests.
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://​creativecommons.​org/​licenses/​by/​4.​0/​), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Unsere Produktempfehlungen

Neuer Inhalt

e.Med Interdisziplinär

Kombi-Abonnement

Für Ihren Erfolg in Klinik und Praxis - Die beste Hilfe in Ihrem Arbeitsalltag

Mit e.Med Interdisziplinär erhalten Sie Zugang zu allen CME-Fortbildungen und Fachzeitschriften auf SpringerMedizin.de.

© Springer Medizin

Bis 11. April 2024 bestellen und im ersten Jahr 50 % sparen!

Literatur
1.
2.
Zurück zum Zitat Hartmann J, Schussler-Lenz M, Bondanza A, Buchholz CJ. Clinical development of CAR T cells-challenges and opportunities in translating innovative treatment concepts. EMBO Mol Med. 2017;9(9):1183–97.CrossRefPubMedPubMedCentral Hartmann J, Schussler-Lenz M, Bondanza A, Buchholz CJ. Clinical development of CAR T cells-challenges and opportunities in translating innovative treatment concepts. EMBO Mol Med. 2017;9(9):1183–97.CrossRefPubMedPubMedCentral
3.
Zurück zum Zitat Brudno JN, Kochenderfer JN. Chimeric antigen receptor T‑cell therapies for lymphoma. Nat Rev Clin Oncol. 2018;15(1):31–46.CrossRefPubMed Brudno JN, Kochenderfer JN. Chimeric antigen receptor T‑cell therapies for lymphoma. Nat Rev Clin Oncol. 2018;15(1):31–46.CrossRefPubMed
4.
Zurück zum Zitat Gattinoni L, Finkelstein SE, Klebanoff CA, Antony PA, Palmer DC, Spiess PJ, Hwang LN, Yu Z, Wrzesinski C, Heimann DM, et al. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J Exp Med. 2005;202(7):907–12.CrossRefPubMedPubMedCentral Gattinoni L, Finkelstein SE, Klebanoff CA, Antony PA, Palmer DC, Spiess PJ, Hwang LN, Yu Z, Wrzesinski C, Heimann DM, et al. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J Exp Med. 2005;202(7):907–12.CrossRefPubMedPubMedCentral
5.
Zurück zum Zitat Kochenderfer JN, Yu Z, Frasheri D, Restifo NP, Rosenberg SA. Adoptive transfer of syngeneic T cells transduced with a chimeric antigen receptor that recognizes murine CD19 can eradicate lymphoma and normal B cells. Blood. 2010;116(19):3875–86.CrossRefPubMedPubMedCentral Kochenderfer JN, Yu Z, Frasheri D, Restifo NP, Rosenberg SA. Adoptive transfer of syngeneic T cells transduced with a chimeric antigen receptor that recognizes murine CD19 can eradicate lymphoma and normal B cells. Blood. 2010;116(19):3875–86.CrossRefPubMedPubMedCentral
6.
Zurück zum Zitat Porter DL, Hwang WT, Frey NV, Lacey SF, Shaw PA, Loren AW, Bagg A, Marcucci KT, Shen A, Gonzalez V, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015;7(303):303ra139.CrossRefPubMedPubMedCentral Porter DL, Hwang WT, Frey NV, Lacey SF, Shaw PA, Loren AW, Bagg A, Marcucci KT, Shen A, Gonzalez V, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015;7(303):303ra139.CrossRefPubMedPubMedCentral
7.
Zurück zum Zitat Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, Braunschweig I, Oluwole OO, Siddiqi T, Lin Y, et al. Axicabtagene ciloleucel CAR T‑cell therapy in refractory large B‑cell lymphoma. N Engl J Med. 2017;377(26):2531–44.CrossRefPubMedPubMedCentral Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, Braunschweig I, Oluwole OO, Siddiqi T, Lin Y, et al. Axicabtagene ciloleucel CAR T‑cell therapy in refractory large B‑cell lymphoma. N Engl J Med. 2017;377(26):2531–44.CrossRefPubMedPubMedCentral
8.
Zurück zum Zitat Kochenderfer JN, Dudley ME, Feldman SA, Wilson WH, Spaner DE, Maric I, Stetler-Stevenson M, Phan GQ, Hughes MS, Sherry RM, et al. B‑cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood. 2012;119(12):2709–20.CrossRefPubMedPubMedCentral Kochenderfer JN, Dudley ME, Feldman SA, Wilson WH, Spaner DE, Maric I, Stetler-Stevenson M, Phan GQ, Hughes MS, Sherry RM, et al. B‑cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood. 2012;119(12):2709–20.CrossRefPubMedPubMedCentral
9.
