July 2015, Vol. 2, No. 4
CAR T-Cell Therapy for B-Cell Acute Lymphoblastic Leukemia: A Review of the Phase 1 Clinical TrialsUncategorized
Outcomes in adult acute lymphoblastic leukemia (ALL) remain poor, with long-term disease-free survival rates of 30% to 40%.1 Salvage chemotherapy regimens demonstrate limited success in inducing and maintaining a second remission, and consequently overall survival (OS) at 5 years after relapse is as low as 7%.2 Patients who achieve a complete response (CR) with salvage therapy may be eligible for hematopoietic stem cell transplantation (HSCT); however, cure rates remain low at 10% to 30%.3-5 Given this poor prognosis, novel agents with alternative mechanisms of action are essential for improving outcomes in relapsed/refractory disease. The recent development of immunotherapies targeting antigens on the lymphoblast cell surface is a promising new direction in the treatment of ALL.6,7
The focus of this review will be chimeric antigen receptor (CAR) T cells, which are genetically modified T cells that express antigen-binding moieties and T-cell activation domains.7,8 Herein we will briefly review the development, structure, and function of CAR T cells and examine the data from early clinical trials implementing this novel therapy in the treatment of B-cell ALL.
Development, Structure, and Function
The initial work demonstrating the potential efficacy of CAR T cells in cancer was conducted in 1993 by Hwu and colleagues.9 They designed a CAR containing an antigen recognition domain derived from a monoclonal antibody and a T-cell signaling domain.9 CD8+ tumor-infiltrating lymphocytes were retrovirally transformed to express a CAR directed against an ovarian cancer cell surface antigen, which resulted in ovarian cancer cell lysis in vitro.9 Subsequent research has explored and refined CAR design, particularly in B-cell proliferative neoplasms.10-22
The basic structure of modern CARs includes an extracellular antigen-binding domain, an intracellular T-cell signaling domain, and an intracellular T-cell costimulatory domain.7,8,23,24 The CAR structure is modular in nature and allows for different elements to be tested, such as various tumor-directed antigen-binding domains and costimulatory T-cell domains.23,25 The antigen recognition moiety is most often a single-chain variable fragment derived from an antibody, such as a murine immunoglobulin, or a fragment antigen-binding derived from human libraries.23 CD19 was an early and popular target in the treatment of hematopoietic malignancies because of its high level of expression on the cell surface in most B-cell malignancies and lack of expression on other tissues, leading to fewer off-target side effects.7,12,22
The CAR cytoplasmic T-cell signaling domain is most often the CD3-? chain, which is a key component of the T-cell receptor CD3 complex that recognizes antigens and subsequently activates the T cell. Specifically, CD3-? has a key role in coupling antigen recognition to intracellular signaling pathways.23,26 First-generation CARs, similar to that designed by Hwu and colleagues, were primarily composed of the antigen recognition moiety and CD3-? as the 2 functional domains.7,8,14,23,27 However, early studies showed that while these first-generation CARs could activate T cells and kill targeted malignant cells, the CAR-expressing T cells were prone to undergoing anergy, and their populations declined quickly.8,23,28-30
Second- and third-generation CARs incorporate 1 or 2 costimulatory domains in addition to the CD3-? T-cell signaling domain, respectively, and have shown improved T-cell signaling strength, cytokine production, persistence, and potency compared with first-generation CARs.21,25,28,29,31-38 The primary costimulatory domains that have been used either separately in second-generation CARs or in combination in third-generation CARs are CD28 and 4-1BB, also known as CD137.21,25,28,31-38
CAR T cells are generated by harvesting peripheral blood mononuclear cells from the patient via leukapheresis and then stimulating the T-cell fraction to proliferate with mitogens.7,39-42 The proliferating T cells are transduced with the CAR gene. Currently, transduction is accomplished mainly via viral gene transfer techniques, either with retroviral or lentiviral vectors.7,39-42 The CAR-expressing T-cell population is then expanded ex vivo with cytokines such as IL (interleukin)-2 to achieve clinically applicable numbers for subsequent adoptive transfer back to the patient.7,39-42 Of note, patients have been shown to have improved responses to CAR T-cell therapy when they are pretreated with lymphodepleting agents.43 This is likely due to a decrease in regulatory T cells and increased access to cytokines needed for in vivo CAR T-cell expansion.6,43-45
