As components of the adaptive immune system, ordinary T cells are formidable defenders. They recognize non-self antigens (e.g., peptide remnants of viruses or intracellular bacteria that have infected a cell) presented to them on the cell surface by major histocompatibility complex (MHC) glycoproteins, and then wield a variety of defensive countermeasures. T cells can destroy cancer cells, too, but cancer has ways of suppressing the MHC mechanism. In the context of cancer, what could a souped-up, bioengineered T cell made from the patient’s own T cells accomplish? A mighTy cell (or, if you prefer, for an autologous product, myT cell), that would recognize cancer cells by antigens on their surface and then destroy them, independent of MHC.
Such agents exist and are known as chimeric antigen receptor (CAR) T cells, which is one of several types of adoptive cell therapy (see the Glossary). Researchers have been working on them for decades, and one, being developed by Kite Pharma in Santa Monica, Calif., is expected to receive FDA approval by the end of 2017. Additional CAR T cells under development at Novartis and Juno Therapeutics may be approved soon, too. (See Table 1 below for a list of selected clinical trials of CAR T-cell therapy that are underway.)
Selected clinical trials of CAR T-cell treatments
|NCT no. / acronym||Interventions||Target||Condition(s)a||Phase||N||Sponsor / collaborators||Start / primary completion|
|axicabtagene||CD19||NHL (DLBCL, PMBCL, TFL)||2||112||Kite Pharma||Jan. 2015
|axicabtagene||CD19||MCL||2||70||Kite Pharma||Nov. 2015
|axicabtagene||CD19||ALL (adult)||1/2||75||Kite Pharma||Nov. 2015
|axicabtagene||CD19||ALL (pediatric, young adult)||1/2||75||Kite Pharma||Dec. 2015
|NCT02926833 ZUMA-6||axicabtagene, atezolizumab||CD19||DLBCL||1/2||31||Kite Pharma, Genentech||Sept. 2016
|CTL019 (tisagenlecleucel-T)||CD19||DLBCL||2||130||Novartis||July 2015
|CTL019 (tisagenlecleucel-T)||CD19||ALL||2||72||Novartis||April 2015
|NCT02706405||JCAR014, durvalumab||CD19||B-cell NHL (DLBCL, MBCL)||1b||42||FHCRC; AstraZeneca, Juno, MedImmune, NCI||Nov. 2016
|JCAR017||CD19||NHL, DLBCL, FL, MCL, PMBCL||1||144||Juno||Dec. 2015
|NCT02028455||JCAR017||CD19||Acute leukemia (age 1–26 years)||1/2||80||Seattle Children’s Hospital||Jan. 2014
|NCT02315612||JCAR018||CD22||FL, ALL, NHL, LCL
(age 1–30 years)
|NCT02311621||JCAR023||CD171||Neuroblastoma, ganglioneuroblastoma||1||40||Seattle Children’s Hospital||Nov. 2014
|NCT02706392||JCAR024||ROR-1||Cohort 1: CLL, MCL, ALL;
Cohort 2: stage 4 NSCLC, metastatic TNBC
|1||60||FHCRC, NCI||March 2016
|NCT02498912||JCAR020||MUC16||MUC16+ solid tumors||1||30||MSKCC, Stanford, Juno||Aug. 2015
|UCART19 (allogeneic)||CD19||ALL, CLL (age ≥16 years)||1||12||Servier||Aug. 2016
|CD19||ALL (age 6 mos. –17 years)||1||10||Servier||June 2016
|NCT02658929||bb2121||BCMA||MM||1||50||bluebird bio||Jan. 2016
This table shows selected clinical trials of CAR T-cell products that are in progress and sponsored by pharmaceutical companies and their collaborators that are in the forefront of this field. In 2015, Kite launched four pivotal trials, ZUMA-1 through ZUMA-4, aimed at winning FDA approval for its lead product, axicabtagene (axi-cel, also known as KTE-C19). Through these trials, Kite hopes to secure indications for several types of NHL. ZUMA-5, ZUMA-7, and ZUMA-8 (not listed) are expected to begin in 2017, enrolling patients with NHL, DLBCL, and CLL, respectively.
a Unless noted, all conditions are relapsed or refractory.
ALL=acute lymphoblastic leukemia, CLL=chronic lymphocytic leukemia, DLBCL=diffuse large B-cell lymphoma, FHCRC=Fred Hutchinson Cancer Research Center, FL=follicular lymphoma, LCL=large cell lymphoma, MBCL= monocytoid B-cell lymphoma, MCL=mantle cell lymphoma, MM=multiple myeloma, MSKCC=Memorial Sloan Kettering Cancer Center, NCI=National Cancer Institute, NHL=non-Hodgkin lymphoma, NSCLC=non–small-cell lung cancer, PMBCL=primary mediastinal B-cell lymphoma, TFL=transformed follicular lymphoma, TNBC=triple-negative breast cancer.
