by Jennifer Maxon and Dr. C.H. Weaver updated 5/2021
CAR therapies utilize T-cells (CAR T), a patient’s own immune cells that are re-programmed to recognize and kill cancer cells throughout the body. The process involves the removal of some T cells from a patient, and through laboratory processes, these T cells are re-programmed to identify a patient’s cancer cells. CAR T cells are now approved for the treatment of lymphomas, myeloma and leukemia and being refined to improve outcomes and treat other cancer types.
What is CAR T-cell Therapy?
In essence, CAR T cell therapy is a type of gene therapy that modifies a patient’s own T cells (a type of immune cell) to detect and kill the patient’s cancer cells. It is unique in comparison to other types of available 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. Importantly, longterm results may be achieved with just one infusion.
The process involves removal of T cells from the patient’s blood to undergo genetic engineering outside of the body, which includes several steps:
- First, a patient’s blood is collected from a vein in the arm. The blood flows through a tube to a machine that removes and collects the T cells, and the rest of the blood is returned into the patient’s body.
- The collected T cells are sent to a laboratory where they are genetically modified, with the use of an inactive virus, to produce specific proteins on their surface. These proteins are called chimeric antigen receptors (CARs). The CARs are important because they enable the T cells to recognize and bind to specific proteins detected on the surface of the patient’s cancer cells, known as antigens.
- The genetically modified T cells, now referred to as CAR T cells, are multiplied in the laboratory into the hundreds of millions.
- The CAR T cells are then sent from the laboratory to the treating hospital where they are infused back into the patient’s body through a vein in the arm. Prior to infusion, the patient undergoes one round of a chemotherapy regimen to reduce the amount of cancer cells as well as other immune cells, which improves the body’s acceptance of the CAR T cells. The Lympho-depleting chemotherapy is often Fludarabine + Cyclophosphamide (FluCy) and is used in order to deplete endogenous T-cells (and Tregs), so that they are not going to antagonise/suppress and allow expansion/proliferation of the infused CAR-T cells.
- Once infused, CAR T cells circulate throughout the patient’s body, and attach to cancer cells. This binding action stimulates an immune attack and destruction of the cancer cells.
From the ACS
The process spanning from the initial collection of a patient’s T cells to the infusion of the modified CAR T cells back into the patient currently takes approximately one week but researchers are working on ways to reduce this.
A “Living” Treatment Since CAR T therapy exploits and harnesses critical properties of live T cells to fight cancer, it is sometimes referred to as a “living” treatment. Researchers continue to modify and improve the efficacy of the CAR T cells once they are infused back into the patients. For example, the extent of time the cells survive in circulation (called persistence) continues to be increased, as does as their ability to replicate in greater amounts in the body (called expansion) to enhance and sustain their anti-cancer activity.
The T cells are in essence a “living drug”; they multiply in the patient’s body and, with guidance from their engineered receptor, recognize and kill cancer cells that possess the antigen.
CAR T Cell Therapy Approvals
Several CAR T cell therapy agents are currently approved for the treatment of advanced B-cell lymphomas. The different agents utilize slightly different methods of genetic engineering to transform the patient’s T cells into CAR-T cells. However all agents produce CAR T cells that bind to the CD19 protein; an antigen found on the surface of B- cells.
- Kymria™ (tisagenlecleucel), is for the treatment of children and young adults up to the age of 25 years with B-cell precursor acute lymphoblastic leukemia (ALL). ALL is the most common cancer, as well as the most common cause of cancer-related deaths, among children in the United States.
- Yescarta™ (axicabtagene ciloleucel), is apprived for the treatment of adults with diffuse large B-cell lymphoma (DLBCL).
- Breyanzi (lisocabtagene maraleucel) On February 5, 2021, the Food and Drug Administration approved Breyanzi (lisocabtagene maraleucel) for the treatment of adult patients with relapsed or refractory large B-cell lymphomas. Breyanzi is a CD19-directed chimeric antigen receptor (CAR) T cell immunotherapy. It consists of autologous T cells that are genetically modified to produce a CAR protein, allowing the T cells to identify and eliminate CD19-expressing normal and lymphoma cells.
