Which Cancer Therapies Use T-Cells?

Understanding CAR T-Cells and Other Immune Therapies

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Your body has different kinds of white blood cells. One kind, the lymphocyte, comes in two main types: the B-cell and the T-cell. Here, in the context of cancer treatment, we are mainly concerned with that second type, the T-cell.

So, what is chimeric antigen receptor (CAR) T-cell therapy? In brief, it’s a cutting-edge therapy that genetically programs your own T-cells to be better at recognizing and attacking the cancer within.

It is one of multiple types of immunotherapies being explored. If you are interested in the biotechnology behind this kind of therapy, a more detailed explanation on how CAR T-cell therapy works offers that perspective.

Here, the focus is on these “living therapies” and other similar treatments that work through T-cells—your body’s “immune system soldiers”—to fight cancer by recognizing and attacking the tumor cells. Some cancer therapies that use your body’s T-cells have already been approved, and others are expected to follow very soon.

Paving the Way With Immune-Based Treatments

Tinkering with your body’s immune system to try to fight cancer is not entirely new. In fact, there are examples of such therapies (that focus on the T-cell response) that have already received FDA approval: sipuleucel-T, ipilimumab, and blinatumomab, for instance.

Treatment

Cancer Type

Immune System Action

Sipuleucel-T (Provenge)

Certain cases of advanced prostate cancer

  • Autologous cellular immunotherapy vaccine
  • Designed to use your own immune cells and activate them to react to markers found on prostate cancer cells.

Ipilimumab (Yervoy)

Certain cases of malignant melanoma skin cancer

  • Immune checkpoint inhibitor
  • Designed to block CTLA-4, a protein receptor on certain immune cells, in order to boost tumor-fighting power

Blinatumomab (Blincyto)

Relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) in adults and children

  • Bispecific T-cell engager (BiTE) immunotherapy
  • Designed to act like a bridge between a cancer cell and a T-cell to promote cancer cell death.

One of them, sipuleucel-T, sounds very much like a CAR T-cell therapy in that it uses your immune cells which are first collected from the bloodstream individually and then processed in the laboratory; they are activated and made to be more responsive to the tumor cells, then infused back into the bloodstream as the therapy.

Sipuleucel-T is considered an “autologous vaccine," or an "autologous cellular immunotherapy,” however, and not a CAR T-cell therapy, since the immune cells are being trained to respond, rather than being genetically manipulated to respond to the tumor cells.

Immune checkpoint inhibitors such as ipilimumab (above) work with your immune system’s various mechanisms of “applying the brakes,” or “hitting the gas pedal” on the body’s immune system, to try to leverage your immune defenses against cancer. Ipilimumab is just one example of a medicine that works in this way. Another example of an immune checkpoint inhibitor is pembrolizumab (Keytruda), which targets an “on-off switch” for T-cells, called PD-1.

CAR-T Cell Therapies: True “Living Drugs”

CAR-T cell therapies, however, are clearly their own distinct entity. T-cells are taken out of your body, genetically programed to better recognize and kill tumor cells, and then re-introduced as the living therapy. The cells can be engineered and grown in as few as 21 days and then they are infused back into the bloodstream.

CAR T-cell therapy is not the kind of therapy that would be used before trying other treatments—at least, not presently. These newer treatments generally arise out of the unfortunate fact that, for patients with late-stage disease, traditional cancer treatments, including surgery, chemotherapy, and radiation therapy, oftentimes offer limited efficacy.

So, thus far, CAR-T cell therapies have only been available to patients who have enrolled in clinical trials, as the treatments are considered investigative in the U.S., but this may soon change. CAR-T cell therapies could become FDA approved and available outside of clinical trials as soon as 2017-2018.

A brief list of some major candidates that are being clinically developed follows.

CTL019 (tisagenlecleucel) by Novartis

CTL019 is a CD19-specific chimeric antigen receptor (CAR)-based T-cell therapy.

Let’s start by unpacking the previous sentence: CD19 is a molecule on certain immune cells called B-cells, and these cells can be the source of certain kinds of leukemia and lymphoma.

A single dose of CTL019 has brought long remissions, and possibly cures (we don’t known yet) to scores of patients in studies who were running out of treatment options.

Here is a run-down of diseases for which CTL019 is being considered currently:

  • CTL019 received FDA Breakthrough Therapy designation for treatment of adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). (Lymphomas are generally categorized into two basic groups: Hodgkin and non-Hodgkin. The most common type of non-Hodgkin lymphoma is DLBCL).
  • CTL019 is also up for approval for the treatment of relapsed or refractory pediatric and young adult patients with B-cell acute lymphoblastic leukemia (ALL).

CTL019 received a unanimous (10-0) vote of approval from the FDA's Oncologic Drugs Advisory Committee, meaning that things look promising for its ultimate approval. Novartis is aiming for CTL019 to be approved for the treatment of relapsed or refractory B-cell ALL in pediatric and young adult patients. Leukemia is the number one childhood cancer, and ALL is the most common form, responsible for around 25 percent of childhood cancers. There are different types of ALL, including B-cell ALL and T-cell ALL, and subtypes within may carry their own prognoses.

CTL019 is currently under priority review and timely approval would make it the first CAR-T cell therapy to be available. The CAR T-cell treatment would be available only for the small number of children and young adults whose leukemia doesn’t respond to standard care. These patients typically have a poor prognosis, but in the pivotal trial testing the therapy in nearly a dozen countries, 83 percent of patients went into remission. A year later, two-thirds remained so.

Because the treatment destroys not only leukemic B-cells but also the healthy, germ-fighting variety, patients need treatment to protect them from infection. They receive infusions of immune globulins every few months as a protective measure.