The first clinical studies of CD19-directed CAR T cells to treat B-cell malignancies were in patients with chronic lymphocytic leukemia (CLL) and B-cell lymphomas.37,46-51 These early studies in humans demonstrated the potential of this new therapy to induce remissions and deplete malignant and normal B cells. They also highlighted the need for pretreatment with lymphodepleting agents to allow CAR T-cell expansion, the importance of CAR T-cell persistence for ongoing antitumor activity, and the presence of several adverse events associated with the treatment.37,46-52
The primary adverse effects initially seen with CD19-directed CAR T-cell therapy have been cytokine release syndrome (CRS), B-cell aplasia, and neurotoxicities.7,8,23,53 CRS is characterized by fever and hypotension, which can progress to organ failure, and is mediated by the upregulation of cytokines with the activation of T cells.49,53 In particular, these initial studies showed elevated levels of interferon-gamma (IFN-?), tumor necrosis factor-alpha (TNF-?), IL-6, and IL-10 in patients treated with CAR T cells.49,53 B-cell aplasia is an “on-target, off-tumor effect due to CD19 expression on normal B cells.23,46,48,49,51 In some patients, the resulting hypogammaglobulinemia has been treated successfully with intravenous immunoglobulin (IVIG), and increased rates of infection have not been reported.51 Neurotoxicities have ranged from delirium to seizures and will be discussed in more detail below.51,53
CD19-Directed CAR T-Cell Therapy for ALL
Building on the initial success of CD19-directed CAR T-cell therapy in CLL, several groups of researchers have applied this novel treatment to patients with B-cell ALL (Table 1).
The investigators at Memorial Sloan Kettering Cancer Center (MSKCC) developed a second-generation CAR with a CD28 costimulatory domain.46,54,57,58 The phase 1 study enrolled patients with relapsed/refractory ALL. Patients received salvage chemotherapy during CAR T-cell production and then underwent lymphodepleting therapy with cyclophosphamide prior to CAR T-cell infusion.46 The first patient enrolled in first relapse and achieved a remission with minimal residual disease (MRD) with salvage chemotherapy prior to CAR T-cell infusion.46 The CAR T cells persisted 5 weeks after infusion, and the patient underwent allogeneic HSCT 8 weeks after infusion. B-cell aplasia was present until the time of transplantation.46 He experienced grade 3 hypotension but no other symptoms of CRS.46
In a subsequent report of 5 patients treated with this CAR T-cell construct, all achieved a CR with MRD negativity, and 4 of the 5 went on to allo-HSCT.57 The authors showed that in vivo CAR T-cell expansion correlated positively with tumor burden at the time of infusion.57 Similarly, they found a positive correlation between both the degree of cytokine elevations and symptoms of CRS after infusion and tumor burden.57 Because many of the patients underwent allo-HSCT, evaluation of CAR T-cell persistence was limited. All patients had recovery of normal B cells, suggesting a lack of T-cell persistence.57
The same group later reported that similar efficacy outcomes were observed among patients who achieved a CR prior to CAR T-cell infusion and those who had residual morphologic disease despite the correlation of tumor burden with T-cell expansion.58 Additional adverse event data were also reported, in particular neurologic toxicities associated with or independent of CRS, including mental status changes, obtundation, and seizures.58 The cerebrospinal fluid (CSF) from patients with these symptoms was negative for CAR T cells.58 Importantly, no participants who had previously undergone an HSCT experienced graft-versus-host disease (GVHD) symptoms after CAR T-cell infusion.58
In a brief update with a total of 24 adult patients prior to CAR T-cell treatment, 10 of the 22 patients evaluable for response remained MRD positive, and 12 had morphologic evidence of disease.54 Overall, 91% responded to CAR T cells, and 90% of these patients were MRD negative. Six patients remained in remission after 1 year. Three of 5 patients who relapsed received repeat CAR T-cell infusion, and 2 of these patients regained CR. Cell levels expanded and peaked at 1 to 2 weeks and were low or undetectable by 2 to 3 months. CRS occurred in 69% of patients with morphologic disease at the time of CAR T-cell infusion but in none of those with MRD.
