Immunotherapy Car-T Cells

Immunotherapy CAR T stands for Chimeric Antigen Receptor T-cell therapy, which is a form of immunotherapy.

With CAR T therapy, your immune system’s T cells are modified to recognize and destroy cancer cells.

CAR T therapy is an option if your primary and secondary treatments failed to eliminate your cancer, or if your cancer has returned after these treatments.

Before receiving CAR T therapy, you will undergo low-dose chemotherapy in order to prepare for treatment. CAR T may also be an option for patients not eligible to receive a stem cell transplant.

The Concept of a “Living Drug”
How does it Work?

CAR T cells are the equivalent of “giving patients a “living drug” As its name implies, the backbone of CAR T-cell therapy is T cells, which are often called the workhorses of the immune system because of their critical role in orchestrating the immune response and killing cells infected by pathogens.

The therapy requires drawing blood from patients and separating out the T cells. Next, using a disarmed virus, the T cells are genetically engineered to produce receptors on their surface called chimeric antigen receptors, or CARs.

These receptors are synthetic molecules, they don’t exist naturally. These special receptors allow the T cells to recognize and attach to a specific protein, or antigen, on tumor cells. The CAR T cell therapies furthest along in development target an antigen found on B cells called CD19.

Once the collected T cells have been engineered to express the antigen-specific CAR, they are “expanded” in the laboratory into the hundreds of millions.

The final step is the infusion of the CAR T cells into the patient (which is preceded by a “lymphodepleting” chemotherapy regimen.

If all goes as planned, the engineered cells further multiply in the patient’s body and, with guidance from their engineered receptor, recognize and kill cancer cells that harbor the antigen on their surfaces.

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Considerations for Patient Selection

CAR T cell therapy is a novel treatment approach, it is generally an autologous cell therapy that may have different patient selection considerations than autologous stem cell transplant (ASCT); some examples include prior lines of therapy, upper age limit, severity of comorbidities, and chemoresistance status.

Patient selection may be based on adequate organ function and physiological reserve. A patient’s ability to tolerate fever and other potentially severe symptoms, such as cytokine release syndrome (CRS) and neurologic toxicity (NT) associated with CAR T cell therapy, should be determined.

Cash based procedure and ability to travel to an authorized treatment center, as well as having an adequate patient support network are key considerations.

CAR T Cell Therapy is an involved process, making it necessary for patients to have competent and committed caregiver support.

Patients will be required to remain within close proximity to the center throughout the process and for a period of time after receiving CAR T cell therapy to monitor for adverse reactions.

6 Steps Process involved in CART-T Cell Therapy

Step 1

The T cells will be removed through a blood draw

The patient’s blood is drawn, and blood cells are organized into groups.

This process is called apheresis, or leukapheresis. T

he patient’s T cells are removed, while the other blood cells are then returned to the body.

Apheresis usually takes 2-3 hours.

Step 2

The collected T cells are sent to a manufacturing site

At the manufacturing site, receptors (or hooks) are added to the T cells, programming them to create the patient’s particular CAR T cell therapy.

This can take from 10 days to several weeks to complete.

Step 3

Patients will prepare for CAR T cell therapy

About 1 week before CAR T cell therapy, patients will receive low doses of chemotherapy to help prepare their body for their new CAR T cells.

The purpose of this chemotherapy is to make room for new, programmed T cells.

While the patient’s CAR T cells are being made at the manufacturing site, their doctor may also recommend other treatments.

Step 4

Returning the programmed T Cells / CAR-T Cell Therapy infusion

At the hospital or clinic, patients will receive their own CAR T cells by infusion.

The infusion process usually takes about 1 hour, but some patients may need to remain in the hospital for a number of days after the infusion, to be monitored.

Step 5

Patients will be monitored for side effects

After the CAR T cell therapy infusion, patients will be monitored closely by their doctor for possible side effects.