Judging by remarks made by representatives and observers of the pharmaceutical industry during the past few years (see box below), CAR T cells are the next big thing in oncology—so much so that some proponents have not been shy about saying cure when they discuss CAR T cells. In a presentation in March 2017, “Focused on the Cure,” Kite Pharma told investors that its in-house clinical manufacturing facility is fully operational and can produce more than 4,000 patient therapies per year, using a process that takes about 16 to 18 days per therapy. Kite has even trademarked a term, eACT, which stands for engineered autologous cell therapy, to encompass CAR T cells and related products.
Several of the pharmaceutical companies in the forefront of this field have forged partnerships with academic institutions (see Table 3 below), and their academic partners have been more circumspect in their remarks.
Collaborations between academia and industry to advance CAR T-cell therapy
|Baylor College of Medicine||bluebird bio
Celgene (also collaborates with bluebird)
|Fred Hutchinson Cancer Research Center||Juno Therapeutics|
|Leukemia & Lymphoma Society||Kite Pharma|
|Memorial Sloan Kettering Cancer Center||Juno Therapeutics|
|National Cancer Institute||Kite Pharma|
|Seattle Children’s Hospital||Juno Therapeutics|
|Tel Aviv Sourasky Medical Center||Kite Pharma|
|University of Pennsylvania||Novartis
CAR T cells have been described as “living drugs” with supraphysiologic properties (Sadelain 2013). They also have been explained as simultaneously incorporating cellular therapy, immunotherapy, and gene therapy. The therapy is delivered by infusion of T cells (cellular therapy) that spurs an immune response to cancer cells (immunotherapy), and genetic modification via viral vectors (gene therapy) triggers a stronger, more targeted immune response. From another perspective, CAR T cell therapy weaves together three therapeutic strategies: transplantation, vaccination, and engineered antibodies (Lim 2017).
The first CAR T cell was described in 1993. They’ve now gone through three generations of refinement, with more generations envisioned.
CAR T cells are modular, and the molecular engineers who assemble them have countless combinations to consider. The critical modules are the extracellular antigen-binding components, which, in theory, can target any molecule that can be bound by a monoclonal antibody, and the intracellular components that transmit signals inside the cell upon binding of the antigen. One of the early versions of a CAR T cell incorporated only those two components and consisted of a single polypeptide chain of an extracellular binding module (known as the single-chain variable fragment, or scFv) fused directly to an intracellular signaling module. Another first-generation design inserted a hinge module between the antigen-binding module and the intracellular signaling domain. These and other first-generation CAR T cells were biologically active, but they didn’t eradicate tumors efficiently in preclinical studies. Researchers learned that CAR T cells relying upon a single signaling domain, CD3-zeta (CD3ζ) couldn’t produce complete T-cell activation and expansion (Daniyan 2016).
To address this problem, CAR T-cell designers adopted the approach employed by native T cells and developed CAR T cells with a co-stimulatory signal for T-cell activation. Second-generation CAR T cells contain a co-stimulatory domain derived from either CD28 or CD137 (4-1BB), which is fused into the polypeptide chain just before the CD3ζ signaling domain. Third-generation CAR T cells contain two or more additional co-stimulatory domains, but it remains to be seen whether third-generation T cells are superior to second-generation T cells (Daniyan 2016).
As the field advances, researchers may add, subtract, and otherwise tinker with CAR T cells as they look for ways to improve response rates while also improving the safety profile of CAR T cells. Safety concerns often arise from “on target, off tumor” adverse effects that occur when the target is found on normal, healthy cells as well as cancerous ones.
The ideal target for CAR T cells would be an antigen found on the surface of cancer cells—and on all of them, not just a subpopulation of the cancer in question—and nowhere else. But such a target does not seem to exist. Often antigens found on cancer cells occur on normal cells as well. And the antigens that are special to a cancer often aren’t found on all the cancerous cells, so they aren’t recognized and elude destruction.
