Update on CAR T Cell Therapies for the Treatment of Cancer

Cancer Connect

by Jennifer Maxon and Dr. C.H. Weaver updated 2/2020

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.

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.
  • 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

The two CAR T cell therapy agents currently approved, Kymria and Yescart, are both for the treatment of cancers that originate in a type of immune cell, called a B-cell. The different agents utilize slightly different methods of genetic engineering to transform the patient’s T cells into CAR-T cells. However, both 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.
  • Yescart™ (axicabtagene ciloleucel), is apprived for the treatment of adults with diffuse large B-cell lymphoma (DLBCL).

Both Kymria and Yescart 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.

Lisocabtagene Maraleucel (liso-cel) is an investigational CAR) T-cell therapy designed to target CD19, which is a surface glycoprotein on lymphoma cells. The TRANSCEND NHL 001 is a phase 1 clinical trial designed to determine the safety anti-tumor activity of liso-cel in patients with relapsed/refractory B-cell non-Hodgkin lymphomas. In the study 269 heavily pretreated patients with recurrent refractory NHL. Patients had received a median of three prior therapies including 35% with prior autologous or allogeneic hematopoietic stem cell transplant and 67% with chemotherapy-refractory disease.

The overall response rate to liso-cel was 73% with 53% achieving a complete response. The median duration of response for all patients was not reached at a median follow-up of 12 months. Median progression-free survival was 6.8 months and median overall survival was 21.1 months. The median PFS and OS for patients who achieved a CR was not reached with 65.1% of patients surviving progression free and 85.5% of patients alive at 12 months, respectively.

Overall 79% had significant side effects including neutropenia anemia, and thrombocytopenia. Instances of any grade cytokine release syndrome (CRS) occurred in 42% 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. Bristol-Myers Squibb expects to complete the submission of a Biologics License Application to the U.S. FDA shortly. Liso-cel is not approved for any use in any country. (9)

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 – FT596

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.

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 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.

FT596 has been designed to address two other limitations of CAR T-cell therapy.

  • 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.
  • The addition of the CD16 protein gives FT596 broader therapeutic activity and versatility. In combination with a drug such as Rituxan (rituximab), FT596 has the potential to lead to deeper and more durable responses and overcome resistance that hampers the long-term efficacy of CAR T-cell therapy.

What are the Side Effects of CAR T Cell Therapy?

CAR T cell therapy can only be administered in facilities that have received distinct certification demonstrating the ability to effectively manage these side effects. The facilities must demonstrate that each healthcare provider involved in the infusion process is qualified in safe procedures and risk management, and all necessary precautions must be available for immediate use.

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?

  • 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.

CAR T for NHL

Kite Pharma reported on 51 patients with advanced diffuse large B-cell lymphoma (DLBCL) who were treated with Kite’s KTE-C19. Initially, 76% of the patients responded to treatment, 47% of patients went into complete remission. By comparison, similar DLBCL patients treated again with chemotherapy in previous studies only achieve an 8%-10% complete response rate. Two lymphoma patients in the study died due to treatment with KTE-C19, the company said. Serious neurological toxicity was reported in 34% of patients.

Another trial evaluating the effectiveness of CAR T cell therapy included 22 patients with different types of advanced B-cell lymphomas that had progressed following prior therapies. All patients received chemotherapy prior to a single infusion of the CAR T cells.

  • Of 19 patients who had different subtypes of diffuse large B-cell lymphoma (DLBCL), 8 achieved a complete disappearance of their cancer; 5 achieved a partial disappearance of their cancer; 2 achieved disease stabilization; and 4 experienced a progression of their disease.
  • Of the 2 patients with follicular lymphoma, and the single patient with mantle cell lymphoma, all achieved a complete disappearance of their cancer.
  • Two patients with refractory chronic lymphocytic leukemia are reported to be in complete remission for 8 years as of May 2019.

KTE-X19: A CAR T-Cell Option for Mantle Cell Lymphoma

Ninety-three percent of patients with relapsed/refractory MCL responded to treatment with KTE-X19, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, according to results from the ZUMA-2 trial presented at the 2019 ASH Annual Meeting.

The ZUMA-2 clinical trial treated 74 patients with relapsed/refractory MCL who had received up to five prior lines of therapy, including an anti-CD20 antibody, chemotherapy, and a BTK inhibitor with a single infusion of KTE-X19 at a target dose of 2×106 CAR T cells/kg.(10)

Findings for the first 60 treated patients with a median follow-up of 12.3 months were reported at ASH.

· 93% overall response rate - 67% complete response

· One-year overall survival of 83%

· Cytokine release syndrome (CRS) in 91% a median of two days after KTE-X19 administration – all resolved.

Although longer-term follow-up is needed to confirm these early study findings CAR T cell therapy appears to be a promising new treatment option for individuals with relapsed or recurrent MCL.

References

  1. National Cancer Institute.(2017). CAR T-Cell Therapy Approved for Some Children and Young Adults with Leukemia. Retrieved from
  2. National Cancer Institute. (2017). Childhood acute lymphoblastic leukemia treatment (PDQ®)- patient version. Retrieved from
  3. United States Food and Drug Administration. (2017). FDA News Release. FDA approval brings first gene therapy to the United States. Retrieved from
  4. 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 from
  5. United States Food and Drug Administration. (2017). Kymriah package insert. Retrieved from
  6. United States Food and Drug Administration. (2017). Yescarta package insert. Retrieved from https: //www.fda.gov/downloads/Biologics-BloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM581226.pdf
  7. 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: . Accessed June 16, 2016.
  8. 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)
  9. 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.

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