There is a possibility that patients may experience severe side effects that require treatment, a longer hospital stay, or which may even cause death.

Time at the hospital will vary based on the patient’s risk of side effects.

Patients will go home as soon as their doctor feels it is safe. However, they may need to return to the hospital if side effects develop after returning home.

Step 6

Continued follow-up

To better understand the long-term results of CAR T cell therapy, doctors will follow a patient to measure whether the CAR T cell therapy is working and to watch for side effects.

The frequency of these follow-ups may vary and will be determined by the doctor.

Complete Understanding
CART-T Cells Therapy

Once an appropriate patient is identified for CAR-T Cell Therapy, the next step is to connect with an authorized treatment center to initiate the screening and enrollment process as appropriate.

An authorized treatment center may also offer assistance in determining patient eligibility, and providing counseling to the patient and caregiver.

An important part of getting patients a step closer to CAR-T cell therapy is to consider patient logistics.

Some patients may need to travel to a treatment center to receive CAR-T Cell Therapy.

Patients will be required to remain within close proximity to the center throughout the process and for a period of time after receiving CAR T cell therapy to monitor for adverse reactions. 

Apheresis

Creation of a CAR T cell therapy begins with collection of the patient’s blood and separation of the lymphocytes through apheresis (Leukapheresis).

Clinicians coordinate collection based on the patient’s treatment regimen to ensure the presence of sufficient numbers of T cells.The procedure is performed at the clinic or infusion center coordinated by the patient’s healthcare team.

Transport & Handling

Once collected, the lymphocytes are immediately packaged by the clinic and handed to the Laboratory or manufacturing facility.

T Cell Engineering

CAR T cell engineering involves a number of steps.

The apheresis product may be processed to remove any cells that inhibit T cell activation and expansion.

The CAR gene construct can then be incorporated into the T cells using one of several different methods.

Finally, the CAR T cells are expanded, or grown, outside the body, to an appropriate dose.

Conditioning Chemotherapy

The patient’s healthcare team administers conditioning chemotherapy to deplete lymphocytes before CAR T cell therapy, which may improve expansion and persistence.

CAR T Cell Infusion

The patient’s healthcare team administers the prepared CAR T cell therapy.

Administration directions vary depending on the CAR T cell therapy.

Monitoring & Follow-up

As part of a manufacturer’s certification of a CAR T cell treatment center, clinics may be required to implement a program to train healthcare staff who prescribe, dispense, or administer CAR T cell therapy about how to monitor, manage, and educate patients on adverse events.

Serious toxicities are known to occur with CAR T cell therapies. These toxicities may require immediate medical attention and may sometimes result in death. They occur in the first few days to weeks after CAR T cell treatment.

Two of the most serious adverse events are Cytokine-release syndrome (CRS) and Neurological toxicity (NT):

  • CRS symptoms can be progressive, must include fever at the onset and may include hypertension, capillary leak (hypoxia), and end organ dysfunction.
  • NT symptoms or signs can be progressive and may include aphasia, altered level of consciousness, impairment of cognitive skills, motor weakness, seizures, and cerebral edema.

Other adverse events include:

  • Serious Infections
  • Prolonged Cytopenias
  • Hypogammaglobulinemia

 

These are not all of the side effects associated with CAR T cell therapies, and the side effects are different from product to product.

Further information on adverse event monitoring and management can be obtained from CAR T cell therapy manufacturers or study investigators.

CAR-T cell therapy is a remarkably promising treatment for cancer patients. This emerging treatment represents one of the biggest breakthroughs since the introduction of chemotherapy.

We are Engineering Patient´s
Immune Cells to treat their Cancers

For years, the foundations of cancer treatment were surgery, chemotherapy, and radiation therapy.

Over the last two decades, targeted therapies like imatinib (Gleevec®)  and trastuzumab (Herceptin®) —drugs that target cancer cells by homing in on specific molecular changes seen primarily in those cells—have also cemented themselves as standard treatments for many cancers.