Researchers from the University of Pennsylvania treated both adults and children with relapsed and refractory B-cell ALL with CAR T cells.59,60 A notable difference from the MSKCC group is that the CAR utilized a 4-1BB costimulatory domain (CTL019). The first 2 pediatric patients treated both achieved a CR with no MRD. They also experienced CRS symptoms as well as reversible neurologic toxicities associated with cytokine elevations.59 This was the first use of tocilizumab to successfully treat CRS. One patient relapsed with the emergence of a CD19-negative clone.
Additional data from a total of 25 children younger than 22 years and 5 adults aged 26 to 60 years have also been reported from these trials.60 Ninety percent (27) of these patients achieved a CR, with 22 of the 27 MRD negative. A subsequent brief update reported that 23 of 27 patients were MRD negative.55 The authors reported a 6-month event-free survival rate of 63% and an OS rate of 78%. CTL019 cells demonstrated a 68% probability of persistence at 6 months after infusion, which was associated with prolonged B-cell aplasia. All patients in the trial experienced symptoms of CRS, and 13 had neurotoxicities. These investigators also analyzed cytokine levels and found that patients with severe symptoms had higher levels of IL-6, IFN-?, and the soluble IL-2 receptor. Similar to the MSKCC trial, they also found that higher disease burden was significantly associated with severe CRS. No patients with prior allo-HSCT experienced GVHD. Three patients who relapsed after CAR T-cell infusion lost expression of CD19.60
Investigators from the National Cancer Institute (NCI) have also recently presented data from a group of 21 patients aged 1 to 30 years treated with CAR T cells.56 The study included 20 patients with relapsed or primary refractory B-cell ALL and 1 patient with non-Hodgkin lymphoma (NHL). The CAR construct contained the costimulatory domain CD28. Lymphodepleting chemotherapy consisting of fludarabine and cyclophosphamide was administered prior to CD19-CAR T-cell infusion. Seventy percent (14 of 20) of patients with B-cell ALL treated achieved a CR, with 12 patients achieving MRD negativity. Ten of these patients subsequently underwent HSCT. This CAR construct contained the CD28 costimulatory domain and only persisted approximately 1 month in most of the patients, similar to the MSKCC CAR. However, these results are limited by the fact that many patients underwent HSCT. Two patients in this study ultimately relapsed with CD19-negative disease. Seventy-six percent of patients experienced CRS, and these investigators again showed this correlated with disease burden and circulating CD19-CAR T cells. Notably, all patients who suffered neurotoxicities had CD19-CAR T cells present in the CSF. Further, the CSF concentration of CD19-CAR T cells was significantly higher in patients with neurotoxicities than in those without. The presence of CAR T cells in the CSF also raises the possibility that they may treat central nervous system (CNS) involvement by leukemia, but it remains unclear what structural difference leads to some CAR T cells crossing the blood-brain barrier and others not.
The Fred Hutchinson Cancer Research Center reported preliminary results from a phase 1/2 trial of a 4-1BB costimulatory domain–constructed CAR T-cell therapy for CD19+ ALL, CLL, and NHL.61,62 A unique feature of the trial is the defined subset composition of CAR T cells infused to the patient; each patient received a 1:1 ratio of CD4+ T cells and CD8+ central memory T cells. Fifteen of 18 evaluable patients with ALL achieved a CR, suggesting promise for this construct as well.62
A trial of fixed ratio CD4+:CD8+ CAR T cells was also performed in children with ALL relapsed after allo-HSCT at the Ben Towne Center for Childhood Cancer Research.63 A third-generation CAR construct with both CD28 and 4-1BB costimulatory domains was used. Five of 6 children treated achieved an MRD-negative CR. All responding patients experienced CRS. Four of the 5 responders had continued CAR T-cell persistence and B-cell aplasia at the time of the report. One patient experienced skin GVHD, although it is unclear if the CAR T cells mediated this adverse event as only 9% of the skin-localized T cells were CAR T cells. This is the first report of possible CAR T-cell–related GVHD, and this will need to be monitored for vigilantly in the upcoming phase 2 clinical trials as larger cohorts are treated.
