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CAR T-Cell Therapy in B-Cell Precursor Acute Lymphoblastic Leukemia

Sep 28, 2017

On August 30, 2017, the FDA approved a chimeric antigen receptor (CAR) T-cell therapy, tisagenlecleucel (Kymriah; Novartis), for the treatment of patients up to age 25 years old, with refractory or second or later relapse B-cell precursor acute lymphoblastic leukemia (ALL).1 This event marked the first time a gene therapy has become available in the U.S., as well as the advent of CAR T-cell therapy into patient care, a major innovation for those with hematologic malignancies.2 As FDA Commissioner Scott Gottlieb, MD, noted:

“We’re entering a new frontier in medical innovation with the ability to reprogram a patient’s own cells to attack a deadly cancer. New technologies such as gene and cell therapies hold out the potential to transform medicine and create an inflection point in our ability to treat and even cure many intractable illnesses.”2

While first-in-class, tisagenlecleucel is only one of several CAR T-cell therapies under development in oncology. This article provides an overview of hematologic malignancies; reviews how CAR T-cell therapies are made and work; discusses the approved CAR T-cell therapy as well as those still under development; and considers some of the unique challenges and concerns that may arise with CAR T-cell therapy in the treatment of patients with hematologic malignancies.

Hematologic Malignancies

In general, there are three main types of hematologic malignancies: leukemia, lymphoma, and myeloma (Table 1). Leukemia can be further categorized as acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myelogenous leukemia (CML).3 ALL is the most commonly diagnosed cancer of children ages 0 to 14 years, accounting for 26% of new childhood cancer diagnoses. ALL is also common among adolescents (ages 15-19).4,5

In contrast, lymphomas begin in lymphocytes and are categorized as either Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL). Most non-Hodgkin lymphomas are B-cell lymphomas, with diffuse large B-cell lymphoma (DLBCL) being the most common; the rest are T-cell/natural killer cell lymphomas.6 Lastly, multiple myelomas arise from abnormal plasma cells and can present as either stable, asymptomatic disease or as progressive, symptomatic disease.7

Table 1. Incidence of Common Hematologic Malignancies3
Type of cancer Estimated new cases in 2017
Leukemia ALL 5,970
AML 21,380
CLL 20,110
CML 8,950
Lymphoma HL 8,260
NHL 72,240
Multiple Myeloma 30,280

In general, treatment of blood cancers depends on multiple factors such as the type, subtype, and features of the cancer, as well as patient characteristics. Typically, treatment may consist of induction, post-remission, and, possibly, maintenance therapy with one or more of the following: chemotherapy, chemo-immunotherapy, radiation, targeted therapies, biologics, immunomodulatory agents, and allogeneic and autologous hematopoietic stem cell transplantation (HSCT).8-14

A substantial number of patients with hematologic malignancies respond to first-line treatment approaches. Unfortunately, patients who are refractory to, or experience a relapse after initial therapy or stem cell transplant, present a treatment challenge as prognosis is normally bleak.15,16 For instance, the SCHOLAR-1 study found patients with relapsed/refractory (R/R) DLBCL receiving salvage therapy had an overall response rate of 20-30% and a median survival of approximately 6 months.17 Similarly, studies have reported that adults with ALL experiencing relapse after initial therapy have a median overall survival of 4½ to 6 months and a 5-year overall survival rate of 3% to 10%; pediatric patients fare slightly better, with an estimated 30% 5-year overall survival rate.8,16 Thus, CAR T-cell therapy is emerging as a viable treatment option for those patients who fail to achieve remission or suffer relapses.

CAR T-Cell Therapy

CAR T-cell therapy is a form of adoptive cell transfer in which T cells are engineered ex vitro by gene transfer technology to express a chimeric antigen receptor (CAR). CAR recognizes a specific tumor antigen expressed on the surface of malignant cells, in a human leukocyte antigen (HLA)-independent manner.18,19 The majority of CAR T-cell therapies rely on autologous T cell populations; however, at least one biopharmaceutical company is exploring allogeneic CAR T-cell therapy, with hopes of developing an “off-the-shelf” option.20,21

It is believed that manufacturing CAR T-cells using T cells from  healthy donors would allow for large-scale manufacturing, reducing time and cost, compared with the individualized manufacturing required for autologous CAR T-cells.20  To date, most of the clinical studies have focused on targeting CD19, a B-cell lineage surface antigen expressed by most B-cell malignancies (e.g., precursor B-cell ALL, CLL, and B-cell NHL), as well as by normal cells.1,19,22

