Chimeric antigen receptor (CAR) T-cell therapy represents a novel and promising therapeutic advance in cancer.1,2 It constitutes a form of personalized therapy that harnesses adoptive cell transfer through genetic engineering of autologous T cells. The initial step in this therapeutic paradigm involves leukapheresis of the patient’s peripheral T cells; this is followed by ex vivo transduction (by retrovirus or lentivirus), which encodes components of a chimeric T-cell receptor. These components include a fragment of a monoclonal antibody that targets the desired tumor antigen as well as signaling domains, the latter being responsible for activation, proliferation, survival, and cytokine production of T cells; cells are then reinfused into the patient. An important advance that has helped make this therapeutic platform more convenient is the relatively straightforward manufacturing process of the peripheral blood-derived re-engineered T cells.
Collectively, these gene-modified immune cells combine the specificity of B cells (via antibody binding) with the proliferative and cytotoxic capabilities of T cells. Binding via a chimeric antibody confers several advantages over classic T-cell–receptor activation, namely the ability to bind to the specific target of interest independent of major histocompatibility complex (MHC) restriction and immune tolerance of the T-cell repertoire. An MHC-independent process may be leveraged to target a multitude of cell-surface markers.
To date, CAR T-cells recognizing the B-cell–associated molecule CD19 have emerged as the most prominent treatment strategy.3 CD19 is a cell-surface protein that is expressed in the majority of B-cell lymphoid malignancies, thus representing an attractive therapeutic approach in these cancers. CTL019 (formerly known as CART19) is one of the most developmentally advanced constructs in this class of personalized immunotherapies. CTL019 is a second-generation CAR T cell that combines an extracellular anti-CD19 antibody fragment with costimulatory intracellular signaling domains, CD3-zeta and CD137 (4-1BB).
‘Unparalleled’ Results in the Refractory Setting
As reviewed in this issue of The ASCO Post, Maude and colleagues conducted pilot clinical trials at the University of Pennsylvania to assess the safety and feasibility of CTL019 CAR T-cell therapy in patients with relapsed and refractory CD19-positive cancers.4 Over an approximate 2-year period, 30 patients were treated (25 children and 5 adults); all patients had relapsed/refractory acute lymphoblastic leukemia (ALL), with all but the one having B-cell disease (one patient had T-cell ALL that expressed CD19). Furthermore, 18 of 30 patients (60%) had relapsed disease after prior allogeneic stem cell transplantation and 3 additional patients had primary refractory disease.
Impressively, 27 (90%) of 30 patients experienced morphologic complete remission 1 month after CTL019 infusion. Further, 22 of 30 ALL patients (73%) had no evidence of minimal residual disease, as measured by multiparametric flow cytometry. These rapid responses and overall highly efficacious results are unparalleled in this refractory and difficult-to-treat patient population.
Of the 27 patients who entered complete remission, 19 (70%) remained in remission, although follow-up is relatively short (ie, median follow-up of 7 months). The probability of persistence of CTL019 at 6 months was 68%, and CTL019 sequences remained detectable by quantitative polymerase chain reaction through 2 years in patients with sustained remissions. Moreover, all remissions were associated with persistence of CTL019. Among patients who achieved remission and subsequently experienced progressive disease, relapse was associated with early loss of CTL019-modified T cells in three patients, and there was absence of CD19 expression in the leukemic cells of three other patients.
This remarkable clinical efficacy was tempered by the development of cytokine-release syndrome, a serious and potentially life-threatening toxicity. Although there were no deaths attributed to CTL019 therapy, 8 of 30 patients (27%) required intensive care support, including vasopressors for hypotension. Nine patients were treated with the anti–interleukin-6 receptor antibody tocilizumab (Actemra), which produced prompt reduction of fever and stabilization of blood pressure; four patients required a second dose of tocilizumab. All patients in this study ultimately recovered from this cytokine storm, with complete reversal of symptoms and normalization of laboratory data.
Despite the universal occurrence of the aforementioned cytokine release syndrome toxicity, the clinical efficacy of CTL019 CAR T-cell therapy is unprecedented in this patient population. On July 7, 2014, the U.S. Food and Drug Administration granted breakthrough therapy status to CTL019 CAR T-cell therapy for the treatment of adult and pediatric relapsed/refractory ALL.
Challenges Still Ahead
Despite the early success of CAR T-cell therapy, there are a number of roadblocks that must be navigated.5 They include optimization of dosing and mitigation of toxicity along with ongoing legal proceedings regarding intellectual property. In addition, it will be important to manage scalability and cost to ensure accessibility and affordability. These issues and others must be addressed to expand the utility of this innovative therapy to other hematologic malignancies as well as solid tumors.
Solid tumor studies are ongoing with CAR T-cell therapy (eg, via CA19-9 and carcinoembryonic antigen constructs), although tumor bulk, tumor heterogeneity, and off-target effects are challenges that need to be overcome.6,7 A strategy being examined to potentially enhance efficacy is a treatment platform using T cells redirected for universal cytokine killing (TRUCK).8 TRUCKs are CAR T cells that are engineered with the additional capacity to induce IL-12 production in the tumor. Release of IL-12 attracts an innate immune response, including macrophages and natural killer cells, which may subsequently augment the antitumor response. Other potential rational treatment approaches that may augment the efficacy of CAR T-cell therapy, include use in combination with other immunology-based therapeutics such as programmed cell death protein 1 (PD-1) blockade.9
Altogether, CAR T-cell therapy represents a significant and exciting advance in the treatment of cancer. Furthermore, CTL019 represents a likely first-in-class personalized T-cell immunotherapeutic that may soon be available to patients in the clinic. Continued study of these agents in clinical trials will be critical in helping to define the most optimal role for this highly novel and personalized therapy. ■
Disclosure: Dr. Evens reported no potential conflicts of interest.
References
1. Corrigan-Curay J, Kiem HP, Baltimore D, et al: T-cell immunotherapy: Looking forward. Mol Ther 22:1564-1574, 2014.
2. Maus MV, Grupp SA, Porter DL, June CH: Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Blood 123:2625-2635, 2014.
3. 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. October 10, 2014 (early release online).
4. Maude SL, Frey N, Shaw PA, et al: Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371:1507-1517, 2014.
5. Amos SM, Duong CP, Westwood JA, et al: Autoimmunity associated with immunotherapy of cancer. Blood 118:499-509, 2011.
6. Junghans RP: Strategy escalation: An emerging paradigm for safe clinical development of T cell gene therapies. J Transl Med 8:55, 2010.
7. Moon EK, Wang LC, Dolfi DV, et al: Multifactorial T-cell hypofunction that is reversible can limit the efficacy of chimeric antigen receptor-transduced human T cells in solid tumors. Clin Cancer Res 20:4262-4273, 2014.
8. Chmielewski M, Hombach AA, Abken H: Of CARs and TRUCKs: Chimeric antigen receptor (CAR) T cells engineered with an inducible cytokine to modulate the tumor stroma. Immunol Rev 257:83-90, 2014.
9. John LB, Devaud C, Duong CP, et al: Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells. Clin Cancer Res 19:5636-5646, 2013.
Dr. Evens is Director of Tufts Cancer Center and Chief of the Division of Hematology/Oncology at Tufts Medical Center and Tufts University School of Medicine.