Discussion of CAR T-Cell Clinical Trials
Overall, the results from the initial clinical trials of CAR T-cell therapy for ALL in adults and children have been very promising, with rates of CR ranging from 70% to 90% in published data.56,58,60 This is much improved compared with historical remission rates with salvage chemotherapy for relapsed patients, especially in adults.2,4 Additionally, most CRs in the CAR T-cell trials were negative for MRD, which is most likely an important factor for preventing subsequent relapse.2
The encouraging remission rates notwithstanding, many questions regarding CAR T-cell therapy have been raised by these initial clinical trials. As many centers are preparing to open phase 2 trials of CAR T cells on a national level, safety issues remain a major concern. Thus far, the published data indicate that most patients with ALL treated with CAR T-cell therapy experience symptoms of CRS.46,56-60 There have been 4 deaths due to severe CRS.61,64 One death reported by the Fred Hutchinson Cancer Research Center Group occurred in a patient who received a high dose of CAR T cells. Similarly, 3 deaths in the University of Pennsylvania trial occurred in patients who received a dose of CAR T cells that was at least twice the median dose received by patients with manageable CRS; additionally, these 3 patients had significant disease burden at the time of treatment and also had evidence of severe infections that likely contributed to mortality.64 The same group also reported progression to macrophage activation syndrome in some patients, with prolonged fever, splenomegaly, hyperferritinemia, and coagulopathy.53,59
It is clear that CRS is associated with increased levels of cytokines, including IL-6, IL-10, and IFN-?, that are produced because of supraphysiologic activation of T cells.53,65 Investigators have additionally shown that there is a correlation between larger tumor burden (including patients with morphologic disease at the time of treatment) and increased severity of the syndrome.53,56,60,65 The association between disease burden and severity of CRS raises the question of whether patients should be cytoreduced initially with a salvage chemotherapy regimen prior to CAR T-cell therapy to mitigate CRS severity. A concern with this approach is decreased T-cell expansion in vivo because of decreased antigen. However, patients on the MSKCC protocol were initially treated with salvage chemotherapy and had excellent responses to CAR T-cell therapy.58 Without a direct comparison of salvage chemotherapy versus only lymphodepletion prior to CAR T-cell infusion, it is impossible to determine if one approach is superior with regard to outcomes and severity of CRS.
Because of the frequency of CRS, diagnostic criteria and management algorithms have been proposed (Table 2). MSKCC investigators defined diagnostic criteria for severe CRS as fever for at least 3 consecutive days, 2 cytokines with a 75-fold increase or 1 cytokine with a 250-fold increase, and at least 1 sign of clinical toxicity (hypotension requiring at least 1 vasopressor, hypoxia, or neurologic toxicity).58 Patients with severe CRS need close observation and possibly anti-inflammatory drugs to control the symptoms, whereas those patients without severe CRS may only require supportive care.58 They also found that patients with severe CRS had C-reactive protein (CRP) levels greater than 20 mg/dL, which can be more readily assessed than cytokine levels.58 Lee and colleagues similarly advocate for the use of CRP to monitor for CRS; however, they suggest an alternative grading system for the severity of the syndrome modified from the NCI Common Terminology Criteria for Adverse Events for antibody therapies.65 Both groups have suggested treatment algorithms for severe CRS that include immunosuppressive therapy. Tocilizumab is recommended by both as first-line therapy and has quickly ameliorated the symptoms of CRS in several patients. It is a monoclonal antibody against the IL-6 receptor, which is upregulated in CRS. Additionally, inhibition of IL-6 signaling has not been shown to impede CAR T-cell expansion or persistence, whereas treatment with corticosteroids, which are known to be lymphotoxic, caused a 5-fold decrease in CAR T cells in one trial.58 Nevertheless, if patients with severe CRS do not respond to 1 or 2 doses of tocilizumab, both algorithms recommend the addition of corticosteroids.58,65