Zurück zum Zitat Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, Grupp SA, Mackall CL. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188–95.CrossRefPubMedPubMedCentral Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, Grupp SA, Mackall CL. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188–95.CrossRefPubMedPubMedCentral
10.
11.
Zurück zum Zitat Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Verneris MR, Stefanski HE, Myers GD, et al. Tisagenlecleucel in children and young adults with B‑cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439–48.CrossRefPubMed Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Verneris MR, Stefanski HE, Myers GD, et al. Tisagenlecleucel in children and young adults with B‑cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439–48.CrossRefPubMed
12.
Zurück zum Zitat Crump M, Neelapu SS, Farooq U, Van Den Neste E, Kuruvilla J, Westin J, Link BK, Hay A, Cerhan JR, Zhu L, et al. Outcomes in refractory diffuse large B‑cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017;130(16):1800–8.CrossRefPubMedPubMedCentral Crump M, Neelapu SS, Farooq U, Van Den Neste E, Kuruvilla J, Westin J, Link BK, Hay A, Cerhan JR, Zhu L, et al. Outcomes in refractory diffuse large B‑cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017;130(16):1800–8.CrossRefPubMedPubMedCentral
13.
Zurück zum Zitat Schuster SJ, Svoboda J, Chong EA, Nasta SD, Mato AR, Anak O, Brogdon JL, Pruteanu-Malinici I, Bhoj V, Landsburg D, et al. Chimeric antigen receptor T cells in refractory B‑cell lymphomas. N Engl J Med. 2017;377(26):2545–54.CrossRefPubMedPubMedCentral Schuster SJ, Svoboda J, Chong EA, Nasta SD, Mato AR, Anak O, Brogdon JL, Pruteanu-Malinici I, Bhoj V, Landsburg D, et al. Chimeric antigen receptor T cells in refractory B‑cell lymphomas. N Engl J Med. 2017;377(26):2545–54.CrossRefPubMedPubMedCentral
14.
Zurück zum Zitat Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, Jaeger U, Jaglowski S, Andreadis C, Westin JR, et al. Primary analysis of Juliet: a global, pivotal, phase 2 trial of CTL019 in adult patients with relapsed or refractory diffuse large B‑cell lymphoma. Blood. 2017;130(Suppl 1):577–577. Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, Jaeger U, Jaglowski S, Andreadis C, Westin JR, et al. Primary analysis of Juliet: a global, pivotal, phase 2 trial of CTL019 in adult patients with relapsed or refractory diffuse large B‑cell lymphoma. Blood. 2017;130(Suppl 1):577–577.
15.
Zurück zum Zitat Abramson JS, Palomba ML, Gordon LI, Lunning MA, Arnason JE, Wang M, Forero A, Maloney DG, Albertson T, Garcia J, et al. High durable CR rates in relapsed/refractory (R/R) aggressive B‑NHL treated with the CD19-directed CAR T cell product JCAR017 (TRANSCEND NHL 001): defined composition allows for dose-finding and definition of pivotal cohort. Blood. 2017;130(Suppl 1):581–581. Abramson JS, Palomba ML, Gordon LI, Lunning MA, Arnason JE, Wang M, Forero A, Maloney DG, Albertson T, Garcia J, et al. High durable CR rates in relapsed/refractory (R/R) aggressive B‑NHL treated with the CD19-directed CAR T cell product JCAR017 (TRANSCEND NHL 001): defined composition allows for dose-finding and definition of pivotal cohort. Blood. 2017;130(Suppl 1):581–581.
16.
17.
Zurück zum Zitat Kenderian SS, Porter DL, Gill S. Chimeric antigen receptor T cells and hematopoietic cell transplantation: how not to put the CART before the horse. Biol Blood Marrow Transplant. 2017;23(2):235–46.CrossRefPubMed Kenderian SS, Porter DL, Gill S. Chimeric antigen receptor T cells and hematopoietic cell transplantation: how not to put the CART before the horse. Biol Blood Marrow Transplant. 2017;23(2):235–46.CrossRefPubMed
18.