How CAR T-Cells Are Made

The design and manufacture of CAR T-cell receptors, as well as vectors (e.g., lentiviral or retroviral) used for gene transfer, vary between biotechnology companies,15,16 although they share similar components (Figure 1).15,23 In their earliest form, first-generation CAR T-cell therapies linked one intracellular T-cell signaling domain (CD3ζ) to an extracellular single-chain antigen-recognition domain (CD19).19,23,24

In an effort to improve the clinical efficacy of CAR T-cells, second-generation and third-generation CARs have been developed through the addition of one or several co-stimulatory signaling domains (CD28, 4-1BB [also known as CD137], CD27, ICOS, or OX40), respectively.16,19,23 

Armored CAR T-cells, designed to enhance CAR T-cell expansion and persistence in an inhibitory tumor microenvironment, are also being investigated as a way to boost efficacy, through additional modifications of the CAR T-cells such as cytokine transgenes or ligand expression transgenes.25,26 Humanized or human single-chain antigen-recognition domains, instead of the typical murine fragments, are also being explored as a way to decrease immunogenicity.19

The search for new target antigens (e.g., CD22, CD123, and BCMA) beyond CD19 is also ongoing with a variety of goals, including: 1) treating patients who do not respond to CD19-targeted therapy; 2) managing patients who experience relapse due to epitope loss; and 3) identifying target antigens that are tumor-specific or overexpressed by cancer cells in order to reduce on-target, but off-tumor toxicities.15,27,28

Figure 1 - Schematic of CAR T-Cell Construct

The Process

The general approach for manufacturing autologous CAR T-cell therapies includes the following steps:

  1. Blood is drawn from patients, undergoes leukapheresis to isolate mononuclear cells, and is cryopreserved for shipment to manufacturing facilities;
  2. Once at the manufacturing facilities, mononuclear cells are thawed and undergo a procedure to isolate and enrich for T cells;
  3. Next, the T cells are activated with antibody-coated beads and the CAR transgene construct undergoes transduction into the patient’s T cell genome using various gene transfer techniques, becoming CAR T-cells;
  4. The CAR T-cells are subsequently expanded ex vivo to large numbers, washed, formulated, and cryopreserved for shipment back to the patient; and
  5. Once the CAR T-cells arrive, they are thawed and re-infused back into the patient, typically after the patient has undergone preconditioning lymphodepletion with chemotherapy.16,18,19,29,30

Mechanism of Action

The mechanism of action of CAR T-cell therapy is not yet fully elucidated; however, it is believed that the CAR receptor, which is expressed on the T-cell surface, recognizes and binds to the target antigen on the tumor cell, resulting in activation of the signaling domains. This, in turn, initiates CAR T-cell cytokine release, anti-tumor activity, expansion, and persistence.1,15,19 The efficacy of CAR T-cell therapy relies upon the reinfused cell population’s ability to expand and persist in vivo in order to amplify the anti-tumor response and facilitate ongoing tumor surveillance.19

CAR T-Cell Therapies Approved and Under Development

Table 2 summarizes the many CAR T-cell therapies approved or under investigation in patients with multiple refractory/relapsed blood cancer indications.

Table 2. Examples of CAR T-Cell Therapy Approved or Under Development 21,31-35
Company Product Target Disease state (r/r)
Novartis Pharmaceuticals* Tisagenlecleucel (CTL019) Anti-CD19 ALL (pediatric and adult), CLL, NHL, MCL, FL
CTL119 Anti-CD19 Multiple B-cell malignancies
Kite Pharma+ Axicabtagene ciloleucel (KTE-C19) Anti-CD19 ALL (pediatric and adult), DLBCL, PMBCL, FL, indolent and aggressive NHL, MCL, CLL
Juno Therapeutics^ JCAR014 Anti-CD19 Adult ALL, NHL
JCAR014 plus durvalumab (AstraZeneca) Anti-CD19 NHL
JCAR017 Anti-CD19 NHL
JCAR018 Anti-CD22 ALL (pediatric), NHL
bluebird bio^ Bb2212 Anti-BCMA MM
Cellectis UCART123 Anti-CD123 AML, BPDCN
Legend Biotech LCAR-B38M Anti-BCMA/antiCD38 MM
Key: ALL: acute lymphoblastic leukemia; AML: acute myeloid leukemia; BCMA: B-cell maturation antigen; BPDCN: blastic plasmacytoid dendritic cell neoplasm; CLL: chronic lymphocytic leukemia; DLBCL: diffuse large B-cell lymphoma; FL: follicular lymphoma; MCL: mantle cell lymphoma; MM: multiple myeloma; NHL: non-Hodgkin lymphoma; *received FDA approval for pediatric ALL; in collaboration with University of Pennsylvania;  +granted FDA priority review for adult NHL; ^in collaboration with Celgene