Neurotoxicities associated with, or independent of, CRS are another area of concern. Some patients have experienced delirium, aphasia, and seizures and have required intubation for airway protection.56,58,59,65 The cause of neurotoxicity in these patients is not clear. The NCI group found that CAR T cells crossed the blood-brain barrier, and that all patients who experienced neurotoxicities had CSF concentrations of CAR T cells that were significantly higher than in those who did not experience neurotoxicities.56 However, the MSKCC group did detect CAR T cells in the CSF.58 This may be due to differences in the respective CAR T-cell constructs, but it also suggests that there must be another mechanism of action. Elevated levels of IL-6 have been found in the CSF from patients with severe CRS and neurotoxcity, and IL-6 is known to play a role in other neurologic conditions.65 Tocilizumab does not cross the blood-brain barrier and is therefore not recommended for management of neurologic symptoms.65 No association has been shown between CNS involvement by ALL and CAR T-cell–associated neurotoxicities.55 Overall, the pathophysiology of neurotoxicity requires further study, which may optimize prophylactic measures or treatment for events.
There also remain several safety risks that we will need to look for in the phase 2 clinical trials. Because HSCT has failed in many patients with relapsed ALL, treatment with CAR T-cell therapy has raised the concern of development of GVHD because the T cells are donor derived. However, to date, GVHD has not been a major adverse effect, and only 1 case of skin GVHD has been reported.63 Other potential complications include uncontrolled T-cell activation and proliferation, replication of the competent retrovirus, and insertional mutagenesis or oncogenesis.
Challenges of CAR T-Cell Therapy and Future Directions
With limited follow-up data available, one of the challenges that CAR T cells face is how long they remain expanded in vivo. A difference in CAR T-cell persistence and subsequent prolonged B-cell aplasia has been observed with CARs that employ the 4-1BB costimulatory domain compared with those with the CD28 domain.56,58,60 This may be due to antigen-independent signaling that occurs with the 4-1BB domain; CAR T cells with CD28 are cleared when there is no CD19 antigen present.58 However, the study of persistence of CAR T cells with the CD28 domain has been limited by a large number of these patients undergoing subsequent HSCT.56,58 Additionally, there have been no direct comparisons of the CAR constructs. The difference in persistence raises the question of whether prolonged presence of CAR T cells is needed for successful treatment. If CAR T-cell therapy is used as a bridge to HSCT, persistence is not necessary and could be detrimental as it is associated with hypogammaglobulinemia due to B-cell aplasia, which is a risk factor for infection and may require treatment with IVIG. On the other hand, if persistence is required, it may depend upon repeat CAR T-cell infusions to sustain remission in patients who are precluded from undergoing HSCT. Alternatively, it is not known if systemic cytokine infusions or programmed death-1 blockade could be utilized safely in the clinical setting to maintain CAR T-cell expansion. Further studies assessing the long-term outcomes of patients treated with CAR T-cell therapy using the different costimulatory domains are needed to further address this issue.
Another early challenge that has arisen with CAR T-cell therapy is the development of CD19-negative clones in patients who have relapsed after treatment. Investigators have suggested developing CARs targeted at other cell surface markers known to be present in ALL, such as CD22, and in the future, dual therapy may be considered to prevent escape due to antigen loss.
Finally, for this therapy to be applied on a larger scale, production time must be shortened and be cost-effective to expedite treatment for acutely ill patients.
Overall, treatment of relapsed and refractory ALL in adults and children with CD19-directed CAR T-cell therapy is extremely promising, but many questions remain about ideal CAR structure, appropriate pretreatment with salvage or lymphodepleting chemotherapy, the duration of response to CAR T-cell therapy, and diagnosis, management, and pathophysiology of the major adverse effects associated with this therapy. Because of the initial success, multicenter phase 2 trials are beginning and will help to elucidate answers to these important questions.
