CAR-T Cell Therapy

By: Will Hurst

What is it?

● CAR-T cell therapy is an innovative therapy used to directly target tumors

using the patient’s own T-cells.
● It is unique in comparison to other types of immune therapies for
cancer, in that the patient’s own T cells are the actual treatment; no other
medications are used as an active component of therapy.
● It has been shown in clinical trials to help 51% of patients achieve
complete remission.
● Long term results may be achieved with just one infusion.
How does it work?

● Doctors extract T cells (a type of white blood cell) from the patient’s
blood through a process called “apheresis.”
● The collected T cells are then genetically modified, with the use of an
inactive virus, to produce specific proteins on their surface called
“Chimeric Antigen Receptor” (Hence the name.)
● These receptors act as a sort of “heat seeking missile” enabling the
modified T-cell to produce chemicals that kill the cancer.
● They are then infused back into the patient’s body via IV and begin
multiplying and attacking the cancerous cells.
 A closer look…

(a) T lymphocytes are genetically modified to express chimeric antigen receptor which is made up of monoclonal antibody targeting
specific antigen of interest. ScFV Single chain variable fragment, Vh Heavy chain, VL Light chain. (b) ScFV portion of CAR T cell
recognizes tumor-associated antigen on the surface of tumor cells, binds to them, and initiates a cascade of cytotoxic signaling,
leading to tumor lysis.
Who can receive this treatment?

● CAR T-cell therapy was approved by the FDA in 2017 for patients with
certain types of non-Hodgkin’s lymphoma who have failed at least two
other types of treatment.
● Currently, UAMS is the first and only hospital in Arkansas approved to
provide this revolutionary new therapy for certain types of non-Hodgkin’s
lymphoma.
● Most recently in March 2021, the FDA approved the use of Abecma® for
the treatment of multiple myeloma.
 Potential Side Effects
● Cytokine Release Syndrome
○ 70-90% of patients experience it
○ Lasts 5-7 days. Starts around day 2 or 3 of infusion
○ “Flu-like” symptoms - fever, fatigue, body aches
○ Completely reversible
● Neurotoxicity
○ Observed in up to 64% of CAR T-cell clinical trials
○ Starts around 5 days after infusion
○ Typically presents with impairment of attention and confusion. Expressive aphasia and
changes in handwriting.
○ Reversible in most patients, although resolution usually takes longer than CRS
Implications for Therapy

● Monitor for flu-like symptoms and educate the patient that this is the body’s immune
response. It is common (70-90% of patients) and it typically lasts 5-7 days. It can be
dangerous though if left untreated, so notify care team. The FDA has extended the
approval of the drug Actemra (tocilizumab) to treat severe or life-threatening CRS
associated with CAR T cell therapy. Clinical trials have demonstrated that one or two
doses of Actemra resulted in complete resolution of severe CRS in nearly 70% of
patients within two weeks.
● Similar to CRS, neurotoxicity is primarily managed by supportive care and close
monitoring. Other potential etiologies, such as stroke, malignancy, infection or
hemorrhage, need to be excluded by appropriate diagnostic tests. Expressive aphasia
and changes in handwriting are considered fairly specific and early signs of
neurotoxicity. It can progress to depressed level of consciousness, coma, seizures,
motor weakness and cerebral edema so notify care team promptly at the first sign of a
status change.
The Patient’s Experience
● This study interviewed 18 diffuse large B-cell lymphoma (DLBCL) patients post CAR-T cell
therapy treatment.
● Questions were designed to capture relevant patient experiences before, during, immediately
after the CAR T procedure, and at 6 months after CAR T.
● Eight main domain impairments were identified in the qualitative analysis: 1) social
functioning, 2) emotional functioning, 3) fatigue, 4) physical functioning, 5) cognitive
functioning, 6) role functioning, 7) sleep, and 8) pain/discomfort.
● RESULTS:
○ Compared with before CAR T therapy, patients reported increased impairment in every
domain during or immediately after CAR T therapy.
○ This impairment improved for each domain 6 months after CAR T therapy except for
pain/discomfort.
○ *Compared with before CAR T therapy, improvement in impairment for each domain was
observed 6 months after CAR T therapy except for fatigue, sleep, and pain/discomfort.*

Cheng R, Scippa K, Locke FL, Snider JT, Jim H. Patient perspectives on health-related quality of life in diffuse large B-cell
lymphoma treated with car T-cell therapy: A qualitative study. Oncology and Therapy. 2021. doi:10.1007/s40487-021-00174-0
Solid Tumors-The Next Obstacle

● In contrast with the efficacy of CAR-T cell immunotherapy in the treatment of

hematologic malignancies, its general efficacy against solid tumors is insignificant.
● Unfortunately, the majority of diagnosed cancers are primarily solid tumors. Thus, a
highly unmet clinical need for further research and development exists in this field.
● Several trials currently apply CAR-T against solid tumors, including glioblastoma,
lung cancer, liver cancer, gastric cancer, renal cancer, prostate cancer.
● Based on a meta-analysis on the efficacy of CAR-T in treating solid tumors, CAR-T
cell immunotherapy produced a comprehensive response rate of 9%
● Although CAR-T cell therapy did not have satisfactory responses in solid tumors,
researchers were still holding an optimistic attitude towards its future efficacy with
more modifications of its structure.
References
1. MD Anderson Cancer Center, DeMarco C. 9 things to know about car T-cell therapy. MD Anderson Cancer Center.
https://www.mdanderson.org/cancerwise/car-t-cell-therapy--9-things-to-know. Published February 26, 2018.
Accessed February 24, 2022.
2. Sterner RC, Sterner RM. CAR-T cell therapy: current limitations and potential strategies. Blood Cancer Journal.
2021;11(4):1-11. doi:10.1038/s41408-021-00459-7
3. Car T-cell therapy. UAMS Health. https://uamshealth.com/treatment/car-t-cell-therapy/. Accessed February 24,
2022.
4. CancerConnect. Car T cell therapy for the treatment of cancer. CancerConnect.
https://news.cancerconnect.com/treatment-care/car-t-cell-therapy-for-the-treatment-of-cancer?redir=1. Published
February 9, 2021. Accessed February 25, 2022.
5. Schubert M-L, Schmitt M, Wang L, et al. Side-effect management of chimeric antigen receptor (CAR) T-cell therapy.
Annals of Oncology. 2021;32(1):34-48. doi:10.1016/j.annonc.2020.10.478
6. Usmani, S. Ciltacabtagene autoleucel, a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell
(CAR-T) therapy, in relapsed/refractory multiple myeloma (R/R MM)
7. Patel U, Abernathy J, Savani BN, Oluwole O, Sengsayadeth S, Dholaria B. Car T cell therapy in solid tumors: A review
of current clinical trials. eJHaem. 2021;3(S1):24-31. doi:10.1002/jha2.356