The TRANSCEND clinical trial evaluated Brevanzi preceded by lymphodepleting chemotherapy, in adults with recurrent large B-cell lymphoma after at least two lines of previous therapy. Of the 192 patients evaluable for response, the overall response rate was 73% with a complete response rate of 54%. Of the 104 patients who achieved CR, 65% had remission lasting at least 6 months and 62% had remission lasting at least 9 months. The estimated median duration of response has not been reached at the time of the approval. The estimated median duration of response among patients with partial response was only 1.4 months.
Overall 79% had significant side effects including neutropenia anemia, and thrombocytopenia. Instances of any grade cytokine release syndrome (CRS) occurred in 46% of patients at a median onset of 5 days. There were neurologic events that occurred in 30% of patients and 21% of patients received tocilizumab and corticosteroids, respectively. (9)
All three are approved for patients whose cancer has either never responded to standard therapies, or has returned following prior therapies. Patients with these types and stages of cancers were previously considered incurable and left with virtually no treatment options.
New Approaches Aim to Enhance CAR T-Cell Therapy
The results of early-phase clinical studies of “second-generation” CAR T cellular immunotherapy products may overcome resistance, reduce side effects and simplify treatment.
CAR T cell therapies are developed by collecting a patient’s own T cells and engineering them to target proteins specific to the surface of their cancer cells and reintroducing these modified T cells back into the patient’s immune system to kill the cancer cells. First-generation CAR T-cell therapies primarily target CD-19, a protein found on the surface of most normal and malignant B cells in B cell cancers such as lymphoma.
Allogeneic CAR T Cell Therapy
Allogeneic derived chimeric antigen receptor (CAR) cell meaning the cells were taken from a non-related healthy donor rather than the patient themselves may have several advantages including;
- The potential to be manufactured in advance and stored for off-the-shelf immediate use which is in contrast to most available CAR T cells which require the use of a patient’s own genetically modified T cells, created through a multi-week manufacturing process.
- Avoidance of CAR T cell cytokine release syndrome and neurotoxicity.
- Lower cost.
Researchers have used allogenic umbilical cord blood-derived chimeric antigen receptor (CAR) natural killer (NK)-cell therapy targeting CD19 in patients with relapsed or refractory non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL), with no major side effects observed. Published in the New England Journal of Medicine 11 patients participating in the study had NK cells isolated from donated umbilical cord blood and genetically engineered to express the CAR, which recognizes CD19. The CAR NK cells were also ‘armored’ with IL-15, an immune signaling molecule that is designed to enhance expansion and survival of the cells.
Side effects experienced by participants were primarily related to the conditioning chemotherapy given before cell infusion and were resolved within one to two weeks and no patient required admission to an intensive care unit for management of treatment side effects. Seventy-three percent of patients responded to therapy and seven of those achieved a complete response. Responses to the CD19 allogenic CAR NK cell therapy were evident within one month following infusion, and persistence of CAR T cells was confirmed out to one-year post-infusion. Importantly NO patients experienced cytokine release syndrome or neurotoxicity. (11)
Off-the-Shelf CAR NK Products in Development
Cellular immunotherapy for B cell cancers could ultimately become an off-the-shelf product, capable of being uniformly manufactured in large quantities as prescription drugs are. FATE and Allogene are leading the way in developing allogenic "off the shelf" CAR T cell therapies and their progress was updated at the December 2020 American Society of Hematology annual meeting. As an off-the-shelf product the time-consuming and costly process that is currently required to treat a patient with CAR T cells is eliminated.
FT596: A product, dubbed FT596, is among the first cellular immunotherapies to be based on off-the-shelf NK cells – the “first line of defense” of the immune system – and is the first cellular immunotherapy to be genetically engineered to contain three active anti-tumor components
FT596 demonstrated comparable ability to kill cancerous white blood cells as standard CAR T cells and, when combined with the drug rituximab, killed cancerous white blood cells that were no longer responding to standard CAR T-cell therapy due to loss of the CD19 antigen target.
The U.S. Food and Drug Administration (FDA) approved Fate Therapeutics’ Investigational New Drug Application for FT596 in September 2019 and the company hopes to begin first-in-human clinical trials for the treatment of B-cell lymphoma and chronic lymphocytic leukemia in the first quarter of 2020.
