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Are Today’s CARs Superheroes or Just Expensive Toys?

By Bradley Haverkos, MD, MPH

Despite the sticker shock, chimeric antigen receptor T-cell (CAR-T) therapy is offering hope for patients who had almost none with prior standard treatment options. Given its life-saving potential, some would go as far as saying that this therapy is “priceless.” Across the hematologic spectrum, CAR-T therapy is changing the treatment landscape. The 2018 Annual Meeting featured several studies with more data and longer-term follow-up for patients with B-cell lymphoid malignancies. A high point at this year’s meeting was also several novel CAR approaches and CAR-T treatment in non–B-cell hematologic malignancies including myeloid diseases and multiple myeloma. There is so much work being done in the CAR-T field that my allotted word limits only allow me to highlight some of the presentations that took place this year.

Frederick Locke, MD, and Sattva Neelapu, MD, were both enthusiastic about the opportunity to present the two-year follow-up from the ZUMA-1 trial, revealing possible durable responses in patients achieving complete remission (CR; #2967, just accepted into The Lancet Oncology). There were additional updates demonstrating safety and toxicity, including in older patients (upper age limit of 83 years) using CAR-T therapy in the “real world,” that was similar to that observed in clinical trials (#91 and #96). Additional data on predictors of response and resistance mechanisms to CAR-T continue to evolve (abstracts #92 and #281). In B-cell acute lymphoblastic leukemia (B-ALL), updated phase I results using CD19-CAR-T therapy in adults with relapsed/refractory (R/R) disease (the ZUMA-3 trial) were presented (#897). Efficacy data in chronic lymphocytic leukemia (CLL) from the Transcend CLL 004, an open-label phase I/II trial of CD19-CAR-T in patients with R/R CLL continue to be encouraging for patients who do not respond to ibrutinib (#300). Since systemic CD19-CAR-T administration for B-ALL and diffuse large B-cell lymphoma has resulted in CR of concurrent central nervous system (CNS) disease, there is an increasing number of CD19-CAR-T trial protocols that no longer exclude patients with active CNS lymphoma involvement. Based on the success of CD19-CAR-T therapy in B-ALL and B-cell lymphomas, Xiuli Wang, PhD, is translating this strategy into a potentially more effective therapy for CNS B-cell disease by using a mouse model to inject CD19-CAR-Ts directly into the CNS to bypass the blood-brain barrier (#965).

The field of CAR-T therapy is expanding to other indications beyond B-ALL and B-cell lymphomas. Sham Mailankody, MBBS, presented impressive safety and clinical responses from the EVOLVE study, which uses a BCMA-CAR-T. A second session on December 3, 2018, further illustrated the safety and efficacy of BCMA-CAR-T (#1009 to #1014). In the world of myeloid malignancies, Feng Liu, MD, PhD, presented an update on a phase I clinical trial with a first-in-human CLL1-CD33-CAR-T, inducing CRs in patients with refractory acute myeloid leukemia (#901). Additional CAR-Ts targeting alternative antigens in myeloid diseases and demonstrating clinical responses were presented (#902 and #701). Continued treatment using CD30-CAR-Ts for classical Hodgkin lymphoma and some T-cell lymphomas has demonstrated promising antitumor activity, despite having previously received brentuximab (abstract #681).

The next generation of novel CAR constructs is being developed and includes ideas such as self-destructing, conditional, or safety CAR-Ts that can prevent toxicity by carrying on/off switches or by only activating under certain conditions. James Kochenderfer, MD, presented a new CD19 construct with theoretically less toxicity (#697). Others presented ideas to increase safety and limit toxicity, such as GM-CSF blockade (#961). New designs that aim to improve efficacy and subvert resistance include fourth-generation CARs, sometimes termed “TRUCKS,” that alter the tumor microenvironment; armored CARs with multiple costimulatory molecules; and multitargeted CARs. Additionally, T-cell receptor–based therapies that can target intracellular antigens are being explored. Safety, feasibility, and preliminary efficacy data using a CAR-T directed at both CD19 and CD22 were the focus of multiple presentations (#277, #278, #279, and #490). Other exciting developments include combinations with CARs including ibrutinib (#298 and #299), and checkpoint blockade (#556). Reuben Benjamin, MD, presented data using an off-the-shelf allogeneic (often referred to as a “universal CAR”) genetically modified CD19-CAR-T manufactured from healthy donor T cells, in which TRAC and CD52 genes were knocked out to allow its administration in non-human leukocyte antigen–matched patients; safety and efficacy data were encouraging (#896). An additional off-the-shelf product targeting CD2 in Sézary syndrome demonstrated the ongoing innovative science using CAR-T to treat T-cell malignancies, which has been an elusive goal (#340). While T cells are the most commonly used cell type for CAR constructs, different cell types have been used to improve CAR cell–based therapy. Further developments in natural killer–cell–based CARs were discussed (#590) as well as other immune effector cell treatment strategies (#341).

CAR-T therapy has the potential to revolutionize the treatment of B-cell and other hematologic malignancies; however, the field is still in its infancy. The U.S. Food and Drug Administration’s approval of CD19-CAR-Ts in the third-line setting for pediatric ALL and adult large B-cell lymphoma is just the beginning of a paradigm shift on how we will treat these malignancies in the future. There is great potential to improve the safety and efficacy of cell-based therapies including further development of off-the-shelf products and combinatorial treatment strategies. It’s possible the innovative changes to the current CAR-T construct and novel approaches will supplant our current FDA-approved CARs, though some would have said the same about rituximab.

Dr. Haverkos indicated no relevant conflicts of  interest.

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