CAR T-Cell Therapy: A Healthcare Professional's Guide - Overview
Medically reviewed by Leigh Ann Anderson, PharmD. Last updated on April 7, 2021.
CAR T-Cell Therapy: An Introduction
Chimeric antigen receptor (CAR) T-cell therapy is a form of immunotherapy -- in fact, the first gene therapy -- now approved by the FDA.
CAR T cell therapy is offering promising options for patients and clinicians who are struggling with cancers that do not respond to, or are ineligible for, other standard options such as surgery, radiation, chemotherapy, or bone marrow transplant.
There are 3 main types of lymphocytes (white blood cells) that have action against cancerous tumors:
- B cells
- T cells
- Natural killer (NK) cells
CAR T-cell therapy works with the patient's own immune system to help boost the cancer-killing effects of the T lymphocyte. Normally, T-cells have a direct killing action on cancer cells and also communicate with the immune system via cytokines -- cell signalling molecules. However, cancer cells can evade the T lymphocytes. The T-cells become less effective, have low proliferation, and don't recognize cancer as a foreign body.
CAR T-Cells: Getting Aggressive on Cancer
Simply put, CAR T-cell therapy is a biomedical engineering feat. The patient's own T-cells are modified to recognize tumor antigens and attack the cancer cells.
What kinds of cancers do CAR T agents treat? For now, certain blood cancers such as:
- Aggressive B-cell non-Hodgkin lymphoma and follicular lymphoma.
- Leukemias, such as acute lymphoblastic leukemia (ALL), have also shown extended remissions in studies with CAR T-cell therapy.
- Mantle cell lymphoma, a rare, aggressive form of non-Hodgkin lymphoma (NHL).
Ongoing studies also report on evolving research involving CAR T-cells directed against solid tumors like:
- Glioblastomas (brain tumors)
- Liver cancer
- Breast cancer
- Lung cancer
- Pancreatic cancer
CAR T-Cell Therapy: A Living Drug
CAR T-cell therapy involves several steps:
- First, blood is taken from the patient via leukapheresis to collect the lymphocytes. The T cells are then isolated.
- Next, the T cells are genetically engineered in the laboratory to produce chimeric antigen receptors (CARs) -- a protein -- on their surface. The genes are inserted into the T cells using an inactive virus. This process leads to the CAR T-cell that recognizes the cancer antigen on the targeted tumor cell.
- The engineered CAR T-cell is then grown in the laboratory for about 2 weeks to produce billions of more cells. The cells are frozen and sent to the hospital where the patient will undergo treatment. The patient receives chemotherapy to kill off some of their white cells prior to infusion. This helps the body to better accept the CAR T-cells.
- The CAR T-cells are re-infused into the patient where they continue to multiply, seek out, and attack the tumor target antigen. CAR T-cells remain in the body after infusion and can continue to function. In investigational studies, some patients have been able to maintain long-term remissions possibly due to this effect.
CAR T-Cell Therapy: The Structure
What are CAR T-cells? CARs are fusion proteins that contain 3 distinct functional domains:
- The first domain is an antibody fragment, also called a target-binding domain, that elicits signals to activate the engineered T cells to recognize and bind to target antigens on the surface of the cancer cell.
- The second component, called the costimulatory domain, allows the CAR T-cells to proliferate and survive.
- The third domain, called the essential activation domain, activates the CAR T-cells.
Many different antigen targets are under research; however, the most common antigen that has been targeted in lymphoma and leukemia trials is known as "cluster of differentiation 19" (CD19).
CD19 is expressed on the surface of most B cells, both healthy and cancerous. CD19 is not found on other healthy cells, and therefore those cells are not targeted by the engineered CAR T-cell.
B-cell aplasia is reported as an expected side effect, and can boost the risk of infections, but has been managed with intravenous immunoglobulin replacement.
CAR T: Further Questions and Ongoing Research
Scientists and clinicians alike are excited about this new therapy that may offer extended survival to certain patients who have exhausted their options for cancer treatments.
However, there are many questions:
- How long is CAR T-cell therapy effective? While some studies have reported extended periods of remission, patients will need to be followed long-term to answer this question.
- What is the cost of CAR T-cell therapy? Genetically engineering personalized immunotherapy is expensive and complicated. Initially, the price tag of the first approval, Kymriah (tisagenlecleucel) from Novartis was set at $475,000 per treatment. Yescarta (axicabtagene ciloleucel) from Gilead/Kite Pharma was set at $373,000 per treatment regimen.
- Can CAR T-cells from donors be harvested and stored, or can a "universal" CAR-T agent be successfully developed? Researchers from the National Cancer Institute (NCI) have reported promising results from a trial using donor-derived CAR T-cells in lymphoma and leukemia.
- Can immune checkpoint inhibitors and CAR-T therapy be successfully combined for synergistic effect and to lower doses and side effects? Studies for these combinations are ongoing.
Targeted Therapy: Advances Continue
While there are still questions to be answered, CAR T-cell therapy has made tremendous advancements in the last two decades.
The first clinical trial with CAR T-cells was in 1996 targeting ovarian cancer, but success was limited in early studies. However, dedicated researchers have now brought forth significant advances into personalized, targeted immunotherapies, including:
- Therapeutic cancer vaccines such as sipuleucel-T (Provenge) for men with metastatic prostate cancer
- Immune checkpoint inhibitors such as pembrolizumab (Keytruda) and nivolumab (Opdivo) used for non-small cell lung cancer (NSCLC), melanoma, and many other malignancies
CAR T-cell therapy such as:
- Yescarta (axicabtagene ciloleucel), given the go-ahead by the FDA in October 2017 for treatment of adult patients with large B-cell lymphoma after at least two other kinds of treatment failed, including diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. In March 2021, Yescarta was also approved to treat adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy.
- Kymriah (tisagenlecleucel), approved in August 2017 for use in relapsed and refractory (r/r) patients up to 25 years of age with B-cell acute lymphoblastic leukemia (ALL). In May 2018, Kymriah was also approved for relapsed or refractory large b-cell lymphoma in adults after two or more therapies.
- Tecartus (brexucabtagene autoleucel), approved in July 2020 for the treatment of adults with relapsed or refractory mantle cell lymphoma (MCL), a rare, aggressive form of non-Hodgkin lymphoma (NHL).
- Breyanzi (https://www.drugs.com/mtm/lisocabtagene-maraleucel.html), approved in Feb. 2021 for the treatment of adults with relapsed or refractory large B-cell lymphoma (LBCL)
- Abecma (idecabtagene vicleucel), approved in March 2021 for adult patients with relapsed or refractory multiple myeloma.
Finished: CAR T-Cell Therapy: A Healthcare Professional's Guide - Overview
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- Marofi, F., Motavalli, R., Safonov, V.A. et al. CAR T cells in solid tumors: challenges and opportunities. Stem Cell Res Ther 12, 81 (2021). https://doi.org/10.1186/s13287-020-02128-1
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