Zurück zum Zitat Cherkassky L, Morello A, Villena-Vargas J, Feng Y, Dimitrov DS, Jones DR, Sadelain M, Adusumilli PS. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J Clin Invest. 2016;126(8):3130–44.CrossRefPubMedPubMedCentral Cherkassky L, Morello A, Villena-Vargas J, Feng Y, Dimitrov DS, Jones DR, Sadelain M, Adusumilli PS. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J Clin Invest. 2016;126(8):3130–44.CrossRefPubMedPubMedCentral
19.
Zurück zum Zitat Schneider D, Xiong Y, Wu D, Nlle V, Schmitz S, Haso W, Kaiser A, Dropulic B, Orentas RJ. A tandem CD19/CD20 CAR lentiviral vector drives on-target and off-target antigen modulation in leukemia cell lines. J Immunother Cancer. 2017;5:42.CrossRefPubMedPubMedCentral Schneider D, Xiong Y, Wu D, Nlle V, Schmitz S, Haso W, Kaiser A, Dropulic B, Orentas RJ. A tandem CD19/CD20 CAR lentiviral vector drives on-target and off-target antigen modulation in leukemia cell lines. J Immunother Cancer. 2017;5:42.CrossRefPubMedPubMedCentral
20.
Zurück zum Zitat Chong EA, Melenhorst JJ, Lacey SF, Ambrose DE, Gonzalez V, Levine BL, June CH, Schuster SJ. PD-1 blockade modulates chimeric antigen receptor (CAR)-modified T cells: refueling the CAR. Blood. 2017;129(8):1039–41.CrossRefPubMedPubMedCentral Chong EA, Melenhorst JJ, Lacey SF, Ambrose DE, Gonzalez V, Levine BL, June CH, Schuster SJ. PD-1 blockade modulates chimeric antigen receptor (CAR)-modified T cells: refueling the CAR. Blood. 2017;129(8):1039–41.CrossRefPubMedPubMedCentral
21.
Zurück zum Zitat Kochenderfer JN, Somerville RPT, Lu T, Shi V, Bot A, Rossi J, Xue A, Goff SL, Yang JC, Sherry RM, et al. Lymphoma remissions caused by anti-CD19 chimeric antigen receptor T cells are associated with high serum interleukin-15 levels. J Clin Oncol. 2017;35(16):1803–13.CrossRefPubMedPubMedCentral Kochenderfer JN, Somerville RPT, Lu T, Shi V, Bot A, Rossi J, Xue A, Goff SL, Yang JC, Sherry RM, et al. Lymphoma remissions caused by anti-CD19 chimeric antigen receptor T cells are associated with high serum interleukin-15 levels. J Clin Oncol. 2017;35(16):1803–13.CrossRefPubMedPubMedCentral
22.
Zurück zum Zitat Ruella M, Kenderian SS, Shestova O, Fraietta JA, Qayyum S, Zhang Q, Maus MV, Liu X, Nunez-Cruz S, Klichinsky M, et al. The addition of the BTK inhibitor Ibrutinib to anti-CD19 chimeric antigen receptor T cells (CART19) improves responses against mantle cell Lymphoma. Clin Cancer Res. 2016;22(11):2684–96.CrossRefPubMed Ruella M, Kenderian SS, Shestova O, Fraietta JA, Qayyum S, Zhang Q, Maus MV, Liu X, Nunez-Cruz S, Klichinsky M, et al. The addition of the BTK inhibitor Ibrutinib to anti-CD19 chimeric antigen receptor T cells (CART19) improves responses against mantle cell Lymphoma. Clin Cancer Res. 2016;22(11):2684–96.CrossRefPubMed
23.
Zurück zum Zitat Eyquem J, Mansilla-Soto J, Giavridis T, van der Stegen SJ, Hamieh M, Cunanan KM, Odak A, Gonen M, Sadelain M. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature. 2017;543(7643):113–7.CrossRefPubMedPubMedCentral Eyquem J, Mansilla-Soto J, Giavridis T, van der Stegen SJ, Hamieh M, Cunanan KM, Odak A, Gonen M, Sadelain M. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature. 2017;543(7643):113–7.CrossRefPubMedPubMedCentral
24.
Zurück zum Zitat Osborn MJ, Webber BR, Knipping F, Lonetree CL, Tennis N, DeFeo AP, McElroy AN, Starker CG, Lee C, Merkel S, et al. Evaluation of TCR gene editing achieved by TALENs, CRISPR/Cas9, and megaTAL nucleases. Mol Ther. 2016;24(3):570–81.CrossRefPubMedPubMedCentral Osborn MJ, Webber BR, Knipping F, Lonetree CL, Tennis N, DeFeo AP, McElroy AN, Starker CG, Lee C, Merkel S, et al. Evaluation of TCR gene editing achieved by TALENs, CRISPR/Cas9, and megaTAL nucleases. Mol Ther. 2016;24(3):570–81.CrossRefPubMedPubMedCentral
25.
