With the approvals of tisagenlecleucel (KYMRIAH™) and axicabtagene ciloleucel (YESCARTA™) last year, chimeric antigen receptor (CAR) T-cell therapies have changed the treatment paradigm for patients with certain hematologic malignancies.
What is CAR T-cell therapy?
CAR T-cell therapy involves re-engineering a patient’s own T-cells to recognize and eradicate cancer. These T-cells are genetically altered to express artificial receptors which enable the T-cells to bind to a specific antigen on the patient’s tumor cells and kill them. Unlike T-cell receptor-mediated immune reactions, CAR T-cell mediated immune reactions lead to direct recognition of extracellular tumor-associated antigens; however, immunogenicity can be challenging.
Figure 1. Normal vs. CAR T-cell
Image credit: Locke, F. L., MD, Gardner, R., MD, & Neelapu, S. S., MD. (2017, December 20). Test Driving CARs: Optimizing Outcomes. Retrieved from https://www.medscape.org/viewarticle/890215_transcript
Development of CAR T-cell Therapies
To date, two CAR T-cell therapies have been approved by the FDA:
- Tisagenlecleucel. Approved for the treatment of adults with relapsed or refractory diffuse large B-cell lymphoma as well as young adult patients up to age 25 with relapsed or refractor acute lymphoblastic leukemia
- Axicabtagene ciloleucel. Approved for the treatment of adults with certain types of B-cell lymphoma who have either not responded to or have relapsed following two or more lines of systemic therapy.
Clinical development of CAR T-cell therapies has accelerated significantly over the past decade, with 144 ongoing trials in the U.S. alone as of August 2018.
Figure 2. CAR T-Cell trials in the US and China2
Source and image credit: The-Scientist.com. Cell and Gene Therapy Tracker: Global CAR T-Cell Trials. Infographic created with data compiled by CellTrials.org.
In recent years, researchers have been making efforts to enhance the efficacy of CAR T-cell based therapies, such as improving the structures of CAR T-cells (see Figure 3) or developing mechanisms — like suicide switches — to make these treatments safer.
Figure 3. Evolution in CAR T-Cell Design
Image Credit: Xu D, et al. The development of CAR design for tumor CAR-T cell therapy. Oncotarget 2018;9(17):13991-14004.
CAR T-cell therapy has a number of advantages compared to other immuno-oncology treatments:
- HLA-independent antigen recognition, enabling universal application
- Selective modification of specific T-cell subtypes
- Rapid generation of tumor-specific T-cells
- Minimal risk of graft-versus-host disease
- Potential for lasting immunity even after a single infusion since it is a living “drug”
- Additional modification capability of the CAR construct
However, CAR T-cell therapy is also associated with a variety of challenges, including:
- High cost
- Length of time required for T-cell processing and modification
- Adverse events, including cytokine release syndrome, tumor lysis syndrome and neurologic toxicity
- On-target, off-tumor toxicity (e.g., B-cell aplasia)
- Off-target, off-tumor toxicity (e.g., agammaglobulinemia)
Managing cytokine release syndrome (CRS)
The reported incidence of CRS in recent trials ranges from 50 to 93 percent, with symptoms spanning the spectrum from mild, flu-like symptoms to severe life-threatening systemic inflammatory responses. Currently, tocilizumab, a monoclonal antibody that competitively inhibits the binding of interleukin-6 (IL-6) to its receptor and hinders IL-6 from exerting its pro-inflammatory effects, is considered first-line treatment for mitigating moderate to severe CRS. In cases where tocilizumab is not effective, steroids have been used. Humanized immunoglobulin (IG)-1 anti-human immunoglobulin (anti-hIL)-6R was also approved by the U.S. FDA in August 2017 for treatment of CRS. To date, prophylaxis with tocilizumab has not been shown to reduce the incidence of CRS.
Future of CAR T-Cell therapy in successfully expanding into solid tumors indications
Looking forward, we are seeing continued investment in CAR T-cell therapies as researchers seek to answer key clinical questions such as:
- Can CAR T-cell therapy be used earlier in the course of treatment?
- Can CAR T-cell treatment replace autologous transplant?
- What is the role of CAR T-cell therapy in maintenance?
- How can CAR T-cell treatment be made safer?
- Will CAR T-cell therapy become an off-the-shelf treatment?
With ongoing research, we hope to see faster, more cost-effective manufacturing and cell expansion using off-the-shelf products with improved safety profiles, making CAR T-cell therapy more accessible and affordable to the patients who need it.
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 The-Scientist.com. Cell and Gene Therapy Tracker: Global CAR T-Cell Trials. Available at https://www.the-scientist.com/infographics/cell-and-gene-therapy-tracker-64450. Accessed April 19, 2019.
 Xu D, et al. The development of CAR design for tumor CAR-T cell therapy. Oncotarget 2018;9(17):13991-14004.
 Zhao Q, et al. The application of CAR-T cell therapy in hematological malignancies: advantages and challenges. Acta Pharm Sin B 2018;8(4):539-551.
 Gauthier J, Yakoub-Agha I. Chimeric antigen-receptor T-cell therapy for hematological malignancies and solid tumors: Clinical data to data, current limitations and perspectives. Curr Res Transl Med 2017;65(3):93-102.
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 Shimabukuro-Vornhagen A, et al. Cytokine release syndrome. J ImmunoTher Cancer 2018;6:56.
 Sebba A. Tocilizumab: the first interleukin-6-receptor inhibitor. Am J Health Syst Pharm 2008;65(15):1413-1418.