The second-best scenario is an antigen found on cancer cells but only on a limited type of normal cells whose destruction could be anticipated and dealt with. Some of the early—and sometimes spectacular—successes for CAR T-cell therapy have occurred in this situation. CAR T-cell therapy has resulted in response rates of 70% to 90% and sustained remission in patients with such advanced B-cell malignancies as acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL). The target antigen, CD19, is found only on B cells, both cancerous and normal B cells. When the normal B cells are destroyed by CAR T cells targeting CD19, intravenous immune globulin can replenish the supply. Moreover, clinicians regard the continued presence of B-cell aplasia (the absence of CD19+ cells) as a welcome sign because it shows that the CAR T-cell therapy still works (Barrett 2015).
Further improvements in efficacy, and especially in safety, may arise from the addition of more modules to T cells, specifically a second chimeric antigen receptor that creates a gated circuit. The Boolean operators AND, NOT, and OR have been used to classify such circuits (Lim 2017).
AND-gate circuits. In AND-gated design, CAR T cells are given receptors that target two different antigens on a cancer cell in order to make them more likely to destroy only cancer cells. The problem has been that binding of a single antigen still has been enough to activate the CAR T cells, jeopardizing normal cells that bear that antigen. In one design, one receptor contains the usual CD3ζ signaling domain while the other contains a different co-stimulatory signaling domain. The idea is that full activation of the CAR T cell will occur only when both receptors have bound with their different targets on the cancer cell.
A different AND-gate circuit features a dual-receptor design. Upon binding to its target, one receptor acts as a primer. Instead of activating the T cell as ordinary CAR T cells do, it triggers the release of an intracellular transcription factor that migrates to the nucleus and causes the T cell to express a second chimeric receptor. Upon binding to a different target antigen, this receptor stirs the T cell into action so that it destroys the cancer cell (Roybal 2016). This new class of receptors is known as synthetic Notch (synNotch) receptors, named for a chimeric Notch receptor. It has been shown in preclinical studies that synNotch AND-gate T cells can discriminate between tissues bearing two target antigens and those bearing only one (Morsut 2016). That means if a pair of antigens can be identified that is particular to a given type of cancer cells, AND-gated CAR T-cell therapy could be designed to home in on cancer cells while leaving other normal cells with just one of the antigens alone.
NOT-gate circuits. Another strategy to spare normal cells bearing an antigen that also is found on cancer cells is to create CAR T cells featuring a NOT-gate circuit. In this design, one chimeric antigen receptor that targets an antigen on cancer cells (and, problematically, on some normal cells) and contains the expected intracellular signaling domain that activates the T cell while another chimeric antigen receptor targets a different antigen found only on the normal cells. In contrast to its mate with T-cell activating killing potential, the second chimeric receptor antigen contains a signaling domain derived from inhibitory receptors such as PD-1 or CTLA-4 (Fedorov 2013). When a CAR T cell designed this way encounters a normal cell bearing both target antigens, the inhibitory signaling prevents or diminishes T-cell activation. But, at least in theory, if it encounters a cancer cell that lacks the antigen that triggers inhibitory signaling, the T cell is fully activated and the cancer cell is destroyed.
These AND- and NOT-gated approaches, which are aimed at preventing on-target, off-tumor adverse effects, should be safer than administration of high-dose corticosteroids or resorting to “suicide switches”—modules inserted into CAR T cells that can trigger T-cell apoptosis in the event of an emergency such as a severe case of cytokine release syndrome (CRS). CAR T cells have been designed that incorporate CD20 or EGFRt as such switches; administration of rituximab (Rituxan) and cetuximab (Erbitux) targets each, respectively, and destroys the cell. Another method of controlled CAR T-cell destruction employs an enzyme, caspase-9, that is activated by administration of a small-molecule drug, rimiducid.
OR-gate circuits. One mechanism by which resistance to CAR T-cell therapy can emerge is loss of the target antigen by cancer cells. A strategy to prevent this from occurring may be to design CAR T cells with chimeric receptors capable of binding with either of two distinct antigens found on the cancer cell. Malignant B cells can become resistant to CAR T-cell therapy targeting CD19 by ceasing to express CD19, so a CAR T cell that targeted an additional antigen specific to the B cells, such as CD22, might be a way of dealing with this resistance.
If CAR T-cell therapy is to become a major advance in cancer treatment, it will need to demonstrate that it is safe and efficacious in the treatment of patients with solid tumors. In addition to providing a nearly ideal target (CD19), the B-cell malignancies against which CAR T-cell treatments have been most effective exist in an environment where CAR T cells enjoy relatively easy access to the cancerous cells. The microenvironment created by solid tumors is far more hostile to T cells (Wu 2015). Solid tumors make it more difficult for T cells to infiltrate the tumor in the first place. If T cells manage to breach that defense, cells in solid tumors are equipped to impede the survival, proliferation, and function of T cells and induce T-cell apoptosis by upregulating proteins such as PD–L1. Since checkpoint inhibitors against PD–L1 and its receptor found on activated T cells, PD-1, are in clinical use to treat malignant melanoma and lung cancer, a logical approach would be to combine these drugs with CAR T cells (Lim 2017).