In clinical trials, CAR T-cell therapies have demonstrated striking efficacy and durability of response in patients with relapsed/refractory (r/r) B-cell malignancies in both pre- and post-transplant disease settings.36 A such, CAR T-cell therapies have generated tremendous interest and support. On August 30, 2017, the FDA approved Novartis’ tisagenlecleucel (Kymriah) for the treatment of patients up to age 25 years old, with refractory or second or later relapse B-cell precursor ALL.1 The FDA approval was based on data from several trials evaluating the safety and efficacy of tisagenlecleucel in pediatric patients with CD19+ B-cell malignancies, including the pivotal registration trial ELIANA (NCT02435849). ELIANA was a phase II, international, multicenter, single-arm, open-label trial that enrolled pediatric patients (aged 3-23 years) with r/r B-cell ALL.  In total, 88 patients were enrolled, 68 were treated, and 63 were included in efficacy analysis.30,37

Reported key results from ELIANA, including update data, showed:
  • Within 3 months of infusion, 83% (52/63) of patients achieved complete remission (CR), all of whom were negative for minimal residual disease (MRD);
  • For patients who responded, the median time to onset of CR was 29 days;
  • Amongst responders, the relapse-free probability was 75% at 6 months and 64% at 12 months and the probability of survival was 89% at 6 months and 79% at 12 months; and
  • Grade 3 or higher cytokine release syndrome (CRS) or neurological events were experienced by 49% and 18% of patients, respectively.30,37

Similarly, Kite’s lead product, axicabtagene ciloleucel (KTE-C19), has been granted FDA priority review for the treatment of adults with refractory aggressive non-Hodgkin lymphoma (NHL), with action expected November 29, 2017.38 In the pivotal Phase I/II ZUMA-1 trial (NCT02348216), patients (N=111) with refractory aggressive NHL (DLBCL, TFL/PMBCL) received a single infusion of axicabtagene ciloleucel.38-40

Reported key results from ZUMA-1, including update data, showed:
  • Overall objective response rate (ORR) was achieved by 82% of patients, with 54% of those achieving CR;
  • At month 6, the ORR and CR were 41% and 36%, respectively;
  • At a median follow-up of 8.7 months, the ORR was 44%, with CR seen in 39% of patients;
  • For those patients who achieved CR, median duration of response (DOR) was not reached; otherwise, median DOR was 8.2 months;
  • Median overall survival was not reached, with 80% of patients still alive at month 6; and
  • Grade 3 or greater CRS and neurotoxicity occurred in 13% and 18% of patients, respectively; all resolved.38-40

Other CAR T-cell therapies and/or indications under development have reported equally impressive study results; select data from some of these studies are provided in Table 3.