The patient treated with FT596 had refractory NHL and received seven prior treatment regimens, including an autologous stem cell transplantation, and was most recently refractory to an experimental cellular therapy. The patient received two doses of treatment with FT596, which resulted in a deepening response as evidenced by further decrease in both tumor size and metabolic activity. No dose-limiting toxicities, no FT596-related serious adverse events, and no events of any grade of cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, or graft-versus-host disease were reported by the investigator. (12)
The process of creating FT596 begins with human induced pluripotent stem cells (iPSCs) that are uniquely capable of unlimited self-renewal and can differentiate into more than 200 types of human cells. The iPSCs are genetically engineered, after which a single clone (genetically engineered cell) is selected and multiplied in the laboratory to create a master engineered cell line that can be repeatedly used to generate cancer-fighting immune-system cells such as NK and T cells.
In addition to engineering FT596 to carry a CAR targeting the CD19 protein – which is produced by nearly all B-cell lymphomas and leukemias researchers inserted two other novel proteins: CD16, which boosts and broadens the NK cells’ ability to kill cancer cells, and IL15, which stimulates FT596 to multiply and survive longer.
FT516 is another universal, off-the-shelf NK cell product candidate which is designed to maximize antibody-dependent cellular cytotoxicity (ADCC), a potent anti-tumor mechanism by which NK cells recognize, bind and kill antibody-coated cancer cells. The first 4 patients with refractory NHL were administered FT516 in an outpatient setting with no requirement for inpatient monitoring. No dose-limiting side effects, cytokine release syndrome, neurotoxicity, or graft-versus-host disease, were observed and 3 of the 4 patients achieved an objective response, including two complete responses following the second FT516 treatment cycle. (14,15)
Allogene reported initial results from the Phase 1 UNIVERSAL study of ALLO-715 in relapsed/refractory multiple myeloma (MM) at the December 2020 American Society of Hematology annual meeting. This is the first time an allogeneic CAR T therapy directed at BCMA has been reported that achieve deep clinical responses.
Allogene's AlloCAR T™ therapy uses T cells from healthy donors which are isolated in a manufacturing facility, engineered to express CARs to recognize and destroy cancer (myeloma) cells, and modified via gene editing to limit autoimmune response when given to a patient. These therapies are then stored for off-the-shelf use on demand. No patient needs to undergo leukapheresis.
Lympho-depleting chemotherapy, such as Fludarabine + Cyclophosphamide (FluCy), is administered before CAR-T cell infusion, in order to deplete endogenous T-cells (and Tregs) to allow expansion/proliferation of the infused CAR-T cells.
In the initial dose escalation phase of the UNIVERSAL clinical trial 6 out of the 9 patients treated responded and remain in remission. Of the 31 patients evaluable for safety, there was no graft-vs-host disease, neurotoxicity, and low-level cytokine release syndrome was reported in 45% of patients and was manageable with standard therapies. The Phase 1 UNIVERSAL study continues to enroll patients at higher doses in an effort to optimize the therapy.
What are the Side Effects of CAR T Cell Therapy?
Currently available CAR T cell therapy can only be administered in facilities that have received distinct certification demonstrating the ability to effectively manage CAR T side effects. The off the shelf CAR T therapies appear to have less side effects but are currently only available in clinical trials.
Cytokine release syndrome (CRS) is a response by the body to the activated CAR T cells. CRS can cause very high fevers, changes in blood pressure and flu-like symptoms if left untreated. In response to the dangers of CRS, 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.
Neurologic effects have also been associated in a small percentage of patients receiving CAR T cell therapy, as well as risk for infection. The risk for infection stems from the fact that the two CAR T agents target the CD19 antigen, which is found on the surface of both cancerous and healthy B-cells. Since B-cells are immune cells that contribute to fighting infection through the production of proteins called immunoglobulins, treatment with CAR T can reduce immunoglobulin levels to dangerously low numbers. Fortunately, immunoglobulins can be administered to patients to counteract this side effect.
How Long Are Patients in The Hospital With CAR T?
An initial summary report of several hundred individuals undergoing CAR T for ALL or NHL found that the average length of hospital stay was 15 days and 15% of individuals had an unplanned readmission to the hospital.(8)
Outpatient CAR T cell Therapy
Moving Forward with CAR T
The momentum created by the initial effectiveness of CAR T cell therapy has prompted robust research efforts within the contextual framework of “living therapy” to improve upon the initial results. Some examples of active research aligned with the CAR T therapy conceptual model include the following:
- Approval for treatment of different types of cancers affecting the blood and lymph system are being sought.