- Rowe JM, Buck G, Burnett AK, et al. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005;106:3760-3767.
- Raetz EA, Bhatla T. Where do we stand in the treatment of relapsed acute lymphoblastic leukemia? Hematology Am Soc Hematol Educ Program. 2012;2012:129-136.
- Fielding AK, Richards SM, Chopra R, et al. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood. 2007;109:944-950.
- Gokbuget N, Stanze D, Beck J, et al. Outcome of relapsed adult lymphoblastic leukemia depends on response to salvage chemotherapy, prognostic factors, and performance of stem cell transplantation. Blood. 2012;120:2032-2041.
- Forman SJ, Rowe JM. The myth of the second remission of acute leukemia in the adult. Blood. 2013;121:1077-1082.
- Ai J, Advani A. Current status of antibody therapy in ALL. Br J Haematol. 2015;168:471-480.
- Kochenderfer JN, Rosenberg SA. Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors. Nat Rev Clin Oncol. 2013;10:267-276.
- Cheadle EJ, Gornall H, Baldan V, et al. CAR T cells: driving the road from the laboratory to the clinic. Immunol Rev. 2014;257:91-106.
- Hwu P, Shafer GE, Treisman J, et al. Lysis of ovarian cancer cells by human lymphocytes redirected with a chimeric gene composed of an antibody variable region and the Fc receptor gamma chain. J Exp Med. 1993;178:361-366.
- Cheadle EJ, Gilham DE, Thistlethwaite FC, et al. Killing of non-Hodgkin lymphoma cells by autologous CD19 engineered T cells. Br J Haematol. 2005;129:322-332.
- Cheadle EJ, Hawkins RE, Batha H, et al. Natural expression of the CD19 antigen impacts the long-term engraftment but not antitumor activity of CD19-specific engineered T cells. J Immunol. 2010;184:1885-1896.
- Brentjens RJ, Latouche JB, Santos E, et al. Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15. Nat Med. 2003;9:279-286.
- Brentjens RJ, Santos E, Nikhamin Y, et al. Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts. Clin Cancer Res. 2007;13(18 Pt 1):5426-5435.
- Cooper LJ, Topp MS, Serrano LM, et al. T-cell clones can be rendered specific for CD19: toward the selective augmentation of the graft-versus-B-lineage leukemia effect. Blood. 2003;101:1637-1644.
- Kochenderfer JN, Feldman SA, Zhao Y, et al. Construction and preclinical evaluation of an anti-CD19 chimeric antigen receptor. J Immunother. 2009;32:689-702.
- Kochenderfer JN, Yu Z, Frasheri D, et al. 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;116:3875-3886.
- Rossig C, Bär A, Pscherer S, et al. Target antigen expression on a professional antigen-presenting cell induces superior proliferative antitumor T-cell responses via chimeric T-cell receptors. J Immunother. 2006;29:21-31.
- Imai C, Mihara K, Andreansky M, et al. Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Leukemia. 2004;18:676-684.
- Marin V, Kakuda H, Dander E, et al. Enhancement of the anti-leukemic activity of cytokine induced killer cells with an anti-CD19 chimeric receptor delivering a 4-1BB-zeta activating signal. Exp Hematol. 2007;35:1388-1397.
- Mihara K, Yanagihara K, Takigahira M, et al. Synergistic and persistent effect of T-cell immunotherapy with anti-CD19 or anti-CD38 chimeric receptor in conjunction with rituximab on B-cell non-Hodgkin lymphoma. Br J Haematol. 2010;151:37-46.
- Loskog A, Giandomenico V, Rossig C, et al. Addition of the CD28 signaling domain to chimeric T-cell receptors enhances chimeric T-cell resistance to T regulatory cells. Leukemia. 2006;20:1819-1828.
- Cheadle EJ, Gilham DE, Hawkins RE. The combination of cyclophosphamide and human T cells genetically engineered to target CD19 can eradicate established B-cell lymphoma. Br J Haematol. 2008;142:65-68.
- Sadelain M, Brentjens R, Rivière I. The basic principles of chimeric antigen receptor design. Cancer Discov. 2013;3:388-398.