Table 3. Examples of Results from CAR T-Cell Therapy Clinical Trials
CAR Disease state Efficacy Select Safety
JCAR017 (TRANSCEND NHL 001)41 Juno Therapeutics/Celgene Adult r/r DLCBL and transformed FL core group (n=44; ECOG performance status 0-1) The ORR was 86% (38/44) and CR was 59% (26/44). At 3 months, the ORR was 66% (21/32) and CR was 50% (16/32). Of those patients in response at 3 months, 90% continued to be in response at 6 months. Severe CRS and neurotoxicity were experienced by 2% (1/44) and 18% (8/44) of patients, respectively; however, 66% (29/44) of patients did not experience any grade CRS or neurotoxicity and no deaths were reported.
r/r DLCBL and transformed FL full data set (n=55; all patients, including those with poor performance status or niche subtypes of NHL) The ORR was 76% (41/54) and CR was 52% (28/54). At 3 months, the ORR was 51% (21/41) and CR was 52% (16/41). Severe CRS and neurotoxicity were experienced by 2% (1/55) and 16% (9/55) of patients; however, 60% (33/55) of patients did not experience any grade CRS or neurotoxicity and no deaths were reported.
CTL019 (JULIET)42 Novartis Adult r/r DLCBL (N=141) At interim analysis (n=51), the 3-month ORR was 45% (23/51), with 37% achieving a CR and 8% achieving a PR. From 3 months through the data cut-off point, CR remained stable. The best ORR was 59%, with 43% achieving CR and 16% achieving PR. 57% of patients experienced any grade CRS; grade 3 and 4 CRS was experienced by 17% and 9% of patients, respectively. Grade 3 or higher neurotoxicity was observed in 13% of patients, with no cases of cerebral edema.
KTE-C19  (ZUMA-3)43,44 Kite Pharma Adult r/r ALL (N=11) 73% of patients achieved complete remission; all responders tested negative for minimal residual disease. Grade 3 or higher CRS and neurotoxicity were experienced by 27% and 55% of patients, respectively; one patient death was attributable to CRS.
bb121 (CRB-401)35 bluebird bio/Celgene Adult, heavily pretreated r/r MM (N=21) Efficacy was evaluated across 4 dose cohorts (50x106, 150x106, 450x106, 800x106). All efficacy cohorts (n=18), ORR was 89%. In the active dose cohorts (>50x106), ORR was 100%, with 73% achieving a very good PR or better and 27% achieving a CR As of the data cut-off (range of follow-up 8 to 54 weeks), no disease progression had been noted in the active dose cohorts. Any grade CRS occurred in 15/21 (71%) of patients; most of these cases were grade 1 or 2, with grade 3 in 2 patients.
LCAR-B38M34 Legend Biotech r/r MM Overall ORR was 100%, with 94% (33/35) of patients demonstrating CR or very good PR within 2 months of treatment. To date, 19 patients have been followed for more than 4 months, with CR, very good PR, and PR rates of 74% (14/19), 21% (4/19), and 5% (1/19), respectively. Transient CRS was experienced by 85% of patients, with 2 patients experiencing grade 3 or higher. No neurological adverse events were observed.
Key: ALL: acute lymphoblastic leukemia; CR: complete response; CRS: cytokine release syndrome; DLBCL: diffuse large B-cell lymphoma; FL: follicular lymphoma; MM: multiple myeloma; NHL: non-Hodgkin lymphoma; ORR: objective response rate; PR: partial response; r/r: relapsed or refractory

Other Indications

Studies have investigated CAR T-cell therapy and solid tumors; however, the results have not been as impressive as those seen with hematologic malignancies.15,24,28 Despite these early results, CAR T-cell therapy for solid tumors (e.g., ovarian, breast, lung, and neuroblastoma) continues to be an area of active research.16,24,31

Challenges and Concerns

Any emerging innovation is accompanied by challenges and concerns; CAR T-cell therapy is no exception. Some of these concerns are briefly mentioned below.

Safety Concerns

While CAR T-cell therapy has demonstrated impressive efficacy, this efficacy is accompanied by significant treatment-related safety concerns. In addition to cytokine release syndrome (CRS) and neurotoxicity, patients may also develop macrophage activation syndrome, hemophagocytic lymphohistiocytosis, tumor lysis syndrome, cytopenia, and febrile neutropenia. On-target, off-tumor toxicities involving normal cells that express target antigen such as B-cell aplasia have also been reported.16,27,29,30

Cytokine release syndrome (CRS) is related to CAR T-cell therapy’s mechanism of action and has emerged as a key safety concern. The result of increased cytokine release, CRS is a systemic inflammatory response and typically manifests with varying symptoms including high fevers, nausea, anorexia, myalgia, encephalopathy, transient hypotension, and breathing difficulties, and may be associated with hepatic/cardiac/renal dysfunction and coagulopathy.16,30,45

Based on CTL019 data, the timing of CRS onset post-CAR T infusion varies, occurring 1-14 days post-infusion for patients with ALL and 14-21 days for patients with CLL.16 Management of CRS depends on the severity and may include supportive care, corticosteroids, and anti-cytokine therapy.1,16,30 Actemra (tocilizumab) is commonly used in clinical trials to manage CRS and recently received expanded FDA approval to treat CAR T-cell-induced severe or life-threatening CRS in patients 2 years of age or older.2

Patients treated with CAR T-cell therapy may also develop treatment-related neurotoxicity; while the pathophysiology is not yet clear, neurotoxicity is possibly related to elevated cytokine levels and/or direct CAR T-cell toxicity.30,45 Neurotoxicity may present with symptoms such as aphasia, confusion, delirium, tremor, seizure, encephalopathy, and hallucinations. Symptoms generally appear to be self-limiting and resolve over several days without long-term sequelae, although antiepileptic medications, steroids, and/or other supportive care may be useful for management.16,30 Cerebral edema, a severe form of neurotoxicity that may be fatal, has occurred in several CAR T-cell clinical trials.46-49