- CAR T cells that target one or multiple antigens, besides CD19, that are unique to different types of cancers are being developed and tested
- The effectiveness of two or more infusions of CAR T cells among patients who were partial or poor responders to the initial infusion, or those who experience a cancer recurrence, is being evaluated.
- Utilization of different types of genetic engineering or modification of a patient’s T cells, as well as utilization of cells other than T cells is also under investigation.
- CAR T therapy using a donor’s T cells is also being explored.
How is CAR – T cell therapy delivered?
Currently available CAR T cell therapy is delivered in the following manner. Allogenic or "off the shelf" CAR T doesn't require leukapheresis as the CAR T cells don't require collection from the patient.
- Because CAR T-cell therapy is made from a patients own white blood cells, blood is collected by a process called “leukapheresis” which concentrates white blood cells.
- The patient’s blood cells are then sent to a manufacturing center to make the treatment.
- Before getting CAR T-cell therapy, the patient will usually have several days of chemotherapy to help the T cells grow.
- When CAR T-cell therapy is ready, the patient’s care team will infuse the cells through a catheter placed into a vein (intravenous infusion). The infusion usually takes less than 30 minutes.
- The patient is then monitored daily for at least seven days after the infusion.
- Patients should plan to stay close to the treatment center for at least four weeks after getting treated. Our care team will help with any side effects that may occur.
- Patients may be hospitalized for side effects until they are under control and it is safe to leave the hospital.
- Patients should not drive for eight weeks following T-cell therapy.
CAR T in Solid Tumors
For patients with leukemia and lymphoma, the T-cell therapies currently being tested in clinical trials seem to work well even with a relatively small number of cells. For patients with solid tumors such as breast, lung or pancreatic cancer, therapies will likely require multiple doses of potent cells to reach and effectively attack the tumors. The pressing problem for those therapies is how to grow cells to large numbers in the lab. Studies are ongoing in solid tumors.
Biliary Tract Cancers16
- National Cancer Institute.(2017). CAR T-Cell Therapy Approved for Some Children and Young Adults with Leukemia. Retrieved here
- National Cancer Institute. (2017). Childhood acute lymphoblastic leukemia treatment (PDQ®)- patient version. Retrieved from cancer.gov/types/leukemia/patient/childall-treatment-pdq
- United States Food and Drug Administration. (2017). FDA News Release. FDA approval brings first gene therapy to the United States. Retrieved here
- United States Food and Drug Administration. (2017). FDA News Release. FDA approves CAR-T cell therapy to treat adults with certain types of large B-cell lymphoma. Retrieved here
- United States Food and Drug Administration. (2017). Kymriah package insert. Retrieved from fda.gov/downloads/BiologicsBlood-Vaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM573941.pdf
- United States Food and Drug Administration. (2017). Yescarta package insert. Retrieved from fda.gov/downloads/Biologics-BloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM581226.pdf
- Kochenderfer J, Somerville R, Lu T, et al. Anti-CD19 chimeric antigen receptor T cells preceded by low-dose chemotherapy to induce remissions of advanced lymphoma. Proceedings from the 2016 annual ASCO meeting. Late-breaking abstract #3010. Available at: abstract.asco.org/176/AbstView_176_165865.html. Accessed June 16, 2016.
- Hartsell A. [Emerging trends in chimeric antigen receptor T-cell immunotherapy in young adults and pediatric patients f](https://www.bbmt.org/article/S1083-8791(18%2931367-3/pdf)
- Wang ML, Munoz J, Goy A, et al. KTE-X19, an Anti-CD19 Chimeric Antigen Receptor (CAR) T Cell Therapy, in Patients (Pts) With Relapsed/Refractory (R/R) Mantle Cell Lymphoma (MCL): Results of the Phase 2 ZUMA-2 Study. Abstract #754. Presented at the 2019 ASH Annual Meeting, December 9, 2019; Orlando, FL.
- [Fate Therapeutics Presents Patient Case Study Demonstrating Clinical Activity of FT596 in Refractory Diffuse Large B-cell Lymphoma](
- Blood. 2020;135(6):399-410)
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