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.

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.

We help you Enhance your own body’s ability to fight, repair and restore through Advanced Regenerative Medicine therapies.

6 Steps Process involved in CAR T Cell Therapy
Complete Understanding CAR-T Cells Therapy
We are Engineering Patients’ Immune Cells to Treat Their Cancers
The Latest Clinically-Developed Cancer Therapy so far?
How are we producing the CAR T Cell?
Understanding & Managing Side Effects
Evolution of CAR T-Cell Therapies
6 Steps Process involved in CAR 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. The 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 CAR-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 Patients’ 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.

How are we producing the CAR T Cell?

A growing number of CAR T-cell therapies are being developed and tested in clinical studies.

Although there are important differences between these therapies, they all share similar components. The CAR on the cell’s surface is composed of fragments, or domains, of synthetic antibodies. The domains that are used can affect how well the receptor recognizes or binds to the antigen on the tumor cell.

The receptors rely on stimulation signals from inside the cell to do their job. So each CAR T cell has signaling and “co-stimulatory” domains inside the cell that signal the cell from the surface receptor. The different domains that are used can affect the cells’ overall function.

Over time, advances in Immunotherapy, specially the engineering of CAR T cells have improved the ability to produce more T cells before the infusion into the patient (expansion) and make them survive longer in the circulation (persistence).

Advances have also been made in how long it takes to produce a batch of CAR T cells. Although it initially took several weeks, many labs have now reduced the time to less than 7 days.

There is no shortage of promising data on CAR T cells used to treat adult patients with blood cancers. CD19-targeted CAR T cells have produced strong results not only in patients with ALL but also in patients with lymphomas. For example, in a small NCI-led trial of CAR T cells primarily in patients with advanced diffuse large B-cell lymphoma, more than half had complete responses to the treatment.

Understanding & Managing Side Effects

Like all cancer therapies, CAR T-cell therapy can cause several worrisome side effects. One of the most frequent is cytokine release syndrome (CRS).

As part of their immune-related duties, T cells release cytokines, chemical messengers that help to stimulate and direct the immune response. In the case of CRS, there is a rapid and massive release of cytokines into the bloodstream, which can lead to dangerously high fevers and precipitous drops in blood pressure.

Ironically, CRS is considered an “on-target” effect of CAR T-cell therapy—that is, its presence demonstrates that active T cells are at work in the body. Generally, patients with the most extensive disease prior to receiving CAR T cells are more likely to experience severe CRS.

In many patients, both children and adults, CRS can be managed with standard supportive therapies, including steroids. And as researchers we have gained more experience with CAR T-cell therapy, we’ve learned how to better manage the more serious cases of CRS.

Another potential side effect of CAR T-cell therapy—an off-target effect—is a mass die off of B cells, known as B-cell aplasia. CD19 is also expressed on normal B cells, which are responsible for producing antibodies that kill pathogens. These normal B cells are also often killed by the infused CAR T cells. To compensate, many patients must receive immunoglobulin therapy, which provides them with the necessary antibodies to fight off infections.

More recently, another serious and potentially fatal side effect—swelling in the brain, or cerebral edema—has been seen in some of the larger trials being conducted to support potential FDA approval of CAR T-cell therapies for patients with advanced leukemias. One company, in fact, decided to halt further development of their leading CAR T-cell therapy after several patients in clinical trials died as a result of treatment-induced cerebral edema.

However, the problem appears to be limited, with the leaders of other trials of CAR T-cell therapies reporting no instances of cerebral edema.Other so-called neurotoxicities—such as confusion or seizure-like activity—have been seen in most CAR T-cell therapy trials. But in nearly all patients the problem is short lived and reversible.

The side effects of CAR T cell therapy will vary from person to person and can be mild, moderate, severe, or may even cause death. Patients should always speak to their doctor about any side effects they may experience.

There are many side effects associated with CAR T cell therapy. Two of the serious side effects patients may need to be aware of include:

Cytokine Release Syndrome (CRS): CRS can happen in the first few days to a few weeks after a patient’s CAR T cells are put back in their body. Symptoms such as:

  • Fever (pyrexia)
  • Fatigue
  • Nausea
  • Chills
  • Low blood pressure (hypotension)
  • Rapid heartbeat (tachycardia)
  • Muscle/joint pain (myalgia/arthralgia)
  • Weakness (asthenia)
  • Low oxygen level (hypoxia)
  • Breathing difficulty (dyspnea)

Neurotoxicity: Neurotoxicity can happen in the first few days to weeks after a patient’s CAR T cells are put back in their body. Symptoms include:

  • Confusion
  • Difficulty or inability to speak
  • Loss of coordination
  • Difficulty walking
  • Shaking movement
  • Seizures
  • Difficulty staying awake
  • Headache

These are not all of the side effects associated with CAR T cell therapies, and the side effects are different from product to product. Patients should talk to their doctor to understand the side effects for specific CAR T cell therapies.

CAR T cell therapy side effects are treated by a doctor using medications and other supportive treatments in the hospital.

Deaths have been reported in clinical trials of CAR T cell therapies

Evolution of CAR 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.

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.

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.

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.

CONTACT US

Cellular Hope Institute – Datran Center 9100 S Dadeland Boulevard, Suite 1500. Miami Fl. 33156 United States

305 560 5337

info@cellularhopeinstitute.com

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