- Sadelain M, Brentjens R, Rivière I. The promise and potential pitfalls of chimeric antigen receptors. Curr Opin Immunol. 2009;21:215-223.
- Geiger TL, Nguyen P, Leitenberg D, et al. Integrated src kinase and costimulatory activity enhances signal transduction through single-chain chimeric receptors in T lymphocytes. Blood. 2001;98:2364-2371.
- Irving BA, Weiss A. The cytoplasmic domain of the T cell receptor zeta chain is sufficient to couple to receptor-associated signal transduction pathways. Cell. 1991;64:891-901.
- Eshhar Z, Waks T, Gross G, et al. Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proc Natl Acad Sci U S A. 1993;90:720-724.
- Rössig C, Pscherer S, Landmeier S, et al. Adoptive cellular immunotherapy with CD19-specific T cells. Klin Padiatr. 2005;217:351-356.
- Brocker T, Karjalainen K. Signals through T cell receptor-zeta chain alone are insufficient to prime resting T lymphocytes. J Exp Med. 1995;181:1653-1659.
- Hwu P, Yang JC, Cowherd R, et al. In vivo antitumor activity of T cells redirected with chimeric antibody/T-cell receptor genes. Cancer Res. 1995;55:3369-3373.
- Haynes NM, Trapani JA, Teng MW, et al. Single-chain antigen recognition receptors that costimulate potent rejection of established experimental tumors. Blood. 2002;100:3155-3163.
- Kowolik CM, Topp MS, Gonzalez S, et al. CD28 costimulation provided through a CD19-specific chimeric antigen receptor enhances in vivo persistence and antitumor efficacy of adoptively transferred T cells. Cancer Res. 2006;66:10995-11004.
- Maher J, Brentjens RJ, Gunset G, et al. Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRzeta/CD28 receptor. Nat Biotechnol. 2002;20:70-75.
- Tammana S, Huang X, Wong M, et al. 4-1BB and CD28 signaling plays a synergistic role in redirecting umbilical cord blood T cells against B-cell malignancies. Hum Gene Ther. 2010;21:75-86.
- Wang J, Jensen M, Lin Y, et al. Optimizing adoptive polyclonal T cell immunotherapy of lymphomas, using a chimeric T cell receptor possessing CD28 and CD137 costimulatory domains. Hum Gene Ther. 2007;18:712-725.
- Finney HM, Akbar AN, Lawson AD. Activation of resting human primary T cells with chimeric receptors: costimulation from CD28, inducible costimulator, CD134, and CD137 in series with signals from the TCR zeta chain. J Immunol. 2004;172:104-113.
- Savoldo B, Ramos CA, Liu E, et al. CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J Clin Invest. 2011;121:1822-1826.
- Milone MC, Fish JD, Carpenito C, et al. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther. 2009;17:1453-1464.
- Tumaini B, Lee DW, Lin T, et al. Simplified process for the production of anti-CD19-CAR-engineered T cells. Cytotherapy. 2013;15:1406-1415.
- Hollyman D, Stefanski J, Przybylowski M, et al. Manufacturing validation of biologically functional T cells targeted to CD19 antigen for autologous adoptive cell therapy. J Immunother. 2009;32:169-180.
- Wang X, Naranjo A, Brown CE, et al. Phenotypic and functional attributes of lentivirus-modified CD19-specific human CD8+ central memory T cells manufactured at clinical scale. J Immunother. 2012;35:689-701.
- Cooper LJ, Ausubel L, Gutierrez M, et al. Manufacturing of gene-modified cytotoxic T lymphocytes for autologous cellular therapy for lymphoma. Cytotherapy. 2006;8:105-117.
- Muranski P, Boni A, Wrzesinski C, et al. Increased intensity lymphodepletion and adoptive immunotherapy—how far can we go? Nat Clin Pract Oncol. 2006;3:668-681.
- Lee JC, Hayman E, Pegram HJ, et al. In vivo inhibition of human CD19-targeted effector T cells by natural T regulatory cells in a xenotransplant murine model of B cell malignancy. Cancer Res. 2011;71:2871-2881.