Recent preclinical studies using a murine model have suggested that dual-specific T cells may warrant further study for treating patients with solid tumors. A viral vaccine was administered to activate T cells bearing a TCR for an antigen delivered by the vaccine. The T cells also were given a CAR for HER2. This approach resulted in durable complete remission of various HER2+ tumors and their metastases, even though the mice also had normal tissues (breast, brain) expressing HER2 (Slaney 2017).
Currently, most CAR T-cell therapy depends on using the patient’s own T cells. The autologous approach means the therapy has to be prepared on an individual, patient-by-patient basis. It is a time-consuming and labor-intensive process that takes from five to 10 days (Fesnak 2016). Here are some of the steps involved:
A more efficient approach might be the use of allogeneic CAR T cells prepared with T cells from a single donor and used as an off-the-shelf treatment for multiple patients. Pfizer and Servier are testing such a product, UCART19, in clinical trials (see Table 1). Another allogeneic CAR T-cell product (Cellectis) targeting CD123 was expected to begin phase 1 trials in 2017.
In addition to all the steps needed to prepare CAR T-cell therapy, patients are often treated with lymphocyte-depleting chemotherapy to eliminate cells that would compete with the infused CAR T cells for growth factors. And after the CAR T-cell infusion, patients must be monitored for the development of adverse effects, notably CRS. When large numbers of CAR T cells are infused, they secrete a flood of cytokines that not only kill targeted cancer cells but also trigger CRS, a systemic inflammatory response that presents as a flu-like malady, usually emerging within one to five days of the infusion. CRS is mild in some but life-threatening in others. Patients with CRS may develop hypotension, decompensated shock, renal insufficiency, and respiratory distress. In severe cases, mechanical ventilation and aggressive vasopressor treatment is required. Some patients also develop self-limited neurotoxicity that may be a manifestation of CRS.
In three phase 1 trials enrolling patients with relapsed ALL who were treated with CAR T cells targeting CD19, complete responses were observed in 67% (N=21), 88% (N=16), and 90% (N=30) of patients. CRS was reported in 100% of patients in two of these trials (N= 16, N=30) and in 76% in the third trial (N=21) (Oluwole 2016). Most cases of CRS were mild (56% to 73%). All were reversible with no therapy-related mortality reported. Tocilizumab (Actemra), corticosteroids, or both were used to treat most of these patients.
Using data from two clinical trials that enrolled 51 patients with refractory or relapsed ALL (an adult cohort of 12 patients and a pediatric and adolescent cohort of 39 patients, ages 5–23) who were treated with CTL019), researchers recently developed a tool to predict which patients were or were not most likely to develop severe CRS (Teachey 2016). As in the ALL trials mentioned above, the rate of complete response was high: 90% among the first 30 patients (25 adults, five children) (Maude 2014). All 30 patients had CRS, and 94% (48/51) of the larger group had CRS (Figure). The 14 patients with severe CRS were treated with tocilizumab, as were seven of the 15 patients with moderate CRS. Patients responded rapidly to tocilizumab. Twelve patients also received corticosteroids and two received etanercept (Enbrel).
Distribution of cytokine release syndrome by severity in 51 patients (adult cohort, N=12; pediatric cohort [age 5–23 years], N=39) receiving CTL019 for treatment of relapsed/refractory ALL. Mechanical ventilation was required by 9 patients; vasoactive medications for shock by 20 (distributive, 19; cardiogenic, 1). Three adults receiving CTL019 died, and the deaths of two of them were attributed to CRS.
Source: Teachey 2016
Although ALL disease burden at the time of infusion had been thought to correlate with the degree of CRS severity, that hypothesis didn’t hold up: low disease burden was found to have strong negative predictive value, but high disease burden lacked strong positive predictive value. Instead, after comparing the cytokine profiles (cytokine encompassing 43 cytokines, chemokines, and soluble receptors) of all the patients, they found that peak levels of 24 cytokines were statistically significantly associated with severe CRS (grades 4–5) compared with less severe CRS (grades 0–3).