But over the past several years, immunotherapy—therapies that enlist and strengthen the power of a patient’s immune system to attack tumors—has emerged as what many in the cancer community now call the “fifth pillar” of cancer treatment.

The Latest Clinically-Developed
Cancer Therapy so far?

A rapidly emerging immunotherapy approach is called adoptive cell transfer (ACT): collecting and using patients’ own immune cells to treat their cancer. There are several types of ACT titled “ACT: TILs, TCRs, and CARs”), but, thus far, the one that has advanced the furthest in clinical development is called CAR T-cell therapy.

Until recently, the use of CAR T-cell therapy has been restricted to small clinical trials, largely in patients with advanced blood cancers. But these treatments have nevertheless captured the attention of researchers and the public alike because of the remarkable responses they have produced in some patients—both children and adults—for whom all other treatments had stopped working.

Second CAR T-Cell Therapy Approved for Lymphoma.

Tisagenlecleucel is a new option for some patients with common lymphoma.

In 2017, two CAR T-cell therapies were approved by the Food and Drug Administration (FDA), one for the treatment of children with acute lymphoblastic leukemia (ALL) and the other for adults with advanced lymphomas. Nevertheless, researchers caution that, in many respects, it’s still early days for CAR T cells and other forms of ACT, including questions about whether they will ever be effective against solid tumors like breast and colorectal cancer.

The different forms of ACT “are still being developed But after several decades of painstaking research, the field has reached a tipping point,  In just the last few years, progress with CAR T cells and other ACT approaches has greatly accelerated, with researchers developing a better understanding of how these therapies work in patients and translating that knowledge into improvements in how they are developed and tested.

Evolution of CART T Cell Therapies

Other refinements or reconfigurations of CAR T cells are being tested. One approach is the development of CAR T-cell therapies that use immune cells collected not from patients, but from healthy donors.

The idea is to create so-called off-the-shelf CAR T-cell therapies that are immediately available for use and don’t have to be manufactured for each patient.

The French company Cellectis, in fact, has launched a phase I trial of its off-the-shelf CD19-targeted CAR T-cell product in the United States for patients with advanced acute myeloid leukemia. 

The company’s product—which is made using a gene-editing technology known as TALEN—has already been tested in Europe, including in two infants with ALL (Acute lymphoblastic leukemia) who had exhausted all other treatment options. In both cases, the treatment was effective.

Other refinements or reconfigurations of CAR T cells are being tested. One approach is the development of CAR T-cell therapies that use immune cells collected not from patients, but from healthy donors. The idea is to create so-called off-the-shelf CAR T-cell therapies that are immediately available for use and don’t have to be manufactured for each patient.

The French company Cellectis, in fact, has launched a phase I trial of its off-the-shelf CD19-targeted CAR T-cell product in the United States for patients with advanced acute myeloid leukemia. The company’s product—which is made using a gene-editing technology known as TALEN—has already been tested in Europe, including in two infants with ALL (Acute lymphoblastic leukemia) who had exhausted all other treatment options. In both cases, the treatment was effective.

Numerous other approaches are under investigation. Researchers, for example, are using nanotechnology to create CAR T cells inside the body, developing CAR T cells with “off switches” as a means of preventing or limiting side effects like CRS, and using the gene-editing technology CRISPR/Cas9 to more precisely engineer the T cells.

But there is still more to do with existing CAR T-cell therapies.

We are particularly enthusiastic about the potential to use CAR T cells earlier in the treatment process for children with ALL (Acute lymphoblastic leukemia) , specifically those who are at high risk (based on specific clinical factors) of their disease returning after their initial chemotherapy, which typically is given for approximately 2 and a half years.In this scenario, if early indicators suggested that these high-risk patients weren’t having an optimal response to chemotherapy, it could be stopped and the patients could be treated with CAR T cells.

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