- Restifo NP, Dudley ME, Rosenberg SA. Adoptive immunotherapy for cancer: harnessing the T cell response. Nat Rev Immunol. 2012;12:269-281.
- Brentjens RJ, Rivière I, Park JH, et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood. 2011;118:4817-4828.
- Jensen MC, Popplewell L, Cooper LJ, et al. Antitransgene rejection responses contribute to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans. Biol Blood Marrow Transplant. 2010;16:1245-1256.
- Kalos M, Levine BL, Porter DL, et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med. 2011;3:95ra73.
- Kochenderfer JN, Dudley ME, Feldman SA, 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;119:2709-2720.
- Kochenderfer JN, Wilson WH, Janik JE, et al. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood. 2010;116:4099-4102.
- Porter DL, Levine BL, Kalos M, et al. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365:725-733.
- Brentjens R, Yeh R, Bernal Y, et al. Treatment of chronic lymphocytic leukemia with genetically targeted autologous T cells: case report of an unforeseen adverse event in a phase I clinical trial. Mol Ther. 2010;18:666-668.
- Maude SL, Barrett D, Teachey DT, et al. Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J. 2014;20:119-122.
- Park JH, Riviere I, Wang X, et al. CD19-targeted 19-28z CAR modified autologous T cells induce high rates of complete remission and durable responses in adult patients with relapsed, refractory B-cell ALL. Paper presented at: 56th ASH Annual Meeting and Exposition; December 6-9, 2014; San Francisco, CA. Abstract 382.
- Grupp SA, Maude SL, Shaw P, et al. T cells engineered with a chimeric antigen receptor (CAR) targeting CD19 (CTL019) have long term persistence and induce durable remissions in children with relapsed, refractory ALL. Paper presented at: 56th ASH Annual Meeting and Exposition; December 6-9, 2014; San Francisco, CA. Abstract 380.
- Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. 2015;385:517-528.
- Brentjens RJ, Davila ML, Riviere I, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. 2013;5:177ra38.
- Davila ML, Riviere I, Wang X, et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med. 2014;6:224ra25.
- Grupp SA, Kalos M, Barrett D, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368:1509-1518.
- Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371:1507-1517.
- Turtle CJ, Sommermeyer D, Berger C, et al. Therapy of B cell malignancies with CD19-specific chimeric antigen receptor-modified T cells of defined subset composition. Paper presented at: 56th ASH Annual Meeting and Exposition; December 6-9, 2014; San Francisco, CA. Abstract 384.
- Turtle CJ, Berger C, Sommermeyer D, et al. Immunotherapy with CD19-specific chimeric antigen receptor (CAR)-modified T cells of defined subset composition. J Clin Oncol. 2015;33(suppl). Abstract 3006.
- Gardner RA, Park JR, Kelly-Spratt KS, et al. T cell products of defined CD4:CD8 composition and prescribed levels of CD19CAR/egfrt transgene expression mediate regression of acute lymphoblastic leukemia in the setting of post-allohsct relapse. Paper presented at: 56th ASH Annual Meeting and Exposition; December 6-9, 2014; San Francisco, CA. Abstract 3711.
- Frey NV, Levine BL, Lacey SF, et al. Refractory cytokine release syndrome in recipients of chimeric antigen receptor (CAR) T cells. Paper presented at: 56th ASH Annual Meeting and Exposition; December 6-9, 2014; San Francisco, CA. Abstract 2296.
- Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124:188-195.
Although vaccines are not yet a standard procedure in the therapeutic management of patients with NSCLC, they may play an important role in the future Therapeutic cancer vaccines are classified as either whole-cell vaccines (such as the belagenpumatucel-L vaccine, developed from 4 different NSCLC cell lines) or vaccines that target [ Read More ]
Personalized medicine in the form of immunotherapy holds promise for maintenance treatment of late-stage ovarian cancer, according to a phase 2 study. The personalized vaccine, made from the patient’s own tumor cells, was able to prolong recurrence-free survival compared with standard of care, according to study results presented at the [ Read More ]