Zurück zum Zitat Park JH, Riviere I, Gonen M, Wang X, Senechal B, Curran KJ, Sauter C, Wang Y, Santomasso B, Mead E, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 2018;378(5):449–59.CrossRefPubMed Park JH, Riviere I, Gonen M, Wang X, Senechal B, Curran KJ, Sauter C, Wang Y, Santomasso B, Mead E, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 2018;378(5):449–59.CrossRefPubMed
26.
Zurück zum Zitat Wang CM, Wu ZQ, Wang Y, Guo YL, Dai HR, Wang XH, Li X, Zhang YJ, Zhang WY, Chen MX, et al. Autologous T cells expressing CD30 chimeric antigen receptors for relapsed or refractory hodgkin lymphoma: an open-label phase I trial. Clin Cancer Res. 2017;23(5):1156–66.CrossRefPubMed Wang CM, Wu ZQ, Wang Y, Guo YL, Dai HR, Wang XH, Li X, Zhang YJ, Zhang WY, Chen MX, et al. Autologous T cells expressing CD30 chimeric antigen receptors for relapsed or refractory hodgkin lymphoma: an open-label phase I trial. Clin Cancer Res. 2017;23(5):1156–66.CrossRefPubMed
27.
Zurück zum Zitat Ramos CA, Ballard B, Zhang H, Dakhova O, Gee AP, Mei Z, Bilgi M, Wu MF, Liu H, Grilley B, et al. Clinical and immunological responses after CD30-specific chimeric antigen receptor-redirected lymphocytes. J Clin Invest. 2017;127(9):3462–71.CrossRefPubMedPubMedCentral Ramos CA, Ballard B, Zhang H, Dakhova O, Gee AP, Mei Z, Bilgi M, Wu MF, Liu H, Grilley B, et al. Clinical and immunological responses after CD30-specific chimeric antigen receptor-redirected lymphocytes. J Clin Invest. 2017;127(9):3462–71.CrossRefPubMedPubMedCentral
28.
Zurück zum Zitat Fry TJ, Shah NN, Orentas RJ, Stetler-Stevenson M, Yuan CM, Ramakrishna S, Wolters P, Martin S, Delbrook C, Yates B, et al. CD22-targeted CAR T cells induce remission in B‑ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat Med. 2018;24(1):20–8.CrossRefPubMed Fry TJ, Shah NN, Orentas RJ, Stetler-Stevenson M, Yuan CM, Ramakrishna S, Wolters P, Martin S, Delbrook C, Yates B, et al. CD22-targeted CAR T cells induce remission in B‑ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat Med. 2018;24(1):20–8.CrossRefPubMed
29.
Zurück zum Zitat Zhang WY, Wang Y, Guo YL, Dai HR, Yang QM, Zhang YJ, Zhang Y, Chen MX, Wang CM, Feng KC, et al. Treatment of CD20-directed chimeric antigen receptor-modified T cells in patients with relapsed or refractory B‑cell non-hodgkin lymphoma: an early phase IIa trial report. Signal Transduct Target Ther. 2016;1:16002.CrossRefPubMedPubMedCentral Zhang WY, Wang Y, Guo YL, Dai HR, Yang QM, Zhang YJ, Zhang Y, Chen MX, Wang CM, Feng KC, et al. Treatment of CD20-directed chimeric antigen receptor-modified T cells in patients with relapsed or refractory B‑cell non-hodgkin lymphoma: an early phase IIa trial report. Signal Transduct Target Ther. 2016;1:16002.CrossRefPubMedPubMedCentral
30.
Zurück zum Zitat Berdeja JG, Lin Y, Raje N, Munshi N, Siegel D, Liedtke M, Jagannath S, Maus MV, Turka A, Lam LP, et al. Durable clinical responses in heavily pretreated patients with relapsed/refractory multiple myeloma: updated results from a multicenter study of bb2121 anti-Bcma CAR T cell therapy. Blood. 2017;130(Suppl 1):740–740. Berdeja JG, Lin Y, Raje N, Munshi N, Siegel D, Liedtke M, Jagannath S, Maus MV, Turka A, Lam LP, et al. Durable clinical responses in heavily pretreated patients with relapsed/refractory multiple myeloma: updated results from a multicenter study of bb2121 anti-Bcma CAR T cell therapy. Blood. 2017;130(Suppl 1):740–740.
Metadaten
Titel
Chimeric antigen receptor T‑cell therapy—a hematological success story
verfasst von
Philipp Wohlfarth, MD
Nina Worel
Georg Hopfinger
Publikationsdatum
06.06.2018
Verlag
Springer Vienna
Erschienen in
memo - Magazine of European Medical Oncology / Ausgabe 2/2018
Print ISSN: 1865-5041
Elektronische ISSN: 1865-5076
DOI
https://doi.org/10.1007/s12254-018-0409-x

Weitere Artikel der Ausgabe 2/2018

memo - Magazine of European Medical Oncology 2/2018 Zur Ausgabe

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.