One of the most common side effects is called cytokine release syndrome, which causes high fever and flulike symptoms that in some cases can be so dangerous that the patient ends up in intensive care. The other major worry is neurotoxicity, which can result in temporary confusion or potentially fatal brain swelling.

To try to ensure patient safety, Novartis isn’t planning a typical product rollout, with a drug pushed as widely and aggressively as possible. The company instead will designate 30 to 35 medical centers to administer the treatment. Many of them took part in the clinical trial, and all have gotten extensive training.

Axicabtagene Ciloleucel by Kite Pharma

Based in Santa Monica, California, Kite Pharma is a company that focuses on CAR and T-cell receptor engineered cell therapies. Kite is developing a CAR T-cell therapy called axicabtagene ciloleucel, which is currently under priority review in the U.S. for the treatment of patients with refractory aggressive non-Hodgkin lymphoma (NHL). Patients with refractory aggressive NHL face a dire prognosis with only a 50 percent chance of surviving six months. This underscores the urgent medical need for these patients.

Like CTL019, axicabtagene ciloleucel also targets the antigen CD19, a protein expressed on the cell surface of B-cell lymphomas and leukemias. The patient's T cells are engineered to express a chimeric antigen receptor (CAR) to target the antigen CD19.

In the drug development and approval process, axicabtagene ciloleucel has a similar profile to that of CTL019, in that the focus in on malignancies that have a B-cell origin, but the B cell ALL does not seem to be a part of its clinical development at this time.

Here is a run-down of diseases for which axicabtagene ciloleucel is being considered currently:

  • Axicabtagene ciloleucel has been granted Breakthrough Therapy Designation status for diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (TFL), and primary mediastinal B-cell lymphoma (PMBCL) by the U.S. FDA and Priority Medicines (PRIME) regulatory support for DLBCL in the EU.

The acceptance as a Breakthrough Therapy by the FDA is supported by data from the ZUMA-1 Phase 2 trial which met the primary endpoint of objective response rate (ORR) recorded after a single infusion of axicabtagene ciloleucel with 82 percent (p < 0.0001). At a median follow-up of 8.7 months, 44 percent of patients were having an ongoing response, which included 39 percent of patients in complete response (CR).

Common adverse events include depletion of the healthy cells that fight infection and help blood to clot. As with CTL019, one of the most common side effects is called cytokine release syndrome, which causes high fever and flulike symptoms that in some cases can be so dangerous that the patient ends up in intensive care. Encephalopathy can result in temporary confusion or potentially fatal brain swelling. There were three deaths throughout the course of the registrational trial not due to disease progression, of which two events, were deemed related to axicabtagene ciloleucel. Again, clinical development of these drugs is expected to proceed with caution.

GoCAR-T, Candidate for Solid Tumors by Bellicum Pharmaceuticals

Houston, Texas-based Bellicum Pharmaceuticals, Inc., has drug candidates that include BPX-601 (GoCAR-T candidate, for solid tumors, designed with the proprietary iMC activation switch to improve efficacy, phase I), and BPX-701 (high affinity TCR candidate, for solid tumors, designed with the CaspaCIDe safety switch, phase I).  

So, what does all that mean? Essentially, this group is working on refining the CAR T-cell technology so that it will afford the clinician more control over the T-cell response. GoCAR-T cells are designed to only be fully activated when exposed to both the cancer cells and an agent called rimiducid. So, ideally, the clinician would be able to control the degree of activation of the CAR-T cells by adjusting the schedule of rimiducid administration, but the cell killing would still occur in a tumor-dependent manner.

Other Candidates

Juno is a company that is now focusing on JCAR017, a CAR-T cell product that targets CD19. Juno is looking to get JCAR017 on the market as early as 2018 for NHL. The company is partnered with Celgene in these efforts.

ZIOPHARM Oncology has a CD19-specific product and is working on a CD33-specific CAR T-cell therapy for relapsed/refractory acute myeloid leukemia (AML). NantKwest is an immunotherapy company focused on using natural killer (NK) cells to treat cancer, infectious diseases and inflammatory diseases.

The company's NK cell-based platform has been designed to induce cell death against cancer or infected cells by three different modes of action—direct killing using activated NK cells (aNK); antibody-mediated killing using haNKs; and targeted activated killing using taNKs.

A Word From Verywell

Some of the early results from CAR-T cell therapy have been very exciting, offering new therapies to groups of patients that never had such options before. There have also been failures, however, and quite a bit of troubleshooting to make these therapies as effective as possible with the least amount of toxicity.

As researchers learn more about the immune response that is harnessed in these therapies, and the impact on the targeted malignancies, a clearer picture of the risks and benefits should emerge.

Sources:

Wang M, Yin B, Wang HY, Wang R-F. Current advances in T-cell-based cancer immunotherapy. Immunotherapy. 2014;6(12):1265-1278. 

Bhoj VG, Arhontoulis D, Wertheim G, et al. Persistence of long-lived plasma cells and humoral immunity in individuals responding to CD19-directed CAR T-cell therapy. Blood. 2016;128(3):360-370.

Kite receives U.S. Food and Drug Administration Priority Review for Axicabtagene Ciloleucel. http://ir.kitepharma.com/releasedetail.cfm?releaseid=1028075 Accessed July 2017.

Morris EC, Stauss HJ. Optimizing T-cell receptor gene therapy for hematologic malignancies. Blood. 2016;127(26):3305-3311.

Park JH, Geyer MB, Brentjens RJ. CD19-targeted CAR T-cell therapeutics for hematologic malignancies: interpreting clinical outcomes to date. Blood. 2016;127(26):3312-3320. 

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