To date, two CAR T-cell therapies have been subjected to FDA action due to patient deaths. Juno Therapeutics’ JCAR015 (ROCKET Trial) for the treatment of r/r ALL was pulled from further clinical development following 5 patient deaths from cerebral edema, and Cellectis’ UCART123 was placed on clinical hold due to one patient death from a combination of CRS, lung infection, and capillary leak syndrome.46,48

While reasons for this are not yet clear, CAR T-cell construct-related factors, conditioning lymphodepletion regimens, dosing, and specific patient factors, such as baseline tumor burden, have been examined for contributory roles.16,46,48,49

Incorporating a suicide gene, or a safety switch, into the CAR construct is currently being investigated as a way to potentially mitigate treatment-associated adverse events. Safety switches cause rapid depletion of CAR T-cell numbers and activity, thus dampening the CAR-T immune response.23,28

Manufacturing Challenges

In addition to being subject to a complex regulatory environment, manufacturing single-patient CAR T-cell therapies is a costly and specialized process.16,27,28 As production of CAR T-cell therapies is scaled up to serve a global population, dedicated facilities, robust manufacturing protocols, and international regulatory collaboration will be required.28

Furthermore, due to the manufacturing time frame associated with CAR T-cell therapy, patients may require bridging therapy as needed to control their cancer while awaiting delivery.30 Earlier production of CAR T-cell therapies took several weeks; many labs have now reduced the time required.15,29 For example, Kite products are manufactured in a centralized facility; the KTE-19 manufacturing process itself takes 6 days, with an approximate turnaround time of 2 weeks.44 Shorter turnaround times may be positively associated with lower production failure rates.29

Lastly, after multiple treatment cycles with lymphocytotoxic agents, patients may have insufficient levels of functional T cells to allow for adequate collection and CAR T-cell generation.16,19 For instance, 9% of patients enrolled in a clinical study of tisangenlecleucel (Kymriah) did not receive the CAR T-cell product due to manufacturing failure.1 Similarly, in the JULIET trial, 6% (9/141) of enrolled patients were unable to undergo infusion due to the inability to manufacture adequate numbers of CAR T-cells. Importantly, manufacturing success rates appear to improve with continuous process improvements; over the course of JULIET, manufacturing success rates improved to 97% for the last 30 patients enrolled.42

Access Challenges

Components of the Kymriah REMS include:1
  • Healthcare facilities that dispense and administer Kymriah must be enrolled and comply with the REMS requirements. Certified healthcare facilities must have on-site, immediate access to tocilizumab, and ensure that a minimum of two doses of tocilizumab are available for each patient for administration within 2 hours after Kymriah infusion, if needed for treatment of CRS.

  • Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense or administer Kymriah are trained about the management of CRS and neurological toxicities.

While clinical trial experience suggests CAR T-cell therapy can be administered in an outpatient setting, management of toxicities generally requires a hospital setting.16 To date, investigational CAR T-cell therapies are currently limited to specialized academic centers involved in clinical trials.19 Furthermore, due to the risk of CRS and neurotoxicity, recently approved tisangenlecleucel (Kymriah) is only available to patients at certified facilities under a Risk Evaluation and Mitigation Strategy (REMS).1

Cost Concerns

Speculation has abounded that CAR T-cell therapy will be expensive, with some expecting a price tag approaching $700,000. However, Novartis recently announced it would charge $475,000 for a one-time treatment with Kymriah. While not yet a done deal, Novartis additionally indicated they are working on a novel pricing model with the Centers for Medicare and Medicaid Services (CMS); Novartis won’t be reimbursed for Kymriah if the patient is not responding by the end of the first month of treatment.50

Contributing to the substantial financial burden are those costs incurred in addition to the actual cost of the CAR T-cell therapy.  These costs include the following:

  • The price of other therapies administered prior to CAR T-cell therapy

  • Costs associated with travel to a certified facility

  • Lodging costs during and up to a month post-treatment to monitor for potential life-threatening side effects.51


CAR T-cell therapy has demonstrated the potential to profoundly change clinical outcomes for patients with r/r disease and previously limited treatment options. The recent FDA approval of Kymriah provides the leading edge for the entrée of CAR T-cell therapies in the community setting. CAR T-cell therapies are still in their infancy and as such, are accompanied by unique learning curves and questions surrounding their use. Fortunately, active efforts are underway to answer many of these questions and help guide clinical decision-making for those who provide care to patients with hematologic malignancies.


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