For predicting which patients were likely to be at low risk of CRS, two cytokines, IFNγ and sgp130, stood out because they peaked during the first three days after infusion and before patients became critically ill (usually triggering treatment with tocilizumab). For the combined adult and pediatric cohorts, the top logistic-regression predictive model had 86% sensitivity and 89% specificity, using Day-3 peak levels of sgp130, IFNγ, and IL-1RA. For the pediatric cohort, the top logistic-regression model had 100% sensitivity and 96% specificity using Day-3 peak levels of IFNγ, IL-13, and MIP-1α. Although IL-6 (the target of tocilizumab) is strongly associated with CRS over the first month after infusion, its levels change little during the first three days after infusion.
The next step would be to use these and other predictive models in clinical trials to determine whether early intervention in patients at high risk of CRS adversely affects the efficacy of CAR T-cell therapy. If early intervention does not impair the efficacy of CAR T-cell treatment, high-risk patients could be monitored and treated in time to preclude the development of life-threatening complications.
Autologous CAR T-cell therapy is likely to be priced very high, so anything that reduces the risk of severe adverse events and the costs associated with treating them will be appealing to those attempting to manage costs. In addition, better understanding of the biology of CRS and its treatment could help move CAR T-cell therapy beyond specialized centers. The development of allogeneic products could also help widen the use of CAR T-cell therapy and possibly lower its price.
At this point, it remains to be seen how widely CAR T-cell therapy will be used. One fork in the road will have it restricted to a relatively small group of patients with advanced leukemia and lymphoma, such as those with advanced B-cell malignancies who have exhausted all other treatment options. Another will find it to be safe and efficacious in the treatment of a wide range of other malignancies, especially solid tumors. There are other forks—and branches off those forks— that CAR T-cell therapy might take.
Some challenges for CAR T-cell therapy, and actual and possible solutions
|Improve response to CAR T-cell therapy||Strengthen intracellular signaling by complementing the single singling domain (e.g., CD3ζ) of a first-generation CAR with a second intracellular signaling module such as CD28 or CD137 (second-generation)
Add two or more intracellular signaling modules (third-generation)?
|Improve expansion of CAR T cells||Add hinge domain between extracellular and intracellular modules|
|Address cytokine release syndrome (CRS)||Treat severe CRS (life-threatening) with tocilizumab (IL-6 receptor antagonist)
Administer tocilizumab before IL-6 reaches peak level?
Treat patient with CAR T-cell therapy before disease burden becomes high?
Employ tool to predict which patients are likely and unlikely to develop severe CRS?
|Address on-target, off-tumor adverse effects||Replenish antibodies via IVIG when CD19 (found on cancerous and healthy B cells) is the target
Use AND- or NOT-gate circuits to spare healthy cells while killing cancer cells that bear the same target antigen?
Add “suicide switch” to CAR T cells that can be activated by physician to eliminate T cells in event of emergency?
|Prevent resistance to CAR T-cell therapy||Employ engineered receptors that can recognize two different antigens found on the cancer cells?
Administer combination therapy or sequential therapy targeting antigen that persists on cancer cells despite loss of original target?
|Increase rate of durable complete responses||Administer CAR T-cell therapy while disease burden is low|
|Treat solid tumors||Create “armored” CAR T cells endowed with genes that express anti-cancer cytokines (e.g., IL-12, IL-18) to facilitate tumor penetration?
Employ synNotch T cells customized to express molecules that enhance killing by the CAR component or alter the tumor microenvironment?
Use dual-specific T cells activated by a vaccine?
|Expense of autologous product||Use allogeneic product?|
|Time to prepare autologous product||Use allogeneic product?|
Of course, healthy skepticism about next-big-things in cancer treatment is wise. For instance, it is not unusual for innovative treatments to produce dramatic results in a narrow group of patients, only to falter in a wider one. Some dark clouds have started to appear on the CAR T-cell therapy’s bright horizon. For example, in some clinical trials in which the initial rate of complete remission was very high, some patients in complete remission a month after treatment relapsed a few months later. Researchers are also refining how CAR T-cell therapy might be used. For example, one analysis of patients with relapsed ALL suggested that a strategy that involved early treatment with CAR T-cell therapy while the disease burden is low could be important to achieving longer-lasting complete responses (Park 2017).
In some cases when patients relapse, the CAR T cells destroyed the cancer cells as intended but cancer cells without the crucial antigen escaped detection and managed to multiply. Such is the nature of cancer. When malignancies are attacked, resistance emerges, and when one mechanism of resistance is thwarted, another springs up.
Still, the modular nature of CAR T cells could provide novel strategies to combat resistance and convert more initial complete responses into lasting complete responses. These and numerous other challenges must be successfully met before CAR T-cell therapy can realize its substantial promise.
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